DEPARTMENT OF HEALTH AND HUMAN SERVICES CENTERS FOR DISEASE CONTROL AND PREVENTION Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009 Atlanta, Georgia Table of Contents Page Acronyms 5-6 Agenda 7-10 Wednesday, June 24 Welcome and Introductions 11-15 General Recommendations Introduction Combination Vaccinations Special Situations Vaccination Records 16-28 Rabies Vaccine Introduction Reduced Rabies Vaccine Schedule: Post-Exposure Prophylaxis 29-37 Poliovirus Vaccine Introduction Updated Recommendations for Routine Poliovirus Immunization Update: VFC Vote 37-43 Measles, Mumps, and Rubella Vaccine Introduction Proposed Changes to Current Evidence of Immunity Requirements for MMR Vaccination for Healthcare Personnel 43-53 Human Papillomavirus (HPV) Vaccines Introduction Bivalent HPV Vaccine Quadrivalent HPV Vaccine Cost-Effectiveness of Male Vaccination Overview of Cost-Effectiveness Models of Male Vaccination Issues and Potential Recommendation Options: Vaccination of Males 53-76 Meningococcal Vaccine Overview of Work Group Activities Update: New Meningococcal Conjugate Vaccine (MenACYW-CRM) Estimate of Effectiveness of Meningococcal Conjugate Vaccine (MCV4) Recommendations for MCV4 Vaccination for Persons at Prolonged Increased Risk for Meningococcal Disease Update: VFC Vote 76-95 Japanese Encephalitis (JE) Vaccine Introduction Revised JE Vaccine Recommendations 95-103 Hepatitis Vaccines Introduction Hepatitis B in Long-Term Care Residents and the Role of Vaccination 104-111 Yellow Fever (YF) Vaccine Introduction: Yellow Fever Vaccine Work Group Proposed Updates to the ACIP YF Vaccine Recommendations 111-116 Public Comment 116 Thursday, June 24 Unfinished Business 116-119 Agency Updates CDC / CCID / NCIRD Center for Medicare and Medicaid Services (CMS) Department of Defense (DoD) Department of Veteran’s Affairs (DVA) Food and Drug Administration (FDA) Heath Resources and Services Administration (HRSA) Indian Health Services (I HS) Immunization Safety Office (ISO) National Institutes for Health (NIH) National Vaccine Advisory Committee (NVAC) National Vaccine Program Office (NVPO) 119-123 Haemophilus Influenzae B (Hib) Vaccine Introduction: Overview of Session GSK Monovalent Hib Vaccine Hib Surveillance Vaccine Supply Hib Vaccine Implementation Plan 123-131 Vaccine Supply 132-136 Measles-Mumps-Rubella-Varicella (MMRV) Vaccine Safety Introduction Parental Perceptions of MMRV Vaccine Evaluation of MMRV and Febrile Seizures: VSD Expanded Chart Review Study Synthesis of Safety Evidence for MMRV Vaccine and Febrile Seizure risk Synthesis of Analytic Framework for MMRV Vaccine Policy Options; Options for Recommendations Update: VFC Resolution 137-165 Role of Pharmacists in Vaccine Administration 166-169 Influenza Session Introduction Session Overview 2008-09 Influenza Epidemiology: Seasonal and Novel Influenza A(H1N1) Influenza Antiviral Medications Novel Influenza A(H1N1) Vaccine Development and Progress Review of Existing Vaccine Prioritization Guidance 170-207 Public Comment 207-208 Friday, June 26 Novel Influenza A(H1N1) Virology and Immunology Vaccine Program Implementation Plans Review of Planned Vaccine Effectiveness Studies Review of Influenza Vaccine Safety Monitoring Plans Summary of Issues 208-232 Pneumococcal Vaccines Overview of Session Planning for Use of PPSV23 to Prevent Novel Influenza A(H1N1)-Associated Pneumococcal Disease Invasive Pneumococcal Disease Burden Caused by PCV13 Serotypes Options for PVC13 Catch-Up Immunization Strategies Update on Investigational 13-Valent Pneumococcal Vaccine (PCV13) Public Health and Economic Impact of PCV13 232-253 Public Comment 252 Certification 252 Participant Roster 253-260 Acronyms AAFP American Academy of Family Physicians AAP American Academy of Pediatrics ACIP Advisory Committee on Immunization Practices AGS American Geriatrics Society ATP According to Protocol BLA Biologics License Application BOI Burden of Illness CAIS Childhood / Adolescent Immunization Schedule CAIV-T Cold-Adapted Influenza Vaccine CCID Coordinating Center for Infectious Diseases CDC Centers for Disease Control and Prevention CID Committee on Infectious Diseases (CID) of the American Academy of Pediatrics (AAP) CIN Cervical Intraepithelial Neoplasia CMS Centers for Medicare and Medicaid Services DBD Division of Bacterial Diseases (of NCIRD) DHQP Division of Healthcare Quality Promotion DoD Department of Defense DSMBs Data Safety Monitoring Boards DSTDP Division of Sexually Transmitted Diseases Prevention [of NCHHSTP] DVA Department of Veterans Affairs DVBID Division of Vector-Borne Infectious Diseases DVD Division of Viral Diseases (of NCIRD) DVH Division of Viral Hepatitis (of NCIRD) DVRD Division of Viral and Rickettsial Diseases EIS Epidemic Intelligence Service EMR Electronic Medical Records FDA Food and Drug Administration GBS Guillain Barré Syndrome GID Global Immunization Division GMCs Geometric Mean Concentrations GMTs Geometric Mean Titers GSK GlaxoSmithKline HICPAC Healthcare Infection Control Practices Advisory Committee HepA Hepatitis A HepB Hepatitis B HHS Department of Health and Human Services Hib Haemophilus influenzae B HMO Health Maintenance Organization HPV Human Papillomavirus HRIG Human Rabies Immune Globulin HRSA Health Resources and Services Administration ID Influenza Division (of NCIRD) IDSA Infectious Disease Society of America IgG Immunoglobulin G IgM Immunoglobulin M IHS Indian Health Services ILI Influenza-Like Illness IND Investigational New Drug IOM Institute of Medicine ISD Immunization Services Division (of NCIRD) ISO Immunization Safety Office (of CDC/OD/Office of the Chief Science Officer) ITT Intent to Treat MCO Managed Care Organization MenACYW-CRM Meningococcal Conjugate Vaccine MCV4 Meningococcal Conjugate Vaccine MMRV Measles, Mumps, Rubella, Varicella MMWR Morbidity and Mortality Weekly Report mOPV1 Monovalent Polio Vaccine Type 1 NACCHO National Association of County and City Health Officials NACI Canadian National Advisory Committee on Immunizations NCHHSTP National Center for HIV, Hepatitis, STD, and TB Prevention (of CDC/CCID) NCHS National Center for Health Statistics NCIRD National Center for Immunization and Respiratory Diseases (of CDC/CCID) NCPDCID National Center for Preparedness, Detection, and Control of Infectious Diseases NCZVED National Center for Zoonotic, Vector-Borne, and Enteric Diseases (of CDC/CCID) NIH National Institutes of Health NIS National Immunization Survey NVAC National Vaccine Advisory Committee NVPO National Vaccine Program Office OCSO Office of the Chief Science Officer OD Office of the Director (of CDC) P&I Pneumonia and Influenza PCV Pneumococcal Conjugate Vaccine PEP Post-Exposure Prophylaxis PhRMA Pharmaceutical Research Manufacturers of America RCA Rapid Cycle Analysis SAGE Strategic Advisory Group of Experts sBLA Supplemental Biologics License Application SHEA Society for Healthcare Epidemiology of America SIVAC Supporting Immunization and Vaccine Advisory Committee SMEs Subject Matter Experts VAERS Vaccine Adverse Event Reporting System VFC Vaccines for Children VSD Vaccine Safety Datalink VZV Varicella-Zoster Virus WG Work Group WHO World Health Organization MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) Centers for Disease Control and Prevention 1600 Clifton Road, NE, Tom Harkin Global Communications Center (Building 19), Atlanta, Georgia June 24-26, 2009 AGENDA ITEM PURPOSE PRESIDER/PRESENTER(s) Wednesday, June 24, 2009 8:00 Welcome & Introductions * Opening remarks * Introductions and administrative announcements Dr. Thomas R. Frieden (Director, CDC and Administrator, ATSDR) Dr. Dale Morse (Chair, ACIP) Dr. Larry Pickering (Executive Secretary, ACIP; CDC) 8:30 General Recommendations * Introduction * Combination vaccines * Special situations information & discussion * Vaccination records Information Vote Vote Vote Dr. Ciro Sumaya (ACIP, WG Chair) Dr. Andrew Kroger (CDC/CCID/NCIRD/ISD) 9:40 Rabies Vaccine * Introduction * Reduced rabies vaccine schedule (post-exposure prophylaxis) Information Discussion Vote Dr. Paul Cieslak (ACIP, WG Chair) Dr. Charles Rupprecht (CDC/CCID/NCZVED/DVRD) 10:55 Break 11:25 Poliovirus Vaccine * Introduction * Updated recommendations for routine poliovirus immunization * Update VFC vote Information Discussion Vote VFC Vote Dr. Lance Chilton (ACIP, WG Chair) Dr. Gregory Wallace (CDC/CCID/NCIRD/DVD) Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD) 11:55 Measles, Mumps and Rubella Vaccine * Introduction * Proposed changes to current evidence of immunity requirements for MMR vaccination for healthcare personnel Information Discussion Vote Ms. Kris Ehresmann (ACIP, WG Chair) Dr. Kathleen Gallagher (CDC/CCID/NCIRD/DVD) 12:30 Lunch 1:30 Human Papillomavirus (HPV) Vaccines * Introduction * Bivalent HPV vaccine * Quadrivalent HPV vaccine * Cost-effectiveness of male vaccination * Overview of cost-effectiveness models of male vaccination * Issues and potential recommendation options: vaccination of males Information and Discussion Dr. Janet Englund (ACIP, WG Chair) Dr. Gary Dubin (GSK) Dr. Rick Haupt (Merck) Dr. Jane Kim (Harvard University) Dr. Harrell Chesson (CDC/CCID/NCHHSTP/DSTDP) Dr. Lauri Markowitz (CDC/CCID/NCHHSTP/DSTDP) 3:00 Meningococcal Conjugate Vaccine (MCV4) * Overview of Work Group activities * Update: new meningococcal conjugate vaccine (MenACYW-CRM) * Estimate of Effectiveness of Meningococcal Conjugate Vaccine (MCV4) * Recommendations for MCV4 revaccination for persons at prolonged increased risk for meningococcal Disease * Update: VFC vote Information Information Information Discussion Information Discussion Vote VFC Vote Dr. Carol Baker (ACIP, WG Chair) Dr. Peter Dull (Novartis Vaccines) Ms. Jessica MacNeil (CDC/CCID/NCIRD/DBD) Dr. Amanda Cohn (CDC/CCID/NCIRD/DBD) Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD) Wednesday June 24, 2009 – continued 4:00 break 4:15 Japanese Encephalitis (JE) Vaccine * Introduction * Revised JE vaccine recommendations Information Discussion Vote Dr. Paul Cieslak (ACIP, WG Chair) Dr. Marc Fischer (CDC/CCID/NCZVED/DVBID) 5:00 Hepatitis Vaccines * Introduction * Hepatitis B in long-term care residents and the role of vaccination Information Discussion Dr. Mark Sawyer (ACIP, WG Chair) Dr. Nicola Thompson (CDC/CCID/NCHHSTP/DVH) 5:30 Yellow Fever (YF) Vaccine * Introduction: Yellow Fever Vaccine Work Group * Proposed updates to the ACIP YF vaccine recommendations Information Discussion Dr. Carol Baker (ACIP, WG Chair) Dr. Erin Staples (CDC/CCID/NCZVED/DVBID) 5:45 Public Comment 6:00 Adjourn Thursday, June 25, 2009 8:00 Unfinished Business Dr. Dale Morse (Chair, ACIP) 8:30 Agency Updates (CDC, CMS, DOD, DVA, FDA, HRSA, IHS, NIH, NVAC, NVPO) Information ACIP Ex Officio Members 8:45 Haemophilus influenzae b (Hib) Vaccine * Introduction: overview of session * GSK monovalent Hib vaccine * Hib surveillance * Vaccine supply * Hib vaccine implementation plan Information Information Information Information Information Discussion Dr. Abigail Shefer (CDC/CCID/NCIRD/ISD) Dr. Remon Abu-Elazeed (GSK) Dr. Michael Jackson (CDC/CCID/NCIRD/DBD) Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD) Dr. Abigail Shefer (CDC/CCID/NCIRD/ISD) 9:45 Vaccine Supply Information Discussion Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD) 10:00 Break 10:30 Measles-Mumps-Rubella-Varicella Vaccine Safety * Introduction * Parental perceptions of MMRV vaccine * Evaluation of MMRV and Febrile seizures: VSD expanded chart review study * Synthesis of safety evidence for MMRV vaccine and febrile seizure risk * Synthesis of analytic framework for MMRV vaccine policy options; options for recommendations * Update VFC resolution Information Discussion Information Discussion Information Discussion Information Discussion Information Discussion Vote VFC Vote Dr. Jonathan Temte (ACIP, WG Chair) Mr. Alan Janssen (CDC/CCID/NCIRD/ISD) Dr. Nicola Klein, Northern California Kaiser Permanente Dr. Karen Broder (CDC/CCID/NCPDCID/DHQP/ISO) Dr. Mona Marin (CDC/CCID/NCIRD/DVD) Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD) 12:30 Lunch Thursday June 25, 2009 - continued 1:45 Role of Pharmacists in Vaccine Administration Information Discussion Dr. Stephan Foster (ACIP Liaison American Pharmacists Association) 2 :00 Influenza * Session introduction * Session overview * 2008-09 influenza epidemiology: seasonal and novel influenza A (H1N1) Information Information Information Discussion Dr. Kathy Neuzil (ACIP, WG Chair) Dr. Anthony Fiore (CDC/CCID/NCIRD/ID) Dr. Lyn Finelli (CDC/CCID/NCIRD/ID) 3:15 break 3:30 Influenza * Influenza antiviral medications * Novel influenza A (H1N1) vaccine development and progress * Review of existing vaccine prioritization guidance Information Discussion Vote Information Discussion Information Dr. Anthony Fiore (CDC/CCID/NCIRD/ID) Dr. Robin Robinson (BARDA) Dr. Norman Baylor (FDA) Dr. Linda Lambert (NIH) Dr. Bruce Gellin (NVPO) Dr. Tom Shimabukuro (CDC/CCID/NCIRD/ISD) 5:30 Public Comment 5:45 Adjourn Friday, June 26, 2009 8:00 Novel Influenza A (H1N1) * Virology and immunology * Vaccine program implementation plans * Review of planned vaccine effectiveness studies * Review of influenza vaccine safety monitoring plans * Summary of issues Information and Discussion Dr. Nancy Cox (CDC/CCID/NCIRD/ID) Dr. Pascale Wortley (CDC/CCID/NCIRD/ISD) Dr. David Shay (CDC/CCID/NCIRD/ID) Dr. Jose Sanchez (DOD) Dr. Cindy Weinbaum (CDC/CCID/ NCPDCID/DHQP/ISO) Dr. Anthony Fiore (CDC/CCID/NCIRD/ID) Dr. Kathy Neuzil (ACIP, WG Chair) 10:00 Break 10:30 Pneumococcal Vaccines * Overview of session * Planning for use of PPSV23  to prevent novel   influenza  A (H1N1) - associated pneumococcal disease * Invasive pneumococcal disease burden caused by PCV13 serotypes * Options for PCV13 catch-up immunization strategies * Update on investigational 13- valent pneumococcal vaccine (PCV13) * Public health and economic  impact of  PCV13 Information Discussion Information and Discussion Information Information Dr. Michael Marcy (ACIP, WG Chair) Dr. Matthew Moore (CDC/CCID/NCIRD/DBD) Dr. Pekka Nuorti (CDC/CCID/NCIRD/DBD) “ Dr. Peter Paradiso (Wyeth) Dr.  David Strutton (Wyeth) 12:30 Public Comment 12:45 Adjourn June 24, 2009 Dr. Tom Frieden Director, Centers for Disease Control and Prevention Administrator, Agency for Toxic Substances and Disease Registry Dr. Larry Pickering Executive Secretary, ACIP / CDC Dr. Dale Morse Chair, ACIP Dr. Pickering called the meeting to order, introducing with great pleasure Dr. Tom Frieden, the newly appointed Director of the United States (US) Centers for Disease Control and Prevention (CDC) and Administrator of the Agency for Toxic Substances and Disease Registry (ATSDR). Prior to having assumed his post at CDC just 16 days before this meeting, Dr. Frieden served as Commissioner of the New York City Department of Health and Mental Hygiene, a position he held for 8 ½ years. During his tenure, important advances in New York City were made in reduction in cigarette smoking; chronic disease control, including diabetes mellitus and obesity; and enhancement of the largest community health records project in the country. Dr. Frieden is a physician with training in internal medicine, infectious diseases, public health, and epidemiology, and is specifically known for his expertise in tuberculosis control. Dr. Frieden began his career at CDC as an Epidemic Intelligence Service (EIS) Officer stationed at the New York City Health Department. Dr. Frieden went on to serve as director of the Bureau of Tuberculosis Control and Assistant Commissioner for the New York City Health Department. In that role, he led a program that rapidly reduced tuberculosis, including a reduction in cases of multi-drug resistant tuberculosis by about 80%. Dr. Frieden then worked for 5 years on assignment to the World Health Organization (WHO) in India where he assisted with national tuberculosis control efforts. The program in India has now treated more than 10 million patients and saved more than 1 million lives. Dr. Pickering stressed that the ACIP members, the 26 liaison organizations, the 8 ex officio members, and members of the audience (including international delegates from Japan and the Agency of Preventive Medicine in Paris, France) were thrilled to welcome Dr. Frieden to the June 2009 meeting of the ACIP. Dr. Frieden expressed his gratitude, pointing out that it had thus far been a great 2 ½ weeks and that he wished he could stay for the ACIP meeting all day. The first thing he learned about being the CDC Director was that it would have been very helpful if he could have cloned himself first, because he was supposed to be in three places at once most of the time. He said he was delighted to join the meeting for at least a short time to recognize the terrific and incredibly important work that ACIP does. Sometimes, when close to a process, it is possible to lose sight of the big picture in terms of the importance of ACIP’s work, particularly as the country moves forward with health reform under the current administration. The evidence base and effectiveness of vaccination is prominent in the understanding and rigor of groups such as ACIP. In fact, ACIP is a model for evidence-based decision making—a model that is well worth understanding and emulating elsewhere in the health system. In addition, Dr. Frieden recognized ACIP for 45 years of outstanding leadership in immunization policy. In many ways, vaccines are not only one of the great success stories of public health, but also hold the potential to have the ultimate in sustainability, which is what eradication represents (e.g., smallpox, and hopefully soon polio). ACIP is the prototype for immunization committees in other countries, and it is hoped that evidence-based vaccine immunization policy will become the norm in the US and globally. There is much in the news in terms of vaccination and influenza. Novel H1N1 presents major challenges in spite of enormous thinking and preparation for pandemic influenza. During this meeting, ACIP was to hear information presented on H1N1, and very important immunization decisions would need to be made in near real-time over the coming days, weeks, and months as they began to learn more about the pattern of infection, disease, and severity of illness; transmission / rapidity of transmission; and availability of vaccines. In addition, it would be essential to continue with the shared responsibility and understanding that the government, health providers, individual patients, and others play key roles in the H1N1 effort. Not only do vaccines effectively prevent disease and save money, but also they are very effective at reducing racial and ethnic disparities. Vaccines are available to all, they prevent illness in all, and they have a great ability to make a considerable difference in health status. At the same time, a number of issues remain to be understood and studied Also known is that the Vaccines for Children Program (VFC) relies heavily upon ACIP, is part of the ACIP meetings, is a critically important component of the US healthcare landscape, and offers important lessons learned as efforts are made to improve vaccinations for children, adolescents, and adults. Dr. Frieden concluded that he primarily wished to thank ACIP for what they do; the attention they give to challenging issues, many of which involve complex reviews of data; their valuable questions and input, and their suggestions / recommendations. It is imperative to focus on two issues: 1) building the data: rigorously assessing what the data show and where that leads them in terms of recommendations, taking into consideration the costs and benefits; and 2) transparency: all deliberations and other information about vaccine policy must be completely open and completely transparent. CDC and ACIP have a bond of trust with the American public, and it is their shared responsibility to respect the intelligence, integrity, and caring of parents, healthcare workers, and others to develop health-based recommendations. People must clearly understand how decisions are reached. That is the most prudent way to make the best possible decisions. In closing, Dr. Frieden thanked the ACIP membership and saluted them for their excellent work in achieving evidence-based public health policy. Dr. Morse thanked Dr. Frieden for addressing ACIP, stressing that it meant a great deal to have the support of the CDC Director and for him to take time to deliver the keynote address. As a fellow New Yorker who was glad to see Dr. Frieden in attendance, Dr. Morse said it was New York’s loss and CDC’s and the nation’s gain. Dr. Pickering recognized several people throughout the room who were to be in attendance throughout the duration of the ACIP meeting to assist with various meeting functions: Antonette Hill, Committee Management Specialist for ACIP, Natalie Greene, Tamara Miller, Tanya Lennon, Suzette Law, and Cindy Fowler. He also indicated that boxed lunches were to be provided for each of the three days of the meeting in the hallway outside of the auditorium for a cost of $10. Coffee and tea were also to be available for the duration of the meeting. Handouts of all presentations were distributed to the ACIP members and were made available for members of the public each day on the tables outside of the auditorium. Slides presented for this meeting will be posted on the ACIP website, generally within a week of the end of the meeting, while the minutes of the meeting will be posted within 90 days of the termination of the meeting. Members of the press interested in conducting interviews with ACIP members were instructed to contact Tom Skinner for his assistance in arranging interviews, and the press table located in the auditorium was pointed. Recognizing the extent of the interest in this particular meeting, two additional rooms were reserved (247 / 248) as overflow space for additional seating. These rooms are located across the hall from the auditorium where the meeting could be viewed in real-time via audio visual all three days. Dr. Pickering recognized and welcomed the following international visitors: Dr. Kamel Senouci, Director of the Supporting Immunization and Vaccine Advisory Committee (SIVAC) Initiative of the Agence de Médicine Préventive, Institut Pasteur, Paris France. This program aims at contributing to the development of national immunization technical advisory groups in six resource-poor countries in Africa and six in Asia. These committees will help national health authorities to establish vaccination advisory groups adapted to their needs and to introduce new vaccines in these areas. This project was funded by a $10 million grant from the Bill & Melinda Gates Foundation, and will be conducted in partnership with the International Vaccine Institute in Seoul, Korea and in cooperation with the World Health Organization (WHO) and its regional and national offices. Dr. Pickering also extended gratitude to three visitors from Japan led by Dr. Nobuhiko Okabe, the Director of the Infectious Disease Surveillance Center at the National Institute of Infectious Diseases in Tokyo, Japan. They came to participate in the meeting of ACIP to observe the US process of immunization policy development, which reflects international reach. Also in attendance was new liaison representative Dr. Alexis Elward from Washington University School of Medicine in St. Louis, who was selected to represent the Healthcare Infection Control Practices Advisory Committee (HICPAC) as its liaison representative to ACIP. All ACIP members were present with the exception of Dr. Susan Lett who had a previous commitment on Wednesday and Thursday, but attended Friday and was connected by telephone for certain sessions. Ms. Amy Groom attended on behalf of Dr. James Cheek from the Indian Health Services (IHS) who was unable to attend. Dr. Sandy Fryhofer attended on behalf of Dr. Greg Poland from the American College of Physicians (ACP) who was unable to attend. Dr. Mark Notalski attended on behalf of Dr. Tamara Lewis from American’s Health Insurance Plan (AHIP) who was unable to attend. Dr. David Salisbury from the Department of Health United Kingdom was unable to attend. To avoid interruptions during the meeting, those present were instructed to conduct all business not directly related to discussions of ACIP in the hallways to avoid disruptions to people in the audience. Attendees were also instructed to turn off all cell phones or place them in the vibrate mode to avoid disruption. The ACIP home page was shown on the screen. The url is: www.cdc.gov/vaccines/recs/acip/ This website is updated at frequent intervals with current versions of the meeting agenda, minutes, presentations, and other information. Other useful and interesting and useful were also shown, which included the following: Vaccine Safety: www.cdc.gov/vaccinesafety/ Vaccine Abbreviations: http://www.cdc.gov/vaccines/recs/acip/vac-abbrev.htm Vaccine Scheduler: http://www.cdc.gov/vaccines/recs/scheduler/catchup.htm Given that the meeting could not begin unless a quorum of members was present, all appointed members were asked to return from breaks and lunch in a timely manner to participate in the meeting. Dr. Pickering stressed the importance of this due to the record number of votes scheduled during this meeting (n=8). The ACIP charter gives the Executive Secretary, or his or her designee, the authority to temporarily designate ex-officio members as voting members. This occurs only when there are fewer than 8 appointed members available or qualified to vote due to potential conflicts of interest (COIs). Ex-officio members are requested formally to vote when necessary and to disclose any potential conflicts of interest if, indeed, they were going to vote. Topics presented at the ACIP meeting include open discussion with time reserved for public comment. In certain circumstances, a formal comment period may be scheduled during the deliberations of a specific agenda item rather than at the end of the day. Comments from the public may be received during open discussions depending upon time constraints. Those who planned to make public comments were instructed to visit the registration table at the rear of the auditorium to have Antonette Hill record their name and provide information on the process. Those who registered to make public comments prior to the meeting were instructed to with Ms. Hill to verify that their names were listed and to receive any additional information. Microphones were placed at each end of the committee tables for the members of the audience to use when they addressed the committee. Those planning to make comments were instructed to identify themselves and their organization before making their comments. As had occurred in previous ACIP meetings, the committee discussed topics related to vaccine safety and engaged in a discussion about of the supply and availability of recently licensed and approved vaccines. With regard to disclosure, the goal in appointing members to the ACIP is to achieve the greatest level of expertise while minimizing the potential for actual or perceived conflicts of interest. To summarize conflict of interest provisions applicable to the ACIP, as noted in the ACIP policies and procedures manual, members of the ACIP agree to forego participation in certain activities related to vaccines during their tenure on the committee. For certain other interests that potentially enhance the members’ expertise while serving on the committee, CDC has issued limited conflict of interest waivers. Members who conduct vaccine clinical trials or who serve on data safety monitoring boards may serve as consultants to present to the committee on matters related to those specific vaccines; however, they are prohibited from participating in deliberations or committee votes on issues related to those specific vaccines. Regarding other vaccines of the affected company, a member may participate in a discussion with a proviso that he or she abstains on all votes related to that vaccine company. The ACIP Secretariat solicits applications throughout the year for candidates to serve on ACIP. Detailed instructions for submissions of name of potential candidates may be found on the ACIP website. Applications may be submitted at any time of the year. Materials in support of the next cycle of applications for ACIP membership (beginning July 2010) are due no later than November 15, 2009. ACIP meeting registration dates are established for security reasons. The CDC complex is a secured environment and pre-registration for meetings is posted on the ACIP website. This pre-registration is time-sensitive for international visitors since the Office of Security and Emergency Preparedness is required to pre-approve access for all non-US citizens visiting CDC facilities. The next ACIP meeting is October 21-22, 2009. Dr. Morse expressed CDC and ACIP’s appreciation to Dr. Robert Beck who was cycling off the ACIP committee following four years of dedicated service as a consumer representative. Mr. Beck’s previous top leadership positions with autism groups, and in the creation of a new national early childhood development screening intervention program that was adopted by the CDC and the Department of Education has proven to be of tremendous benefit to ACIP for four years. While serving on the ACIP panel, Mr. Beck chaired the Evidence-Based Recommendation Work Group and participated in the Anthrax, HPV, Japanese Encephalitis (JE) and other vaccine work groups. More important have been his major contributions to ACIP’s deliberations where he has provided a unique perspective, asked probing questions, provided keen insights, and kept everyone well-rooted in the real world. With gratitude from CDC and ACIP, Mr. Beck was presented with a certificate and an award made of glass to represent what he had added to the transparency and clarity of ACIP’s work. Mr. Beck said he was absolutely overwhelmed by the ACIP experience over the past four years, and by having the opportunity and privilege to work with some of the most wonderful people he had ever met. He stressed how talented each member of the committee is, and acknowledged the incredible amount of time and effort each of them contributes. Even after 20 plus years of being in and out of government, until joining ACIP, he had no idea how much work they do and how important the individuals are who make up the committee. Their work benefits the public health of the entire nation. He concluded that it had truly been his privilege to be a member, and that he had been deeply touched by each member in the nicest way. He wished them all the very best of continued success. The following conflicts of interest were declared: Dr. Janet Englund: sanofi pasteur; MedImmune; Novartis Pharmaceuticals, ADMA Biologics, Inc. Dr. Cody Meissner: Payments are made to Tufts Medical Center from Wyeth and MedImmune The remainder of the members declared no conflicts. Overview Ciro Sumaya, MD, MPH ACIP Chair Dr. Sumaya pointed out that the general recommendations are published in the Morbidity and Mortality Weekly Report (MMWR) at approximately three- to five-year intervals. General recommendations addresses immunization issues relevant to all vaccines, and topics ad hoc that cannot be attributed to a single vaccine. General recommendations are directed to providers who are administering many different vaccines every day, and who come from variable backgrounds (e.g., physicians, nurse-practitioners, nurses, pharmacists, medical assistants). Thus, the recommendations are made as user-friendly as possible. During this session, information was presented on combination vaccines, special situations, and vaccination records. There are complex issues that must be addressed with respect to combination vaccinations. Working from the last iteration of the general recommendations, the General Recommendations Work Group refined, reviewed, and made some changes. Special situations were reviewed from an updating / editing standpoint, with few changes. The vaccine records section, a very important and fast moving field, was edited and updated. For the next session of ACIP in October 2009, the final recommendations on altered immune-competence will be reviewed. There remain some outstanding issues in this area, particularly with respect to transplant patients. In addition, the vaccination programs will be reviewed for infants and children, adolescents, and adults. A final vote on the entire document is anticipated during the October 2009 meeting. The document will then proceed to the CDC clearance, with an expected publication date of April 2010. Andrew Kroger, MD, MPH CDC / NCIRD / ISD / EIPB Turning first to combination vaccines, Dr. Kroger indicated that the general recommendations language is derived from a 1999 specific Morbidity and Mortality Weekly Report (MMWR) on combination vaccines for childhood immunization that describes what combination vaccines are, states a preference for the use of combination vaccines, and offers supplementary guidance on issues like the interchangeability of products and extra vaccination doses. It has been 10 years since that specific statement was published, since which the environment has changed. There are many new vaccines, and many new combination vaccines. It will be important to define what a combination vaccine is definitively. New reactogenicity data with one combination vaccine (e.g., MMRV) suggest a higher risk of febrile seizures with the combination product compared to single component administration. Originally a work group dedicated solely to combination vaccines was constituted to address the fact that the 10-year old recommendations must be updated. This workgroup initially focused on specific products such as Pentacel® and KINRIX™. It was clear from the outset that a more general perspective was necessary, not only because of the issues with the MMRV vaccine specifically, but also because any discussion of combination vaccines brings in general immunization topics like simultaneous vaccination, vaccine administration, and other types of programmatic issues. It was deemed necessary to deal with these issues, which is when the task fell to the General Recommendations Work Group. A manuscript was drafted and reviewed by four members of the original Combination Vaccines Work Group prior to being discussed by the General Recommendations Work Group, a draft of which was provided to the ACIP members in their briefing documents. On page 2, line 6, a combination vaccination is defined as “a product whose components can be equally divided into independently available routine vaccines.” The draft also contains Table 5 which is located at the end of the Combination Vaccine section. This table lists the combination vaccines, which include: COMVAX™, TriHIBit ®, Twinrix®, PEDIARIX™, ProQuad ®, KINRIX™ and Pentacel®. The definition would exclude a laundry list of other vaccines (e.g., HepB, RV, TT, DT, DTaP, Hib, IPV, PCV7, MMR, Var, HepA, TIV, LAIV, MCV4, Tdap, Td, HPV, PSV4, PPSV23, ZOS, Ty21A, YF, JE, Typhim VI, Rabies, BCG, Anthrax, and Smallpox. Vaccines such as inactivated polio virus vaccine, IPV, pneumococcal conjugate vaccine, PCV7, MMR, Td, and TDaP are excluded from the definition even though they do consist of multiple antigens for different strains of the various microbes or the antigens. For these, separate components are not routinely available. The Tdap vaccine is not considered to be a combination vaccine by the strict definition because it really cannot be equally divided into separate vaccines; that is, Td is an available vaccine, but a single antigen acellular pertussis component does not exist. In addition, Dr. Kroger pointed out that the general preference statement needed to be revisited. As listed in the 2006 general recommendations, the current stated preference for combination vaccines is, “Use of licensed combination vaccines is preferred to separate injection of their equivalent component vaccines to reduce the number of injections and missed opportunities to protect through vaccination.” Based on the history, the work group met by teleconference to discuss the advantages and disadvantages of combination vaccines. Before offering options for revisions to this statement, Dr. Kroger reviewed these advantages and disadvantages with the larger membership. Vaccines have site-specific requirements. As many as nine vaccines could be recommended at a single visit. If the wrong site is used, vaccine could be less effective (HepB, Rabies) or more reactogenic (most adjuvant-containing vaccines injected subcutaneously). A challenge of vaccine administration and particular guidance needed for specific vaccines include: the need to re-administer vaccine doses if the wrong site is used for Hepatitis B or Rabies vaccine; and issues of reactogenicity when vaccines that contain aluminum adjuvants are injected subcutaneously. Another topic that has been discussed is the issue of patient preference for a reduced number of injections. The existing literature on this topic does not narrowly address a combination vaccine. A paper published in 2001 by Maureen Kolasa [Kolasa MS, et. Al. Impact of Multiple Injections on Immunization Rates Among Vulnerable Children. Am J Prev Med. 2001; 21(4), p. 261-266] suggests that providers and patients seemed comfortable with increasing the number of injections per visit from 3 to 4, but this was in a historical context of the switch from the oral polio vaccine to the inactivated polio vaccine. There have been other discussions and focus groups about this topic, but there is limited published literature. There is evidence in the literature that combination vaccines improve vaccination coverage. In a retrospective analysis of over 18,000 Georgia infants, Marshall and colleagues demonstrated that the use of COMVAX™ and PEDIARIX™ improved the coverage of the DTaP, IPV, 4:3:1, 4:3:1:3, and 3:3:3 (by 3 to 6 percentage points) [Marshall GS, Happe LE, Lunacsek OE et. Al. Pediatr Infect Dis J 2007. 26:496-500, 2007]. These are good data and this is an important question. More data are need with respect to exactly why the coverage has improved in terms of whether it is due to reduced injections, reduced requirements for visits, or both. While this is really unknown, it is probably a combination of both. There is also improvement of vaccination timeliness. There are several studies on this. In 2700 children in Germany, it was documented that vaccine doses were given earlier if combination products were used. The difference was not huge (less than a month) [Kalies H, Grote V, Verstraeten T, et al. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J. 2006;25:507–512]. A study of 5,000 children in Georgia documented a timeliness rate of 66% versus 61% for the DTaP, IPV, Hib, and HepB components if the DTaP-HepB-IPV vaccine was used [Happe LE, Lunacsek OE, Kruzikas DT, et al. Impact of a pentavalent combination vaccine on immunization timeliness in a state Medicaid population. Pediatr Infect Dis J. 2009; 28:98-101]. Reduced shipping and storage costs are also advantageous. With regard to the outright cost of vaccines, the cost of shipping can be presumed to be less if shipping fewer products. Older combination vaccines are, on average, cheaper than the sum of the components. However, for newer vaccines, the combinations are more expensive. The issue of storage is complicated and relates to how providers respond to any type of preference recommendation in the first place. If preference is given, they may purchase both combination and single component vaccines. It is likely that they will not purchase as much of the single component product, which probably would have an effect of reducing the amount of storage space required. Vaccines are stored in refrigerator and freezers. If more storage space is required, there will be a cost for an additional unit. Providers who purchase single components MMR and Var vaccines, and combination MMRV vaccine, store them all in the freezer, although MMR does not need to be stored there. There were discussions in the work group pertaining to how complicated it is for providers to use a single component MMR vaccine with the single component varicella vaccine, given that one must be frozen and one can either be frozen or refrigerated. Providers probably preferentially place the MMR in the freezer, which may have a storage effect due to the need for freezer space in the first place or the lack of enough freezer space. With MMRV vaccine alone, one could argue that a simple freezer message could be endorsed. Another advantage is the reduced cost of extra health care visits. It is not crystal clear why combination vaccines improve rates, but perhaps it is related to reduced healthcare visits. Data from the 1999 National Immunization Survey indicate that 71% of children receive no more than four immunizations per visit. What is not definitive in that data is whether more than four doses were acceptable and if not, how that would affect extra vaccination coverage. Data on missed opportunities to vaccinate discuss the fact that not all of the doses may have been given at a visit that were recommended for that visit, but it is not entirely clear how the combination versus single component factors into this or how much weight can be given to this difference. CDC recommends vaccination not only at well visits, but also at any kind of visit as long as the child is not ill. Thus, there are many reasons for missed opportunities that are beyond the scope of combination vaccines. Combination vaccines also facilitate the addition of new vaccines into immunization programs, and present opportunities to educate and re-educate providers about the diseases prevented by various components. This is another opportunity to bring training messages forward. There are disadvantages of combination vaccine as well. The first regards increased risk of adverse reactions. There is known to be approximately a two-fold higher risk of febrile seizures in children 12 to 23 months old vaccinated with MMRV instead of MMR + V. Additionally, an observational study of 3938 6- to 10-week old infants showed an infant receiving Pediarix® to be 6.8 times more likely to receive a fever work-up than infants who received the single component vaccines [MMWR March 14,2008 57; Thompson LA, Irigoyen M Matiz LA, et al. The impact of DTaP-IPV-HB vaccine on use of health services for young infants. Pediatr Infect Dis J. 2006;25:826-831]. This was already expected from the pre-licensure trials and this particular issue is currently undergoing follow-up studies to clarify exactly what this increased risk is about. Confusion and uncertainty also represent a disadvantage. CDC recommendations are very complicated, so confusion and uncertainty make constant education necessary. In the case of a combination vaccine preference, we have witnessed extra doses of an antigen being administered. Patients are seen by different providers, they have different contracts for different types of vaccines, and data from the National Center for Health Statistics (NCHS) suggests that 95% of children do have a usual place of health-care. Thus, 5.5% of children see more than one provider. With the complexity of health care delivery as it is, multiple venues for vaccine administration are expected. A single provider may be limited with a particular choice of a formulation for a set of antigens. He/she may only provide one particular combination product and since every single possible combination is not available for every provider, a patient who sees multiple providers may be in the environment where they have to be administered an extra antigen or perhaps even skip an essential antigen if a provider decides not to administer the combination product. There is evidence that vaccine components are not as effective when given in combination (e.g., reduced immunogenicity). This reduced immunogenicity typically occurs when a particular combination vaccine is given off-label or against ACIP recommendations. An example is TriHIBit ® which is licensed for the fourth or last dose of the Hib series. If it is given as one of the first 3 doses, pre-licensure trials suggest reduced immunogenicity of the Hib components in this instance. ACIP recommends repeating the Hib component. This would not be a problem if vaccines were administered correctly all of the time; however, this does not happen and mistakes do occur. Extra doses of antigen in the fixed product represent another disadvantage. This can be an issue even when a patient stays with the same provider. Sometimes an extra dose of antigen is necessary when using combination vaccines. Because CDC universally recommends a birth dose of Hepatitis B vaccine, if the provider chooses to use 3 doses of PEDIARIX™ as per the product insert recommendations, they will administer 4 doses of the Hepatitis B component overall because PEDIARIX™ cannot be used for the birth dose of Hepatitis B vaccine. Similarly, if Pentacel® is administered per product insert, 5 doses of IPV total would be administered in 41% of states per an informal survey of state health departments in 2008. Another disadvantage pertains to differences in shelf life. Combination products can have a shorter shelf life. PEDIARIX™ is an example of this. The shelf life of PEDIARIX™ is 24 months and the shelf life of the single component INFANRIX ® is 36 months. The actual number may vary from what is listed in the product insert because obviously things can change depending upon supply issues. However, many providers are going to use the information that is presented to them in the product insert. Based on the aforementioned advantages and disadvantages, the work group crafted three potential options for revision to the general preference statement for combination vaccines and discussed the pros and cons of each. Option 1 is to make no changes to the 2006 statement, leaving it as, “the use of licensed combination vaccines is preferred over separate injections of their equivalent component vaccines if licensed and indicated for the patient’s age.” This option was not favored by any members of the work group. The pros are that this option requires no revised communications messages, it is the status quo, and it is simple to implement. The cons are that providers are currently faced with a lack of flexibility regarding choice of antigens due to restrictions that may exist for their formularies, increased costs of vaccinations, increased activities like screening and counseling that may need to occur with the use of a combination product, et cetera. Just because there are fewer injections does not necessarily mean that there is any less labor involved, and that comes with a cost and should be appropriately reimbursed. Another con to leaving the recommendation as is regards the history of ACIP having removed a preference for the particular specific combination vaccine, MMRV, over MMR + V so it seems like some change in this language should naturally follow. Option 2 involves adding language to the existing preference for combination vaccines to state, “The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines if licensed and indicated for the patient’s age, but depends on the vaccination status of the patient, provider preference, patient preference, the potential for adverse events, and vaccine availability.” The pros for this statement are that it is still a general recommendation for combination vaccine with caveats. There will be a potential for less missed opportunities, it recognizes programmatic issues and vaccine availability as important considerations, and it is permissive and allows a choice for the provider and patient. The major con is that the language is somewhat wordy and complex and it may take some time for people to remember the criteria. Option 3 is to state that there “is no preference for the use of combination vaccines over separate injections of the equivalent component vaccines.” The pros for this option are that it is concise statement, emphasizes choice for provider and patient, provides a clean slate for evaluating safety and efficacy of vaccines in the pipeline, and the vaccine contracting environment already restricts the choice of formulation. The cons for Option 3 include the potential limitation of administration site space, storage space may be limited (single component products take up more space), and reduced availability of combination vaccines leads to more injections. Following the work group discussion of the advantages, disadvantages, and options, no members chose Option 1, a few chose Option 3, and many providers chose Option 2. Some members of the work group who chose Option 2 were comfortable with Option 3, but a plurality of the work group members who actually expressed a preference favored the general preference for combination vaccines with criteria and caveats. There was considerable discussion and the work group believed that they needed to ask ACIP to weigh in on Option 2 versus Option 3. Discussion Dr. Marcy pointed out that there is another advantage to combination vaccines. There are two studies showing that it takes about a minute plus or minus to draw up the vaccine. A practitioner who has many patients and many vaccines can save a half an hour in the course of a day, which is no small amount. If he gives DTaP, Hep B, and IPV, it is worth $25 in administration fees. If he gives DTaP, Hep B, and IPV separately it is worth $75 in administration fees. Thus, the separate vaccines do have an economic advantage for the practitioner who wishes to use them separately. Dr. Ehresmann indicated that her personal preference was Option 3 for a number of reasons. From the perspective of a state health department and making vaccines available, there are clear advantages to using combination vaccines for the provider and the patient. The statement in the general recommendations will not likely stop manufacturers from producing combination vaccines, but may stop providers from using them. It “levels the playing field” in terms of choice. Dr. Sawyer indicated that he was a work group member and an Option 2 advocate. Given that private insurers and others may mandate that providers use separate vaccines, he expressed concern that Option 3 may lead to the unintended consequence that separate vaccines are given even when not intended. From a practitioner standpoint, Dr. Temte noted that one of the disadvantages regarded the decrease in availability of single component vaccines. Among the members of the American Academy of Family Physicians (AAFP) from whom he had heard, there was a major issue regarding HIB vaccines. Anytime recommendations are changed or interim guidance is offered because of vaccines not being available, it creates significant problems for the vaccine provider community. One of the disadvantages is the seeming decrease of availability of single component vaccines. He wondered whether the work group addressed this. Dr. Kroger responded that the issue was at least considered when the group discussed the limitations. They did not address issues of shortages per se. There is language that discusses shortages later in the section following the preference statement. That is an important limitation in terms of which particular antigens can be used or not used at a particular time. Dr. Meissner expressed concern about how combination vaccines might be perceived by the public. The definition is interesting in terms of which vaccines can be conveniently separated. However, people may perceive MMRV as a combination that could be administered as a monovalent vaccine if there is not some statement. For example, in Option 3 the recognition is completely removed of the advantages of the combination vaccines. This could become a slippery slope and there will be more interest among certain segments of the population about using monovalent vaccines. Dr. Judson suggested that the solution was to remove any economic advantage to giving separate antigens, or conversely to potentially reward giving combinations because of the complexity and additional counseling that has to take place. Given that there are probably arguments both ways, Dr. Morse pointed out that a cost-benefit analysis may be needed to make determinations either way. Dr. Englund indicated that she favored Option 2, pointing out that there had been a major effort by pediatricians over the past 20 years to move toward combination vaccines because of the updates showing that this is patient and family preference. To move away from the direction practice had been moving for 20 years seemed to be a major step backwards. Dr. Baker also favored Option 2; however, she did not believe anyone would understand it as written. It could be solved generally by revising it to “preferred over individual components.” It could remain with the rest of the language in the text, by leaving “generally preferred” at the end of the sentence, or including a quick “but” with a quick phrase. Dr. Cieslak also expressed a preference for Option 2, but because of the number of conditions, he thought it amounted to not being a recommendation. He suggested truncating it after “age.” Dr. Meissner suggested reviewing the combination vaccine section in the 2009 Red Book, which was recently distributed, as a potential template for phrasing this recommendation. Dr. Sumaya noted that the work group did not achieve consensus; however, a larger portion of the group preferred Option 2. While he agreed with truncating it after “age,” it would really then become Option 1. Perhaps they could truncate it and pick one or two priority items to be explicit. Dr. Sawyer suggested keeping the patient and provider preference statements, which would encompass the rest of them. The provider should take adverse events into account, while the patient will take number of injections into account. He thought it should be truncated at “depends on provider and patient preference.” Dr. Morse inquired as to why the work group felt it was necessary to include “if licensed and indicated for the patient’s age” because it seemed like that was general. Dr. Kroger responded that it was a holdover of the status quo statement. He thought it was important to emphasize this point because of the position, timing, and spacing section. They want to ensure that vaccines are being administered at the ages for which they are recommended and if licensed for a particular dose and a particular age. Dr. Ehresmann made a motion to support Option 2 with modification to the wording. She suggested rather than saying “provider and patient preference” to state that it is the patient’s preference, but the provider’s preference based on their deliberation over a scientific evaluation. Dr. Baker seconded the motion for Option 2. Dr. Chilton was opposed to saying just “patient preference.” While respect for patient preference is good, the language would require the physician to stock all of the available vaccines, which is neither possible nor reasonable. Dr. Duchin (NACCHO) favored Option 2 in that combinations are generally preferred; however, he thought it was very important for ACIP to annotate the recommendation with the specific considerations that health care providers might take into account when they decide whether or not they want to use a given combination vaccine. There are many different combination vaccines, each with its own plusses and minuses. Vaccines will also appear in the future after this recommendation is issued that may have unforeseen cost and benefits. He wondered if, when ACIP statements are issued on individual vaccines, there will also be a preference expressed in those statements for combinations and how that would relate to this recommendation and the general recommendations as a whole. Dr. Leonard Freidland (GSK) clarified that the shelf life for both INFANRIX® and PEDIARIX™ is 36 months. Providers will not find shelf life dates in product inserts. Instead they are directed to look at the expiration data on the vaccine being used, and not to use the vaccine has expired. He also indicated that the follow-up on the adverse event profile for PEDIARIX™ has been completed. He directed the committee to an article in Pediatrics in December 2008. A post-marketing study was conducted in which over 60,000 infants received PEDIARIX™ and close to 60,000 control subjects received separate vaccines. 120,000 doses of each vaccine were followed. Short reviews were conducted for 22,500 infants who received PEDIARIX™ and similar numbers of the separate vaccines. There was no increased evidence of medically attended fever within 4 days after vaccination after any dose in the infants who received PEDIARIX™ versus the separate vaccines. Dr. Phil Hosbach (sanofi pasteur) said that sanofi pasteur was pleased to see that Option 2 was being consider, given all of the investment. The policy drove manufacturers to spend hundreds of millions of dollars to develop combination vaccines for the benefits that were outlined. He begged the chair’s indulgence to make a recommendation for the wording that might help simplify this, “Use of licensed combination vaccines are generally preferred to reduce number of injections and missed opportunities. Vaccine-specific considerations that might modify this general preference are discussed in the recommendations for specific recommendations for individual vaccines.” Dr. Mark Feinberg (Merck; NVAC) stressed that the discussion ACIP was having carried with it long-term implications. Manufacturers do respond to the guidance offered by providers and importantly by ACIP in terms of what vaccines to develop in the future. One of the components under discussion by the National Vaccine Program Office (NVPO), NVAC, and a number of other partners is the National Vaccine Plan. One of the components of the National Vaccine Plan is focused on stimulating the development of optimized and appropriate vaccines for the future. A clear determinant to what manufacturers do and how quickly they do it has to do with the clarity of guidance provided by important groups like ACIP. Therefore, he encouraged ACIP members to take their discussions very seriously. If they could not achieve clarity and consensus during this meeting about the guidance they wanted to provide, he suggested that they take this back to the work group and present it at a later time when a clear recommendation that would provide the best guidance for public health in the future was developed. Deborah Wexler (Immunization Action Coalition) raised an issue that troubles nurses with regard to combination vaccines in that some vaccines are not licensed for use in certain age groups. PEDIARIX™ is recommended for doses 2, 4, and 6 months of age or the first 3 doses. Some nurses need to give those three doses, DTaP #4, IPV #3, and Hepatitis B #3 at 18 months of age. PEDIARIX™ is not licensed for that use. Many children need KINRIX™, DTaP, and IPV at age 3 who are behind on immunizations. Most nurses would prefer giving a combination vaccine to those children. With that in mind she wondered whether ACIP would make a recommendation outside of FDA licensure, which ACIP has a history of doing, to make it easier to facilitate giving those three doses of vaccine somewhat outside of the FDA recommendations for the use of PEDIARIX™ or the use of DTaP / IPV vaccine. Dr. Ehresmann said her concern about the wording was that “provider preference” did not give enough credit to the provider for their assessment and evaluation of the patient. Dr. Baker thought they agreed to insert “licensed” in the statement for licensed combination vaccines, given some combination vaccines are not licensed for certain ages. Dr. Sandy Fryhofer (American College of Physicians) indicated that she is a practitioner who treats the mothers of children. Given that vaccines are in the spotlight, she expressed her hope that some language would be included about adverse events. Her fear was that if only a combination vaccine was available, many mothers may opt out entirely not have their children vaccinated. This is also an ethnic and racial disparities issue because some of these individuals might not have the option of going to a private facility to acquire their vaccines if they cannot obtain it through public means. Dr. Morse clarified that from the discussion, it appeared that there was significant consensus for Option 2, but that the actual wording had not been solidified. He thought they should define exactly what they were voting for, or at least the general principle of the vote, and then return the next day with specific language. Dr. Lett pointed out that one variable which must be kept in mind was vaccine availability. Dr. Kroger clarified the proposed revisions: add “licensed” before the first combination, change “provider preference” to “provider evaluation,” keep “patient preference,” leave “vaccine availability,” and perhaps remove “vaccination status of the patient.” Dr. Baker suggested the following language, “The use of a licensed combination vaccine generally is preferred over separate vaccine components or component vaccines, but depends on patient preference and evaluation or assessment.” She preferred “provider assessment” rather than “evaluation,” although she was willing to accept “evaluation." Dr. Judson thought the goal was to shorten this as much as possible, but it now seemed that they had 5 or 6 options on the table. He thought that critical for the first sentence was the statement that the “combination vaccine is preferred and if licensed for the patient’s age,” which would be helpful to a skilled practitioner. However, if indicated did not seem useful because it did not seem that anyone would use a vaccine if it was not indicated. He thought the second part really was about provider preference because patients would likely not make that decision separate from or even in opposition to the provider. Dr. Baker stressed that patient preference was an increasingly important issue. It struck Dr. Beck that the issue really regarded how they modified the word “provider.” Everything else seemed to be fitting into place. He agreed that patient preference was important, but that there must be a way of describing the involvement of the provider in this joint decision. Dr. Sawyer agreed that one or two words were needed to describe provider involvement. He reminded everyone that in the text would be all of the advantages and disadvantages that were outlined, which the provider is supposed read and evaluate for each patient. Motion: General Recommendations for Combination Vaccines Dr. Ehresmann made a motion to approve Option 2 with modifications to be made to the wording by the work group as discussed. Dr. Baker seconded the motion. The motion carried with 15 affirmative votes, 0 abstentions, and 0 negative votes. The following Option 2 clarification was presented to the ACIP members during the second day of the June 2009 meeting: The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment*, patient preference, and the potential for adverse events. *Provider assessment should include storage costs, number of injections, vaccine availability, vaccination status, likelihood of improved coverage, and likelihood of patient return visits. Dr. Kroger then directed the members’ attention to the recommendation regarding Special Situations, which is a laundry list of topics faced by providers on a regular basis, including: * Concurrently Administering Antimicrobial Agents and Vaccines * Tuberculosis Screening and Skin Test Reactivity * Severe Allergy to Vaccine Components * Latex Allergy * Vaccination of Preterm Infants * Breast Feeding and Vaccination * Vaccination During Pregnancy * Persons Vaccinated Outside the United States * Vaccinating Persons with Bleeding Disorder and Persons Receiving Anticoagulant Therapy Two of these sections, Tuberculosis Screening and Skin Test Reactivity and Vaccination of Preterm Infants, required minor updates to address new vaccine-specific recommendations that have been published. For tuberculosis screening and skin test reactivity, the general recommendations have not recommended an interval between the live viral vaccine and a tuberculosis test. It is known that diseases such as measles can suppress the response to a tuberculosis test and generate false negatives. There is a need to adjust the general recommendations to take into account new tuberculosis-specific recommendations that have been published for two-step testing, which involves basically two doses of the purified protein derivative. A recommendation is also needed to clarify whether the risk of test suppression from a live vaccine also exists for a new TB test. Since the last recommendations were published, there is a newly available test known as the interferon-gamma release assay. Based on consultation with the TB subject matter experts (SMEs), the recommendation should be for the same spacing intervals with live vaccines and the new tuberculosis tests. This is basically a minor update. Vaccination of preterm infants requires an update as well. ACIP has generally recommended vaccinating preterm infants following the same chronologic age recommendation as term infants, but there have always been a few exceptions to this. Additional language will be added to emphasize testing of HBsAg-unknown mothers for HBsAg even after HepB is administered. This is an important part of determination to use HBIG within 7 days of birth. Another minor clarification is the recommendation to defer rotavirus vaccination of infants 6 weeks old and still in neonatal nursery (or neonatal intensive care unit). Two special situations, Vaccination During Pregnancy and Persons Vaccinated Outside the United States, require fairly major revisions. A reference has been added to Vaccination During Pregnancy for ACIP’s Guiding Principles for Development of ACIP Recommendations for Vaccination during Pregnancy and Breastfeeding, which was published in May 2008. New concepts have also been added from the Tdap pregnancy-specific document, also published in May of 2008 that recommend: Deferral of Tdap (ACIP Vaccine-specific recommendations), use of Td, limited situations when Td can be deferred (new reference MMWR May 30, 2008), and use of Tdap postpartum regardless of interval from last Td. Based primarily on expert opinion, the risk of infant pertussis disease from withholding a dose of Tdap from a post-partum woman outweighs the risk of a local reaction to the Tdap vaccine from a post-partum woman who may have received Td in pregnancy. The work group acknowledged that there may be future on-going discussion of this topic. It was not clear how specifically to word this in the general recommendations statement. Further consideration should be given to this issue, given that there is a considerable amount of language in the 2006 document specifically regarding the use of tetanus toxoid-containing vaccines in pregnancy. The work group wanted to clarify ACIP’s counseling recommendations for pregnant women that may have inadvertently been administered MMR vaccine. The 2006 document mentions a theoretical risk, but does not describe in detail why the risk exists. The new language is as follows: Data from studies of children born to mothers vaccinated with rubella vaccine during pregnancy demonstrate rubella antibody levels that probably represent passive transfer of mother’s antibodies during pregnancy. No cases of congenital rubella or varicella syndrome or abnormalities attributable to fetal infection have been observed among infants born to susceptible women who received rubella or varicella vaccines during pregnancy, although a theoretical concern exists . . . If vaccination of an unknowingly pregnant woman occurs or if she becomes pregnant within 4 weeks after MMR or varicella vaccination, she should be counseled about the theoretical basis of concern for the fetus; however, MMR or varicella vaccination during pregnancy should not be regarded as a reason to terminate pregnancy (6, 8, 189). This language originated in the leads from the MMWR series published in JAMA in June 1989, so this much specificity has not been carried forward through all of the documents since then, but it is cited in all of those documents, so it was presented here as part of the general recommendations. Another topic in special situation that requires some changes is Persons Vaccinated Outside of the United States (US). The 2002 document was originally written to focus exclusively on internationally adopted children, but it has been broadened to include all persons vaccinated outside of the US, which means that ACIP needs to take into account the new vaccines since 2006: rotovirus vaccine, human papilloma virus vaccine, and zoster vaccine. The Vaccination Records section revisions consist primarily of clarifications and updates. Strong emphasis is placed on the role of a vaccination record in avoiding extra doses. The language that has been added reads: Appropriate and timely vaccination documentation not only helps ensure that persons in need of one or more recommended vaccine doses receive them, but also that adequately vaccinated patients are not administered excess doses. Curtailing the number of excess doses administered to patients aids in controlling costs incurred by patients, providers, insurers, vaccination programs, and other stakeholders. Additionally, there are isolated examples of excess doses increasing the risk of an adverse reaction (e.g. excess reduced doses of tetanus toxoid and frequent dosing of pneumococcal polysaccharide vaccine causing local reactions). The effect of this language is primarily to emphasize the importance of provider records and provider responsibility. Language is included to stress that providers should document serology results, vaccination doses, et cetera. Additional language is included to encouraging post-partum mothers to receive a record on discharge from the hospital because Hepatitis B vaccine should be given in that venue. Language is also included to describe potential capabilities of immunization information systems (IIS) with respect to vaccine management and documentation of adverse events, and there is an update on statistics pertaining to IIS enrollment. Discussion Dr. Chilton pointed out two minor differences between the general recommendations and the rotavirus statement. There is a statement in the rotavirus policy statement saying that some experts would prefer the vaccine that does not contain latex or that does not have a latex stopper for those patients who are at high risk of later having a latex allergy (e.g., spina bifida patients). The rotavirus policy statement also includes a proviso that if there are epidemiologic considerations that dictate use of rotavirus vaccine in a newborn intensive care unit, it could be done using local some expert opinions. He wondered whether this language could be included in the general recommendations as well. Dr. Kroger agreed that it would be a good idea to add language along those lines. Dr. Morse wondered whether everything had to be included in the general recommendations or if the general guidelines could refer to the other guidelines. Dr. Englund was concerned that if they changed the general recommendations they would have to change the rotavirus recommendations as well. Perhaps referring to the specific guidelines was a better idea for the deferral of rotavirus vaccination of preterm infants 6 weeks old. Dr. Temte noted that while for vaccination records some language was included about immunization information systems, there appeared to be nothing about electronic medical records (EMRs). He uses EMRs regularly with virtually every adult patient. Their EMRs have a tab to the Wisconsin immunization registry. Given the effort on the part of the current administration toward the use of EMRs in general, it should be in the forefront of ACIP’s recommendations to fully integrate EMRs with immunization information systems. Dr. Kroger suggested making a reference under provider responsibilities to the fact that these products exist. With respect to recommending the interferon-gamma release assays, Dr. Marcy thought there was limited data for children under 4 or 5 years of age. In terms of measles vaccine, he suggested including a caveat regarding the age limitation for data. A second data-driven part is on page 21, “regardless of recent history of Td vaccination, pregnant women should receive a dose of TDaP as soon as possible after delivery.” If Td has been given to a woman at the beginning of the second trimester and following delivery, this is about six months. He knew of no data showing the safety of TDaP less than 18 months after Td. Scott Halpern’s data goes down to 18 months. Dr. Pickering responded that a recent article was published showing the period of 1 month with no adverse events. However, the numbers were small The discussion reminded Dr. Morse of the annual discussions of the children, adolescent, and adult guidelines when additional ideas were proposed. He thought they must look at this as a continuous quality improvement and that all of the excellent ideas proposed should go back to the work group so that they could continue to upgrade and improve this document each time. He stressed that it was not necessary to complete the final product at each meeting because they would never complete it. He had thus far heard no arguments against the recommendations which include minimum additional language and / or minor clarifications. Therefore, he suggested moving forward with a caveat that they would continue to improve the revisions with the next iteration. Dr. Baker agreed with Dr. Marcy that there was no convincing data on safety; however, it is a risk-benefit issue because of the incredible risk to the baby of acquiring pertussis, which is likely to be fatal if the mother and everyone around the baby are not immunized. Motion: Special Situations and Vaccination Records Dr. Baker made a motion to approve the recommendation of the work group regarding Special Situations and Vaccination Records. Dr. Sawyer seconded the motion. The motion carried with 15 affirmative votes, 0 abstentions, and 0 negative votes. Dr. Judson noted that while they voted to approve, he wondered whether there were statements as there were for Tb Screening and Skin Test Reactivity that may conflict with or connect to other recommendations. For instance, booster skin testing or double skin testing is generally for people over 40 in whom immunity may have waned. If this is stated to pediatricians trying to give doses to infants or children, this will be confusing as it does not apply to them. There are no data for infants and children for QuantiFERON ®, let alone where practitioners might order it. Dr. Morse requested that Dr. Judson put this in writing and refer it back to the work group so that it could be included in the deliberations. Background Dr. Paul Cieslak ACIP, WG Chair Dr. Cieslak briefly reviewed the background information pertaining to rabies vaccine. Given that the human rabies vaccine supply has been tenuous since 2007, ACIP formed a work group to draft interim recommendations regarding how the supply should be managed in the event of a shortage. Draft interim recommendations in the event of a shortage of rabies biologics were previously distributed to ACIP in which alternative schedules during a shortage were proposed. The work group proposed alternative schedules, including a 4-dose schedule, and it was the opinion of the work group that the 4-dose schedule would not result in reduced efficacy in the post-exposure setting. Therefore, the work group was asked to evaluate alternative schedules, specifically for more routine use. There are two rabies vaccines available in the US. The Novartis vaccine is the purified chick embryo cell vaccine, which is available for post-exposure and pre-exposure immunization without any current limitations. The sanofi pasteur vaccine, the human diploid cell vaccine, is available only for post-exposure prophylaxis at this time. Due to supply issues, there must be a local public health risk assessment and a password restricts its use [www.sanofipasteur.com]. The terms of reference for the ACIP Rabies Work Group were to review the evidence for a reduced schedule of rabies vaccine in the post-exposure setting; provide the available evidence to ACIP for discussion of dropping the 5th dose; and revise the existing statement accordingly. Human Rabies Biologics: Consideration of a Reduced Vaccine Schedule in Post-Exposure Prophylaxis Dr. Charles Rupprecht CDC / CCID / NCZVED / DVRD Dr. Rupprecht reported that the sources of evidence the work group has reviewed included basic studies of rabies virus pathogensis, overall immunization principles and kinetics specifically regarding rabies vaccines, available data from human clinical trials, national and international epidemiological surveillance data. Members of industry and international subject matter experts, particularly with regard to the WHO collaborating centers, have been consulted as well. The supply limitations developed during late 2007 when the 2008 ACIP rabies statement was already well into its editorial deliberations with the MMWR. The work group felt strongly that there should be discussions with ACIP and preparation of recommendations well before the onset of a true shortage. Besides increases in vaccine availability, a reduced schedule would possibly result in minimization of adverse biomedical events, will limit additional health expenditure, and provide a rational legacy for development of future biologics. With the onset of the application of comparative health effectiveness data, the work group felt strongly that the current institution of the ACIP evidenced-based approach would be a sound one for the objective rationale application toward rabies immunizations. The work group also recognizes that this would be a departure from the claim of the product insert. However, using the following figure from a prior publication by Pickering and Orenstein, Dr. Rupprecht reminded ACIP members that this body does not simply “rubber stamp” label claims: Obviously, immunization practices differ from what the claims are specifically. It is also important to recognize that, on the basis of the available data, there were no comparative clinical trials that specifically assessed the administration of human rabies immune globulin in 1, 2, 3, or 4 doses. The product inserts were developed on the basis of the existing 5-dose schedule. Historically, rabies immunizations have undergone changes in schedules, routes, and the formatted material that was used going back to the 1885 premier work by Pasteur when 14-21 doses of sequentially desiccated spinal cord of rabid rabbit was homogenized and used as a vaccine. Originally, in 1980s the human diploid cell vaccine was suggested for an optional 6th 90-day dose which was then later dropped without any experimental comparative studies as well as in the US and a 5-dose series was used and similarly incorporated with the purified chick embryo vaccine, the PCEC vaccine. Similarly, there has been a 4-dose series in long use from a global standpoint, the 2-1-1 series in which 2 doses of vaccine are administered on day 0 (requires availability of both vaccine doses on day 0, limits IM sites for HRIG, et cetera). The work group did not consider this particular schedule for several reasons, not the least of which was that they felt strongly that there was no utility of 2 doses being administered on day 0 compared to the single dose. In addition, there was concern that because of the possibility for complications or mistakes, administration of 2 doses on day 0, with having to have an infiltration site for immune globulin, further negated the utility of having a 2-1-1 schedule as opposed to simply dropping of the 5th dose for a 4 dose total regimen. In regard to rabies virus pathobiology, the work group believes that what occurs in the first few days is critical by a current modern understanding of this acute, progressive encephalitis. The rationale for all post-exposure prophylaxis is to prevent viral invasion from the locality to the nervous system. All of the ACIP recommendations from inception to date have emphasized early wound care, passive immunity (e.g., infiltration of rabies immune globulin at the bite site), and rabies vaccine to stimulate the development of active immunity via a prime-boost strategy. The following model of rabies virus pathogenesis was first proposed in the 1960s, and from experimental studies to date strongly suggests that the reason post-exposure prophylaxis works in the hours to days after exposure is because the virus is retained in the periphery: When comparing incubation periods of human rabies cases that occurred in the US in past decades, a median is approximately one month. Clearly the administration of a 5th dose on day 28 after exposure has little if anything to do with the amelioration of basic rabies virus pathogenesis and similarly has probably no saving utility for severe exposures on the face, head, or direct inoculation into the brain itself. Based on a variety of clinical studies, rapid induction of rabies virus neutralizing antibodies is accepted as a critical surrogate of successful intervention. In clinical trials of rabies vaccination, all healthy individuals developed detectable rabies virus neutralizing antibodies by day 14. No significant differences were documented between a 4- versus a 5-dose rabies vaccine schedule in the relative amount of neutralizing antibodies produced. In comparison of studies using 4 doses of vaccine, when given in a regimen that included rabies immune globulin, equivalent outcomes were observed. It is clear from these clinical studies that there is a relatively rapid induction of rabies virus neutralizing antibodies, which has been accepted as a critical surrogate of successful intervention since there is no defined seroprotective level per se. A combination of these studies over time, regardless of the type of the two vaccines licensed in the US, is compared in the following graph: As reflected in the graph, rapidly from day 0 to day 14, everyone develops rabies virus neutralizing antibody. Relatively shortly thereafter, the antibodies begin slowly to decline regardless of the administration of the 5th dose on day 28. Based upon epidemiological surveillance, in the US no failure of human post-exposure prophylaxis has been identified during the past 30 years (since use of modern cell culture vaccines and RIG). Outside of the US, rabies has occurred in human patients who had no prophylaxis, substantial delays in initiation of prophylaxis, or significant deviations from recommended prophylaxis. The work group could find no failures attributable to an absence of the fifth and last vaccine dose on day 28. In terms of public compliance, cross-sectional studies at the state or county level indicate that public adherence to the existing human PEP schedule is not 100%. One study of human PEP in New York (1998-2000) found that approximately 13% of persons did not complete the full schedule, and approximately 2% only completed 4 vaccine doses, 2 of which involved documented exposures to laboratory-confirmed rabid animals, without incident. Grossly extrapolated, approximately 1,000 persons likely receive only 3 to 4 doses of vaccine in the US each year, of which approximately 30 to 40 would involve exposures to rabid animals. In addition, unpublished epidemiological data collected by CDC during a 2008 investigation of frequencies of animal exposures and a correlation with prophylaxis in Puerto Rico demonstrated that a 4-dose vaccine regimen provided an immunological response comparable to the standard 5-dose regimen. In this limited survey 30 (16%) of 191 patients exposed to suspected rabid animals received fewer than 5 doses of vaccine. Consent and sera were obtained from 18 patients, from whom three had received only 1 vaccine dose, 6 had received 2 doses, 5 had received 3 doses, and 4 had received 4 doses. Eleven (61%) of the 18 sera (two of the 2-dose patients, all 5 of the 3-dose patients, and all 4 of the 4-dose patients) exhibited complete virus neutralization at the 1:5 dilution using the RFFIT assay. Adequate titers were detected in the sera of all 9 patients who received only 3 or 4 doses of vaccine, 118, 144, 146 and 153 days after the 3rd (and last) doses and 126, 143, 168 and 215 days after the 4th doses of vaccine were administered. To date, none of these patients have developed rabies. [K. Robertson et al., 2009 (unpublished)]. From the time of Pasteur, animals have been used as important surrogates in preclinical testing of rabies vaccines. Such research on basic immune response and vaccine efficacy in a variety of species have provided significant inferences to human clinical trials. Models from laboratory rodents to non-human primates demonstrate that the absolute number of doses of a potent vaccine is not critical if timely intervention occurs after experimental infection, including the combined use of immune globulins. For example, in a recent mouse model in which all 10 animals in the control group succumbed, and in which post exposure prophylaxis was instituted 24 hours after exposure, in the 4 comparative groups of animals that either received 1 dose, 2 dose, 3 dose, or 4 doses of vaccine, the number of animals surviving in each of those groups respectively was 8 of 10, 9 of 10, 9 of 10, and 7 of 10. The survivorship rate was irrelevant to the number of doses administered. The animals in each group were bled 3 months after the exposure and initiation of PEP. Similar to the human data obtained from Puerto Rico, as the number of doses increased from 2, to 3, to 4, there were no significant differences of survivorship. In another animal model using Syrian hamsters, it was also demonstrated that regardless of the absolute number of vaccine doses in PEP initiated 24 hours after animals were infected with rabies virus compared to controls, there was no significant difference in survivorship of those animals. From the standpoint of randomness in this experiment, there was 100% protection in a group where animals that received 4 doses as opposed to 89% survivorship in a group where 5 doses of vaccine were administered [R. Franka et al., 2009, Vaccine, submitted]. With respect to health economics in the US, there may potentially be some minimal cost decreases to health care payers and the health care system if the regimen was reduced from 5 to 4 doses. The work group recognized that there were not going to be any new clinical trials, nor any insipient changes in the label insert regardless of the ACIP recommendation. The number of visits by patients would decrease as a consequence of eliminating that last visit which is quite important, particularly in rural areas where individuals have to travel a number of miles. Insured patients are unlikely to see an increased cost per dose (cost per complete series of vaccine should remain unchanged). Preliminary assessments support the positive national health benefits associated with a reduced schedule of rabies vaccination. Overall, there is no anticipation that changing the current recommended schedule of 5 vaccine doses to 4 vaccine doses during rabies post-exposure prophylaxis would substantially alter the health economics of rabies prophylaxis. In summary, no direct post-exposure efficacy trials have compared 5 doses to 4. The work group review included published and unpublished studies of rabies virus pathogenesis, experimental animal studies, human clinical trials, and epidemiologic surveillance data. The work group concluded that taken in toto, the evidence suggests that no rabies case would result from reducing the post-exposure vaccination schedule from 5 doses to 4. Based upon feedback, a draft document was prepared by the rabies working group for ACIP review and vote. Discussion Dr. Baker thought the new document was highly improved and she supported the work group’s recommendation. Dr. Meissner pointed out that human nature being what it is, if there is a small percentage of exposed individuals who do not obtain all 5 doses and receive only 4, presumably if 4 doses are recommended, there will be a small percentage who will receive only 3 doses. Based upon the data, it appears as though that this is still likely to provide adequate protection. He also noted that the 2009 Red Book still recommends 5 doses and references the 2008 ACIP guidelines, which is likely to engender a great deal of confusion for pediatricians. Dr. Rupprecht confirmed that Dr. Meissner was correct in his assumption on the basis of the comparative data. Most of the critical functions occur between day 0 and 14. While Dr. Chilton appreciated the very good wording in the new document, he wondered what the ramifications may be of handing the manufacturer a de facto 20% windfall increase in profits by stating in the document that the cost of 4 vaccine doses is likely to be as great as that of 5. Dr. Meltzer, a senior health economist and a member of the work group, took responsibility for that comment. It was based on a comment made to ACIP in the public forum last session during which one of the manufacturers said that they currently sell this as an entire treatment rather than a per dose treatment and they are unlikely to change the price per treatment. In the notes and in the write up, this is referenced. He did not believe anything ACIP said gave license in and of itself to any manufacturer to raise or reduce the prices, given that they work based on market forces. Dr. Rupprecht added that it was their attempt to be transparent on the basis of the remarks that were made during the last meeting. Dr. Morse noted that in the report it was noted that a substantial review of the Zagreb 2-1-1 regimen was not included. However, he wondered what evidence was included as supportive. The regimen approved by WHO in 1992 has continued to be in practice. Dr. Rupprecht responded that those original studies were actually suggested in the 1980s and reviewed by WHO subsequently. From some of the work that was done, as well as some other comparative data, it has been shown there is an maximum amount of effective antigen that can be presented to the immune system at any one time, after which no further increases occur in antibodies, GMTs, protection, et cetera. That can be demonstrated experimentally and clinically, which is one of the reasons the work group felt strongly that there really was no utility of 2 doses of vaccine administered on day 0. Similarly, there were some suggestions clinically that when the Zagreb schedule was used, there was some strong suggestion of interference of immune globulin with those 2 doses of vaccine that were administered on day 0. Hence, on the basis of the clinical suggestions of potential interference and the lack of any utility of providing what is already a very potent product on day 0, and because of the implications during a shortage of not necessarily having 2 doses present on day 0, the work group believed that inclusion of the Zagreb schedule would only lead to additional confusion. Dr. Judson noted that 20 to 30 years ago, there was a statement some place that there was no evidence that rabies post-exposure prophylaxis started after 72 hours, or 3 days, or 4 days was effective. Now they were saying that there have been no cases of rabies if post-exposure prophylaxis was used. He wondered whether the prior impression had been modified. Dr. Rupprecht replied that the review of the cases in which human rabies developed in spite of post-exposure prophylaxis suggested that immune globulin was not used, immune globulin was inappropriately used, or there was a significant delay in use. The excellent review by Wilde and others showed that there were some other complicating factors. The majority of failures were in cases in which heterologous products were suggested. The work group made note of and brought to the committee’s attention some of their concerns about the unavailability of intact immune globulins (IG). For example, if one used F(ab)2 prime products in which the Fc fraction is removed from the IG, that will significantly alter the kinetics, biological half life of circulating fragments and outcome of intervention. There have been no failures with timely use of one of the human rabies immune globulin products licensed in the US. The last major epidemiological study of post-exposure prophylaxis was the one by Helmick et al that suggested that there was a median delay of approximately 5 days between when a person was exposed and when they presented for post-exposure prophylaxis. That does not mean people should delay that long or misconstrue the numbers and present at their leisure. Obviously, this is an urgent emergency. Delay could result in death. They do not want the 5-day or 72-hour numbers to suggest that people should be turned away. In fact, there was a notable case in the US of a person exposed abroad. When she presented to her clinician, due to the amount of time that had passed from exposure, she was told that she should have already had prophylaxis and that it is too late to give it now. Probably the best would be to say that it is an urgent emergency and that timely application is highly recommended. Dr. Duchin (NACCHO) agreed with this recommendation, but had a lingering concern about the fact that health care providers may be troubled by the discrepancy in the package labeling with the FDA recommendation versus the ACIP guidance. He wondered if ACIP could provide standardized language that health jurisdictions across the country could use when responding to these concerns so that they would all be speaking with one voice. He also wondered whether there was any precedent of a discrepancy of this type. Dr. Rupprecht indicated that in the preamble of the recommendation, there should be some discussion along those lines as to the evidence-based approach and whether it supports the utility of 4 versus 5 doses, what the basis of that evidence is, and that clearly it would be in conflict with what the product claim would be. There had already been a considerable amount of outreach to health departments in 2009 due to the on-going supply issues. Depending upon the recommendations of ACIP, new outreach efforts would likely begin immediately. In terms of other discrepancies between labeling and ACIP recommendations, Dr. Morse noted that in 2008 Hepatitis A vaccine could be used in lieu of immunoglobulin for basic post-exposure prophylaxis. Dr. Rupprecht added that historically, from the standpoint of the rabies vaccine, the last time there was the discrepancy was when ACIP first recommended intradermal vaccination for pre-exposure purposes before the product was licensed. Discussion of times when there have been discrepancies would be useful in the preamble for better health communications and clarity with practitioners. Dr. Baker noted that another example was the label on influenza vaccinations, which do not include pregnant women as a target population. Ms. Stinchfield pointed out that another cost consideration is the amount of nursing time that goes into reminder recall and follow-up. A reduction of 20% in that effort would be substantial. Clement Lewin (Novartis Vaccines) indicated that the supply constraints that existed in 2008 no longer represented a problem. Novartis has invested approximately $100 million in increasing the capacity of and upgrading the facility in Marburg. He also re-emphasized a point that he made at the last meeting, which was that the ACIP recommendation would essentially be an off-label recommendation. Novartis does not recommend the use of its vaccines off label; therefore, if any provider or health care personnel contact the company, the answer would be that 5 doses are recommended in accordance with the label. This is likely to lead to considerable confusion. Many people have highlighted that ACIP recommendations have not always been aligned with the package insert. While that was true, in the 10 to 15 years he had been working in vaccines, he could not recall ACIP actually making a broad recommendation. This would be like saying they decided HPV vaccine should be 2 doses based on the evidence, but the FDA has not approved that indication. This very broad decision was highly likely to cause a significant amount of confusion amongst the medical community. Dr. Ehresmann noted that during the last ACIP meeting there was also a comment that the manufacturer did not intend to request a change for the package insert. She wondered whether there was a way that someone other than the manufacturer could do so. Dr. Baylor (FDA) A change must be requested by the US license holder, which would be the manufacturer. Although there are examples of safety issues in which the FDA could request that manufacturers submit safety data, the FDA did not perceive dropping a dose as a safety issue per se. Dr. Temte did not foresee a problem. If there is clear ACIP guidance, it will be translated to state partners, practitioners, and other experts. From a clinician’s point of view, he said he rarely consults a product insert on a vaccine. Dr. Morse was struck by the fact that the Zagreb 4-dose regimen has been approved since 1992 by WHO. He wondered whether there was a second package insert used by manufacturers in other countries or if that was simply not addressed. Dr. Hosbach (sanofi pasteur) responded that he was unfamiliar with package inserts outside the US. He pointed out that historically, manufacturers were permitted to include ACIP recommendations in the package insert. That was somewhat helpful when there was a conflict. However, that is no long permissible by FDA. As a manufacturer, they do receive many calls from physicians and providers about how to utilize vaccines, including rabies vaccine. They also will recommend what is on the package insert in these cases. Chris Hahn (CSTE) commented that at the city health department, they receive numerous calls from providers as well. Their response would be that ACIP has recommended 4 doses, but that they should be aware that the FDA package insert still says 5 doses. Dr. Morse wondered how the Red Book would handle this. Dr. Pickering responded that it would be updated in the on-line version immediately. Dr. Bocchini (AAP) responded that the Committee on Infectious Diseases (COID) would review the recommendations and make a decision, which would be published in the AAP newsletter and included in the Red Book on-line immediately to make practitioners aware as soon as possible. Dr. Baker requested elaboration on what city, local, and / or state health departments say about ACIP’s influenza and Hepatitis A recommendations with respect to pregnant women. Dr. Hahn (CSTE) responded that if they were aware of discrepancies, they try to give the provider all of the information. They do not receive a lot of calls from providers about influenza vaccination for pregnant women. She thought the ACIP recommendation was fairly well accepted in the provider community and was simply followed. Dr. Ehresmann said that Minnesota would follow the ACIP recommendations in general as a standard and would explain any discrepancies. Dr. Morse said that New York would tend to go with the ACIP recommendations. They would also raise the issue with the State Advisory Committee to seek their support. Motion: Reducing Rabies Post-Exposure Prophylaxis from 5 to 4 Doses Dr. Baker made a motion to approve the recommendation of the work group regarding a reduced schedule from 5 to 4 doses for rabies post-exposure prophylaxis. Dr. Meissner seconded the motion. The motion carried with 14 affirmative votes, 1 abstention, and 0 negative votes. Overview Dr. Lance Chilton Poliovirus Vaccine Work Group Chair Dr. Chilton stressed that polio still exists. Poliovirus has spread from Nigeria, India, Afghanistan, and Pakistan where it is still endemic. Therefore, it continues to be a threat to the US and the reminder of the world at this point despite the desire to have solved the problem by the year 2000. By 2010, the problem still will not be solved. There is still a threat of long distance importation to poliovirus into the US and for that reason, the decisions on poliovirus vaccine dosing and intervals remains important. The problem that needed to be solved by the work group and ACIP regarded when a third dose of inactivated polio vaccine should be given, and when or whether a fourth dose is needed. The work group plan was limited. They engaged in conference calls between February and April. At the end of those calls, there was remarkable unanimity of opinion. Polio Eradication Program: India 2009 Observations Robert L. Beck, JD ACIP Member Mr. Beck said he was privileged to be part of a group of 45 volunteer Rotarians from around the world who travelled to India in February 2009 to vaccinate children against polio. They worked in the streets and slums in several cities in northern India where they vaccinated more than 1,000 children. He spent about a month in India working with the polio program and then travelling on my his own through northern and central India, based upon which he made several observations. The polio program is successful. One of the three endemic strains of polio in India has been successfully eradicated, and the two remaining strains show great promise that they will be eradicated as well. That is a major step forward. This program is not a once a year event, but is offered several times a year due to limits within the current oral vaccine and because of migrating populations. It is a very people-intensive project, with thousands of government and volunteers involved to vaccinate millions of children. The program has been in operation for decades and with the successes, personnel are showing signs of wearing out. Mr. Beck believes that Indian state and local personnel need visible, public encouragement and recognition to keep up program momentum. Continued funding remains important, but personnel support is also needed. Thus, one of the comments he brought back to India and the US was that he thought something needed to be done to buoy up the people working at the state and local levels to help them stay the course of their important involvement in the program. The program is also unique from another standpoint. The Gates family and foundation have contributed hundreds of millions of dollars for support of the program. The Rotary Foundation has also donated hundreds of millions of dollars and is one of the best known US charities. CDC is the primary face of the US government in this project and is also doing a good job. The combination of these three organizations makes this project a uniquely positive American / USA story, and that story should be told. The program is really also a world class international relations opportunity. To Mr. Beck it is akin to the Marshall Plan following WW II. Its success has the potential for a strategic, macro, impact in this region of the world. It is a non-military program. Implementation is through local people, for benefit of local people. Billions of people in the relevant geographic area will see the benefits from such a program, including 1.5 billion Indians, 3.0 Chinese just over the rather porous border, and billions more residing in Russia and India’s Muslim neighboring countries. This program is an immense international opportunity in addition to its wonderful public health benefits. Mr. Beck extended his personal gratitude to Dr. Jean Smith who is a tremendously dedicated person. Dr. Smith lived and worked in India for many years. Her work included the polio program. She arranged special briefings for him before his India trip to make it more meaningful. In summation, Mr. Beck concluded that the Polio Eradication Program is a major public health success in India. It has the potential for becoming a major international relations success in the region, and this program is worth continued support. Updated Recommendations for Routine Poliovirus Immunization Gregory S. Wallace, MD, MS, MPH, Medical Officer National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Dr. Wallace presented a follow-up to the Poliovirus Work Group’s February 2009 presentation regarding the deliberations of the work group on the recommendations for the routine inactivated polio vaccine (IPV) schedule, including a schedule when combination vaccines are used, minimum intervals for IPV, and when accelerated schedules should / should not be used. The work group proposed no changes to the current routine schedule for poliovirus vaccines. If 4 doses of IPV-containing vaccine are administered prior to age 4 years, an additional dose should be administered at age 4 to 6 years. For instance, with Pentacel, if the first 4 doses for DTaP, Hib, and IPV are given as per the schedule, an additional dose is proposed at 4 to 6 years of age. This is equivalent to Canada’s routine IPV schedule. The reason for this proposal from the work group has to do with the continued threat of importation, given that polio has not yet been eradicated, and because incomplete data are available on the duration of immunity into adulthood with last dose at age 15 to 18 months. A footnote is proposed to the recommended schedule to emphasize the 4- to 6-year old dose, which reads, “The final dose in the series should be administered on or after the 4th birthday.” With regard to minimum intervals for IPV, age and dose intervals do affect the seroconversion response. Seroconversion rates are generally better when administered at 2, 4, and 6 months of age with the primary schedule, as opposed to the 2, 3, 4 month, or 6, 10, 14 week schedule. In addition, maternal antibody levels at the first dose are inversely related to seroconversion levels, particularly in the first 6 months of life. Longer intervals are optimal for booster response, and there should be at least 6 month intervals prior to the booster dose as this is optimal for memory cell maturation. For the proposed catch-up schedule, the only change is the interval between the third and fourth dose being extended to 6 months. It was 4 weeks previously. There is also proposed footnote language about early doses that reads, “In the first 6 months of life, minimum age and minimum intervals are only indicated if the person is at risk for imminent exposure to circulating poliovirus (e.g., traveling to a polio endemic region or during an outbreak). A fourth dose is not necessary if the third dose was administered at age 4 years or older and at least 6 months have elapsed since the second dose.” That is equivalent to the routine recommendation for adults who have not been previously vaccinated. With respect to next steps, pending an ACIP vote and deliberations and Notice to Readers, the draft is ready to be sent through clearance to clarify and summarize the recommendations. This will be available for reference and text for 2010 immunization schedule and the updated general recommendations publication. The nearly 10-year old ACIP recommendations and reports will be updated in the near future, but no fundamental changes are proposed. This will potentially be ready for a vote in October 2009. Discussion Dr. Sawyer expressed concern about the minimum interval language. He asked whether the intent was for the same language to be a footnote on the regular schedule in addition to the catch up schedule (e.g., in the first 6 months of life, the minimum age and minimum intervals are only indicated if the person is at risk for imminent exposure). That will not apply to anyone unless they travel outside of the US. He wondered if, for example, a patient presented to their provider only 5 weeks after the previous dose the recommendation was that they not receive the next dose. This did not seem like a very practical recommendation, and he suggested softening of that statement so that it is not interpreted that the provider should not give this vaccine under any circumstances. A soft minimum interval that applies in some circumstances but not in another is really not tenable. It comes into play with some software programs because an immunization registry will program forecasting based on minimum intervals, but there are examples where Comprehensive Clinic Assessment Software Application (CoCASA), a CDC program used to assess immunization coverage, does not respect the same minimum intervals with regard to missing immunizations or invalid doses. That has created confusion in San Diego because clinics are following the immunization registry forecast, and then are being evaluated by the county health department with CoCASA such that they receive two different answers about whether a dose was or was not appropriate. Dr. Wallace responded that for the general routine schedule, the footnotes do not usually include minimum intervals, and he thought everyone was aware of the space issues for the schedule itself. Certainly, the text can be included in the MMWR that announces a schedule that addresses accelerated schedules and minimum intervals. The concern has been minimum intervals being used inappropriately as routine accelerated schedules, which was why the work group felt the need for that and to provide the information on the first 6 months of life; however, the minimum intervals are as they are, so if a 4-week interval is used between dose 1 and 2 and 2 and 3, it would be considered a valid dose by CDC. With regard to the 4-year old age group dose in light of the Hib shortage, it seemed to Dr. Schuchat that there would be many children over the next year or so who would be receiving their booster dose of Hib-containing vaccine late at perhaps age 3. She wondered if the committee considered whether someone received their 4th dose of IPV-containing vaccine at age 3, they would require another polio dose at 4 to 5 years of age. Dr. Wallace responded that this issue did arise. While the work group recognized that this is an issue, they did not feel that there was sufficient information to inform that adequately. They had developed footnotes and information with many more caveats, but the work group ultimately decided that this would add to the confusion rather than clear it up. To provide some level of comfort, David Greenberg (sanofi pasteur) reported that in the clinical trials, the Pentacel doses were given on schedule at 2, 4, and 6 months of age with the 4th dose at 15 to 18 months of age. There was good persistence of antibody with 95% of children maintaining seroprotective levels at 4 to 5 years of age. Not that this would change the language, but just to offer some additional reassurance that there are antibody levels that persist for years. Dr. Wallace responded that this information was considered by the work group, but the deliberation of the work group pertained more to what is unknown into adulthood. In the pre-eradication era, they wanted to err on the side of making sure that coverage and protection was as complete as possible. This may become less of an issue as more data become available about protection in adults. Dr. Sawyer remained somewhat uncomfortable with the modification of a catch-up schedule. The intent of a catch up schedule is to catch children up. It seemed as though they were recommending that children could be caught up for everything else except polio. Translating that into practice is very challenging for a provider. Providers will give children their DTaP but not give their polio and will hope to get them back in for that. Given the potential for confusion, he suggested changing the language from “only indicated” to “only recommended” or “usually recommended.” The implication of the word “indicated” is that it is contra-indicated in other circumstances. Dr. Wallace agreed that the language could be changed from “indicated” to “recommended” or “routinely recommended”. To be clear, he stressed that the point of the footnote was not to tell people not to catch children up. It was to offer information so that people did not accelerate a routine schedule only in the first 6 months of life. This would involve potentially one or two doses at the most. However, it is important not to have a routine 6-, 10-, 14-week schedule. Motion: Poliovirus Vaccine Dr. Temte made a motion to approve the recommendation of the work group regarding poliovirus vaccine with the slight modification suggested by Dr. Sawyer. Dr. Ehresmann seconded the motion. The motion carried with 13 affirmative votes, 1 abstention, and 1 negative votes. Dr. Sawyer clarified that he voted “no” because he remained concerned about the concept of a minimum interval, which they did not really mean in certain circumstances. To him, if they were not comfortable with the minimum of 4 weeks, it needed to be changed to whatever they were comfortable with. Practitioners will have to deal with this question a lot in deciding what truly constitutes a valid dose. Dr. Seward thought there was additional wording in the MMWR. There are scientific data showing that there is quite inferior immune response if three doses are given of IPV on the accelerated schedule, so the routine recommendation is 2, 4, and 6 months. What they were thinking about with combination vaccines is the tendency for the catch-up vaccination schedule to become routine. Therefore, they wanted fairly strong wording to indicate that it should not be used on a routine basis. Acceleration should only be used under very rare situations. Catch-up is a separate issue. If a child is one year old and they have not had any vaccine, the risk of no protection is being weighed in terms of achieving some immune response as quickly as possible. Given the global epidemiology of polio as it has been known for some years, Dr. Judson wondered why the US still started so young. Many of these questions would not arise if not starting at such a young age. That obviously excludes people who would be travelling or in very special situations. Dr. Morse thought it was linked to other immunizations, which is a longer discussion. Regarding the issue of catch-up versus regular schedule, Dr. Sawyer pointed out that the current language was in conflict with the general principles of immunization, which says to give every vaccine that can be given at a visit as long as they are within the recommended age limits. Contradiction in this language compared to other language raises the potential for problems. VFC Resolution Update: Polio-Containing Vaccines Dr. Jeanne M. Santoli Immunization Services Division National Center for Immunization and Respiratory Diseases Dr. Santoli reviewed proposed changes to the VFC resolution that would address the minimum interval issue that was just discussed, as well as continuing to streamline the resolutions through references to published links. Going through the components of the VFC resolution, the eligible group is defined as infants and children at least six weeks of age for the recommended schedule for 2, 4, and 6 to 18 months, and 4 to 6 years. The resolution refers to the current polio statement found at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4905a1.htm For the dosage intervals, specific information is included based on the day’s discussion. The minimum interval from doses 3 to 4 is extended from 4 weeks to 6 months. The minimum interval from dose 1 to 2 and dose 2 to 3 remains at 4 weeks, and the minimum age for dose 1 remains 6 weeks of age. In addition, because each product has particular characteristics, the following links to the ACIP recommendations and notices that are related to each product are included: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4905a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5210a8.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5739a5.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5739a4.htm For the recommended dosage and the contraindications, the resolution refers to the FDA webpage through which package inserts can be found: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 When a new recommendation and / or notice related to the changes that were voted upon is published, the language and links in this document that can be replaced by that new link. This is similar to the pneumococcal resolution discussed in February 2008. Motion: VFC Resolution Update for Polio-Containing Vaccines Dr. Chilton made a motion to approve the VFC resolution as stated. Dr. Baker seconded the motion. The motion carried with 14 affirmative votes, 1 abstention, and 0 negative votes. Discussion Dr. Katz said that given the remarks by Dr. Chilton, Mr. Beck, and Dr. Judson, he thought there was an element of reality which had not quite been portrayed. The polio eradication effort was supposed to have ended in 2000, making the effort 9 years behind. Each year, the reported numbers of cases are almost the same. For 2008 it was 1,562 cases. He stressed that those were paralytic cases. For every paralytic case, there can be anywhere from 100 to 1,000 individuals excreting virus silently and causing transmission. Nigeria has had the same numbers of polio cases almost every year for the last 7 years because of failure to deliver vaccine. In contrast, children in India (Uttar Pradesh and Bihar) receive 7 to 10 doses of oral vaccine and they still have not eliminated polio. Thus, there may be a problem with the overall approach. As Mr. Beck pointed out, there is volunteer and donor fatigue. He reminded everyone that both CDC and WHO have committees on polio research and it is quite apparent that the programs followed since 1988 are simply not bringing polio to an end. There must be changes in the initiative, imagination, and funding of CDC and WHO to determine better ways to eradicate polio. Otherwise, they would have to accept it as a disease that will never be eliminated. Overview Ms. Kristen Ehresmann ACIP Member Ms. Ehresmann pointed out that the ACIP measles, mumps, rubella (MMR) vaccine policy statement had not changed since 1998, with the exception of some changes related to the mumps outbreak in 2006. During the 10 years since the last policy statement was published, there was a shift into an era of post-elimination for measles and rubella. It is important to remember this in making decisions and discussing this topic. Decisions should be made that include aggressive follow-up to maintain this post-elimination status. There was vigorous discussion among the MMR Vaccine Work Group members. Within the work group, she was the lone vote with a public health perspective. Therefore, the proposed changes that the CDC staff provided the group did not go over very well and she I was solemnly voted down. The concern of her colleagues was feasibility and cost-benefit for institutions if a fairly strong approach was taken to recommending two doses of vaccination all of the time for persons born before 1957. Thus, they worked with CDC staff to develop excellent compromise language that addressed the concerns of the clinical and public health sectors. The new language was unanimously accepted. It was also presented to the Healthcare Infection Control Practices Advisory Committee (HICPAC) and was approved during their recent meeting. Proposed Changes of MMR Vaccine Evidence of Immunity Requirements for Healthcare Personnel Dr. Kathleen Gallagher Division of Viral Diseases, NCIRD Dr. Gallagher presented an update on the proposed changes to the MMR vaccine evidence of immunity requirements for healthcare personnel. With regard to background, today’s healthcare workers are at increased exposure to a variety of infectious diseases, including vaccine preventable diseases. There are specific recommendations to address vaccination or the corresponding proof of immunity requirements for healthcare workers. The two documents that address those issues were published in the MMWR in 1997 (Immunization of Healthcare Workers) and 1998 (Measles, Mumps, and Rubella—Vaccine Use and Strategies for Elimination of Measles, Mumps, Rubella, and Congenital Rubella Syndrome and Control of Mumps). During the national mumps outbreak in 2006, vaccine policy recommendations for children and high risk groups, including health care workers, were revised including the addition of 1 to 2 doses of the mumps or MMR vaccine. Although these diseases are rare, measles and mumps in health care facilities continue to occur. Virtually all measles cases will visit at least one health care facility during their infectious period. Quite frequently, because measles is not the initial diagnosis suspected, they have multiple health care exposures. A study conducted in Washington State in the late 1990s showed that health care workers had a much greater increased risk of acquiring measles when compared with adults of their own age with the relative risk of 19 (95% CI 7.4, 45.4, p< 0.01) [Steingart KR, Tomas AR Dykewicz CA, Redd SC. Transmission of measles virus in healthcare settings during a communitywide outbreak. Infect Control Hosp Epidemiol. 1999; 20: 115-19]. It is known from measles epidemiology that in the late 1980s and early 1990s, many health care workers were reported with measles (n=643), 27% of whom were born before 1957 [CDC. MMWR. 1998; 47{RR-8}:1-57]. During the 2006 mumps outbreak in the US, there were numerous health care related exposures. It is also known that nosocomial transmission of measles and mumps occurs in health care facilities and has been documented. In the post-elimination era for measles, from 2001-2008 there were 27 reported measles cases that were transmitted in health care facilities, which is about 5% of all US measles cases. In 2008, this was 11% of cases. There is considerable economic expense and a large public health effort involved with trying to contain these exposures and outbreaks. In 2008, Arizona had the largest US nosocomial outbreak of measles in over 20 years (n=14). There were many health care related exposures, not just in the original hospital. In three hospitals in this Arizona community, almost 8000 health care workers were exposed, of whom 25% had no documentation of immunity to measles in their occupational health records. These workers were serologically screened and 5% of the employees born before 1957 and 11% of those born after were susceptible to measles based on serologic testing. Nosocomial transmission of mumps can occur as well. The last well-documented occurrence of this was in Tennessee in 1986 and 1987 when there was nosocomial transmission of mumps in two hospital emergency departments that infected six health care workers and in two long-term care facilities where nine patients were infected. The current ACIP recommendations state that health care personnel without other evidence of immunity should routinely receive two doses of MMR vaccine for measles and mumps and one dose of MMR vaccine for rubella. These recommendations also stress the importance of vaccination to protect healthcare personnel and their responsibility to avoid transmitting these diseases and thereby causing harm to patients. These recommendations also include a permissive recommendation for one or two doses of MMR vaccine for unvaccinated health care workers born before 1957. The current ACIP MMR vaccine presumptive evidence of immunity requirements for health care workers indicate that health care workers are considered to be presumptively immune if they have met one of four conditions: documentation of administration of appropriate vaccination against measles, mumps, and rubella; laboratory evidence of immunity; documentation of physician diagnosed disease for measles and mumps (this is not allowed for rubella); or birth before 1957. The latter three evidence of immunity criteria are what health care personnel are required to provide as far as documentation to be exempt from being vaccinated. There are also numerous footnotes in this language: *May vary depending on current state or local requirements. + Health-care facilities should consider recommending a dose of MMR vaccine for unvaccinated workers born before 1957 who are at risk for occupational exposure to measles and who do not have a history of measles disease or laboratory evidence of measles immunity. The footnotes allow variability with regard to state and local requirements and again provide some permissive vaccination consideration for health care personnel born before 1957. The language for measles and mumps outbreaks states, “During outbreaks, health-care facilities also should strongly consider recommending a dose of MMR vaccine to unvaccinated health-care workers born before 1957 who do not have serologic evidence of measles or rubella immunity or a history of measles disease.” [CDC. MMWR 1998;47{RR-8}:1-57]. The language for a mumps outbreak states, “During an outbreak, health-care facilities should strongly consider recommending 2 doses of a live mumps virus vaccine to unvaccinated workers born before 1957 who do not have evidence of mumps immunity.” [CDC. MMWR Notice to Readers. 2006;55(22):629-630]. The changes proposed during the February 2009 ACIP and HICPAC meetings included the addition of laboratory confirmation of disease, elimination of documentation of physician diagnosed disease for measles and mumps, and elimination of birth year before 1957 to state, “Currently, healthcare personnel are considered immune if they have one or more of the following: 1) Appropriate vaccination against measles, mumps, and rubella (i.e., administration on or after the first birthday of two doses of live measles and mumps vaccine separated by greater than or equal to 28 days and at least one dose of live rubella vaccine); 2) Laboratory evidence of immunity or laboratory-confirmation of disease.” During those two meetings feedback was received from both groups that suggested mixed support for the removal of birth year before 1957 as proof of immunity. Members of HICPAC and ACIP felt that requiring unvaccinated health care workers born before 1957 to be either serologically screened or vaccinated was not cost-effective, especially given the current low burden of disease. Thus, the issue was further discussed with the ACIP Adult Vaccine Work Group along with some external invitees, including some members of HICPAC. Based upon these deliberations, proposed language was developed. The proposed language was presented during the June 2009 HICPAC meeting and was voted on and approved by that body. The first proposed change is the addition of laboratory confirmation of disease as adequate proof of immunity for measles, mumps, and rubella. The rationale for this is that this change is being made for completeness and consistency. Although they are rare, cases of measles, mumps, and rubella still occur. Naturally acquired immunity is robust and long-lasting; therefore, it is reasonable to conclude that if a health care worker can provide laboratory evidence of disease, they should be considered immune. For surveillance purposes, this type of data is routinely relied upon to define whether or not a person is a case of measles, mumps, and rubella. This proposed change will also be consistent with the varicella recommendations which already include laboratory confirmation of disease [CDC. Prevention of Varicella. Recommendations of ACIP. MMWR. 2007;56{RR-4}:1-37]. The second proposed change is to delete the documentation of physician diagnosed disease as adequate evidence of immunity for measles, mumps, and rubella. The impetus behind this change comes from many state and local public health colleagues who anecdotally report situations in which this criterion is not being adhered to as intended. For example, there have been anecdotal reports of scenarios in which physicians on staff at a facility where they are exposed report that they remember having measles as a child, which serves as their documentation of physician-diagnosed measles. In practice, it has become increasingly difficult for any health care worker who may have had clinical measles or mumps to be able to contact their childhood provider as they are either no longer in practice or are deceased. In addition, the accuracy of a clinical diagnosis of disease without laboratory confirmation has declined substantially, especially with vaccine modified disease (mumps). Numerous studies have documented the decline in the predictive value positive of clinical diagnosis (in the absence of lab confirmation) with declines in disease incidence. In the case of mumps, it is known that there are numerous etiologies for non-epidemic parotitis. A study conducted in the early 1970s demonstrated that only 40% of vaccinated patients with parotitis could be lab confirmed as having mumps [Brunell, 1972]. Another study conducted over 30 years later showed that only 2% of 800 clinical mumps cases were lab confirmed and alternative etiologies could be found for 14% of these cases [Davidkins, 2005]. Studies conducted to assist with the documentation of measles elimination in the US showed the PVP declining from 74% to 1% [Hutchins, 2004]. Additionally, 87% of cases of rash illness that met the measles clinical case definition during 1997 / 1998 were ruled out with appropriate lab test [Harpaz, 2004]. Changes are also proposed to the footnotes to the tables, which refer to both routine circumstances and outbreak situations. For routine circumstances, the wording recommended is, “For unvaccinated personnel born before 1957 who lack laboratory evidence of measles, mumps and/or rubella immunity or laboratory confirmation of disease, healthcare facilities should strongly consider recommending two doses of MMR vaccine (for measles and mumps) and one dose of MMR vaccine (for rubella), respectively.” The change here from the current wording would basically be to change the wording from “consider” to “strongly consider” and from one to two doses of MMR for measles and mumps. The recommendations for rubella would remain unchanged. For outbreaks, the wording would read, “For unvaccinated personnel born before 1957, who lack laboratory evidence of measles, mumps and/or rubella immunity or laboratory confirmation of disease, health care facilities should recommend two doses of MMR vaccine during an outbreak of measles or mumps and one dose during an outbreak of rubella.” The change here is a wording change that from “should strongly consider recommending” to just “recommending” and from one doses of MMR to two doses of MMR. The rationale for changing the language in these footnotes is that it allows health care workers born before 1957 to still be considered immune, but also allows facilities that have been screening and / or vaccinating these individuals to have ACIP and HICPAC support to continue this practice. Health care facilities can weigh for themselves the risk of an exposure to measles, mumps, or rubella in their facility and the cost associated to them if such an exposure were to occur. It also allows for aggressive vaccination of health care providers, including those born before 1957, when an outbreak occurs. It is known from anecdotal reports and from surveys conducted in convenience samples that some health care facilities are already screening and / or vaccinating health care workers for measles, mumps, and rubella regardless of age. Of 38 respondents to a survey sent out on an occupational health listserv for health care facilities earlier this year, 26% reported that they conducted serologic screening and / or vaccination of all their employees, regardless of age. An additional 21% reported that they screened and vaccinated all new employees, regardless of age. The footnote wording proposed for routine circumstances will provide the support of ACIP and HICPAC for these facilities to continue these practices. The anticipated burden to health care facilities in implementing these policies is likely to be low. A few health care workers will likely have lab confirmation of disease and there should be little or no cost associated with this change. It would basically be the health care worker having to acquire documentation from their medical provider. The proportion of health care workers with a history of disease as their only documentation of evidence of immunity is likely small, and many of these employees are likely to have been born before 1957. These policies could be implemented with other annual routine disease prevention measures, such as influenza vaccination and tuberculosis (TB) testing. Implementation could be started soon and phased in within a few years. In conclusion, current policy was established more than a decade ago and needs to be updated. In the era of both measles and rubella elimination, the goal is 100% immunity in high risk populations. The tolerance for any cases or exposures has decreased. Health care personnel are at high risk for exposure, so it is important to protect them preemptively. Given the current epidemiology of measles worldwide, it is likely that there will be continued importations in the US, and measles exposures and outbreaks are likely to continue in health care facilities. Future mumps exposures in health care facilities are also likely. Some facilities already have policies in place that are consistent with the proposed changes. Discussion Dr. Baker requested further information about the intent of “strongly recommended” from “recommended” for routine. Dr. Gallagher responded that the original proposal was to remove the 1957 requirement entirely. This was a compromise to provide stronger language in support of facilities that were already doing this even though it was not the current recommendation. It was not clear to Dr. Baker why, if some facilities were already doing this, they needed ACIP’s support. Ms. Ehresmann replied that the rationale was that ideally they would like a statement reading, “It is recommended, even in a routine setting.” However, the work group recognized from the feedback received from clinicians and the membership that this would not be practical or financially feasible for many institutions. Dr. Chilton sympathized with the Tucson hospitals where this occurred, given that this was the largest outbreak in the last 20 years. However, the fact that it involved 8000 health care workers, some of whom were born before 1957, was not persuasive to him that the entire country should be immunizing everybody his age or thereabout. The costs associated with that seemed to be much greater than the benefit associated with adopting a changed policy for that throughout the country. Dr. Gallagher agreed, indicating that this comment was also made during the February 2009 ACIP and HICPAC meetings. The proposed revision would actually allow birth before 1957 to remain as proof of immunity. The caveat was that if facilities were so inclined, the recommendation would support that. The work group heard people’s concern about the cost and benefit of vaccinating everybody before 1957, especially considering that few health care workers have been affected by this. It is also known anecdotally and from the surveys that some facilities are already doing this preemptively because they have made a choice for risk-benefit or other reason in their facilities to vaccinate everybody born before 1957. The work group felt that the proposed language would help support that. Dr. Judson agreed with Dr. Baker that there should probably be only one level of recommendations: recommended or not recommended. He also noted that he was involved in some of the discussions through the Adult Vaccine Work Group on hospital workers, and was head of a hospital infection control committee for about 20 years at Denver General Hospital. There have only been a handful of cases in the US. No cases have been endogenously transmitted for a very long time. All of the outbreaks have stemmed from importations. When he reviewed the state health department records in Colorado, he found that there have been no cases of measles in health care workers and only one or two exposures. Thus, the recommendation is speaking to a problem that does not exist in most places. In another 10 years, this will be completely irrelevant because nobody working then will likely have been born before 1957. Dr. Seward said she perceived these as minor changes to the existing recommendations. She pointed out that it is currently standard of care to vaccinate during an outbreak. Over the last 10 years, she had never come across a health department that did not screen and vaccinate every healthcare worker born before 1957 during outbreaks. That is the current standard of care. Dr. Judson agreed and thought that this was why there was no problem. He did not plan to vote against this. He found these to be very minor issues and that measles control in the US has been highly successful. With regard to Dr. Judson’s comment about one level of language, Dr. Temte reported that two days earlier the Evidence-Based Work Group strongly advised against doing anything other than “recommend” or “do not recommend.” He thought it was also confusing to see “should consider” and “recommend” in quick success. This seemed to be saying, “We should do this, but we are going to back away from this because we are only considering it.” He cautioned that using three partial words together really watered down the recommendation. Dr. Sawyer said that the term “health care facility” suggested to him larger entities that have policy making bodies, which most single private offices probably do not have. It was not clear to him whether this recommendation extended to all places where health care is delivered. Dr. Gallagher responded that when she used the term “health care facilities” in her presentation, frequently it was because the groups surveyed represented larger health care facilities. However, the recommendations would apply to all health care workers. Dr. Sumaya said he had no preference for saying “strongly considered” versus “considered” or “strongly recommended.” He wondered what the difference was in true contraindications. Dr. Marcy wondered why documentation of physician diagnosed rubella was not one of the criteria. Dr. Gallagher replied that rubella cannot be well-diagnosed clinically. Dr. Marcy pointed out that the same was true for measles and mumps, so “physician diagnosed” should be eliminated for them as well. The last three cases he saw of mumps were of neumoparatitis and lymphadenitis. “Physician diagnosed” is simply meaningless. This is still included for international travelers and students at post-high school. He supported use of “should consider” versus “may wish to consider.” Dr. Gallagher responded that the recommendations they were discussing focused only on health care workers. When the full 1998 recommendations are updated, consideration could be given to eliminating “physician diagnosed for international travelers and post-high school students. Dr. Morse pointed out that some agreed upon, standardized criteria should be developed to avoid problems within individual discussions and negotiations. Dr. Meissner inquired as to whether they should say “laboratory evidence of immunity” or if they should be more specific. With the 2006 mumps outbreak, they learned that cellular immunity did not correspond to protection against disease. Dr. Gallagher requested clarification about whether Dr. Meissner was suggesting that something specific be included about types of laboratory confirmation that are acceptable. Dr. Meissner responded that people do not look at cellular immunity as a measure. It is a complicated assay, and cellular immunity is not necessarily a marker of immunity. The question regarded whether to be specific about what constitutes immunity. He was thinking specifically in terms of those born before 1957. Dr. Seward suggested defaulting to the guidance in the surveillance manual for the case definitions and what constitutes confirmation of disease, which is immunoglobulin M (IgM), polymerase chain reaction (PCR) culture, and rise in immunoglobulin G (IgG). Ms. Ehresmann summarized that it appeared that there was agreement for some of the proposed changes. Eliminating physician diagnosis of measles, adding laboratory confirmation, and outbreak seemed to have consensus. They appeared to be stuck on routine circumstances and the language issue (strongly consider, et cetera). She wondered whether it would be possible to make a recommendation to vote on less than everything or address the issues upon which they seemed to be stuck. Dr. Gallagher put up the proposed wording, upon which ACIP members were to vote: Proposed Wording: Table 1 Acceptable presumptive evidence of immunity to measles, rubella and mumps for persons who work in health care facilities* (Table 1) 1) Documented administration of …( 2 doses of live measles virus vaccine, one dose of live rubella vaccine, two doses of live mumps)?, or 2) Laboratory evidence of immunity or laboratory-confirmation of disease, or 3) Born before 1957 & £ @ For rubella, the following statement is included “(except women of childbearing age who could become pregnant ++)” Proposed Language: Footnotes (For persons born before 1957) Footnote for ROUTINE circumstances: £ “For unvaccinated personnel born before 1957 who lack laboratory evidence of measles, mumps and/or rubella immunity or laboratory confirmation of disease, healthcare facilities should strongly consider recommending two doses of MMR vaccine (for measles and mumps) and one dose of MMR vaccine (for rubella), respectively.” Footnote for OUTBREAKS: @ “For unvaccinated personnel born before 1957 who lack laboratory evidence of measles, mumps and/or rubella immunity or laboratory confirmation of disease, healthcare facilities should recommend two doses of MMR vaccine during an outbreak of measles or mumps and one dose during an outbreak of rubella.” Discussion Dr. Seward reminded everyone that the wording in existence from the 1998 iteration is “should consider” for the routine recommendation, and a lot of people are already doing this. Dr. Neuzil wondered whether they wanted facilities to “consider recommending” or “to vaccinate.” Dr. Seward replied that this was pretty standard language that implies vaccinating. Dr. Neuzil thought this should be very clear, “Should strongly consider administering or vaccinating with 2 doses.” Dr. Judson noted that the positive predictive value of a clinical diagnosis of mumps and rubella was never very good, except in an epidemic or a very common situation, so it was probably worthless. Most physicians could diagnose measles very well when the disease was occurring frequently; however, now they cannot. Positive predictive value becomes virtually meaningless for measles which barely exists except for the occasional importation. Citing studies from the 1990s or 2000s really has no meaning to current deliberations. He thought “clinical diagnosis” should be removed in all cases as evidence of immunity. Ms. Ehresmann pointed out that they appeared to have reached consensus on everything but the routine circumstance. The 1998 language says “should consider recommending,” for which a suggestion was made to more clearly specify vaccinating versus recommending. With that in mind, she wondered if they could move forward with a vote. She was unclear on the use of the term “strongly” because there was a lot of discussion that it was not appropriate to use modifiers. Dr. Pickering thought that the evidence-based medicine guidelines were not quite finished, but there is a move toward evidence bases for everything. Most evidence-based guidelines do not include adverbs as descriptors. Dr. Katz wondered whether “two doses of MMR vaccine,” could be stated as “two properly spaced doses.” Dr. Gallagher replied that this wording is in the table, but they could add it to the footnote or refer back to the table to define what “appropriately administered” means. Motion 1: MMR Vaccine Evidence of Immunity for Healthcare Personnel Ms. Ehresmann made a motion to approve the recommendation of the work group for evidence of immunity for healthcare personnel with the suggested changes. Dr. Baker seconded the motion. No vote was take, given that the discussion continued. Following up from the HICPAC perspective, Dr. Elward pointed out that in the discussion during the February 2009 ACIP meeting, concern was expressed about making across the board recommendations of vaccination in routine circumstances due to the cost implications and the unfunded mandate it might impose on health care facilities in the absence of evidence that there are problems with measles control outside of outbreak situations. She indicated that HICPAC approved the language shown with these footnotes. Dr. Morse noted that consideration should be given to whether ACIP was comfortable with having a different recommendation from HICPAC. Dr. Seward said it would be preferable for the ACIP recommendation to be the same as HICPAC. Dr. Schuchat reminded everyone that HICPAC and ACIP are advisory committees to CDC. CDC will utilize the committees’ recommendations to develop and issue final recommendations. Therefore, it is unlikely that there would be two different recommendations. CDC is trying to harmonize with itself. Dr. Cieslak proposed that they remove the footnote for routine circumstances from the motion. Dr. Gallagher wondered whether, based on the wording changes suggested for the first footnote, a change needed to be made to the wording on the second footnote to make the language consistent (e.g., change the word “recommend” to “vaccinate”). Dr. Neuzil stressed that they were not making the recommendation for facilities to consider recommending. She believed they were making a recommendation to vaccinate, which was her interpretation of what she was voting on. Dr. Chilton pointed out that based on the data presented, it appeared that only 5% of those born before 1957 would be susceptible. Therefore, the cost to prevent cases to those born before 1957 who are exposed to measles, mumps, or rubella is about $2,800 per person. That seemed unacceptable. Dr. Judson added that an arbitrary cut off had been established for immunity for which there is no real basis. He thought 5% may be a very high figure. That is, probably well less than 5% would actually be susceptible. Motion 2: MMR Vaccine Evidence of Immunity for Healthcare Personnel In light of the comments made by Drs. Schuchat and Seward, Ms. Ehresmann revised her motion to approve the recommendation of the work group for evidence of immunity for healthcare personnel as it was written to be consistent with HICPAC. Dr. Baker withdrew her second and Dr. Sawyer seconded the revised motion. The motion did not carry with 4 affirmative votes, 0 abstentions, and 11 negative votes. Motion 3: MMR Vaccine Evidence of Immunity for Healthcare Personnel Dr. Baker made a motion to accept the footnote for outbreaks as listed and modify routine circumstances to read “for unvaccinated personnel born before 1957 who lack laboratory evidence of measles, mumps and / or rubella immunity or laboratory confirmation of disease, health care facilities should consider vaccinating personnel with two doses of MMR vaccine at the appropriate interval.” Dr. Neuzil seconded the motion. The motion carried with 11 affirmative votes, 0 abstentions, and 4 negative votes. Dr. Cieslak requested clarification regarding whether this actually represented a change. The old language did not discuss the number of doses for routine vaccination. Dr. Seward replied that the old language was one dose for measles and one dose for rubella and until 2006, it was one dose for mumps. In 2006 it was changed to two doses for mumps, which is the current routine recommendation. The measles is the most severe of the three illnesses, so they thought it was logical to make the routine recommendation consistent for outbreaks and give two doses for measles as well. For routine, it was a change from one dose to two for measles. It is currently two doses for mumps. That was changed in 2006. It has always been one for rubella because rubella is basically a one-dose policy. This is just making it consistent for measles and mumps. Dr. Judson said there was a scientific dissidence. For the outbreaks having two doses, he did not believe there was any evidence or immune-competent adults to suggest that a second dose would do anything to respond to an outbreak. By the time this second dose is administered, the outbreak is over and the population is generally immune, especially for measles. It was noted that the outbreak in Arizona lasted for about 5 months. Overview Janet Englund, MD Chair, ACIP HPV Vaccine Workgroup Dr. Englund indicated that during this session, members would be hearing about two issues that would soon be coming up for an ACIP vote: 1) bivalent HPV vaccine in females, last discussed with ACIP in October 2008; and 2) quadrivalent HPV vaccine in males, not previously considered by ACIP. The bivalent HPV vaccine is a two-component HPV vaccine. The biologic license for application was first submitted with interim data from the phase III vaccine trial in 2007. Following feedback from the FDA, GlaxoSmithKline (GSK) decided to wait for end-of-study data, which was submitted to the FDA in March 2009. The HPV Vaccine Work Group is preparing for an ACIP vote, which may take place in October 2009. Therefore, data are being presented to the full ACIP membership during this session so that they would be prepared for the potential upcoming vote. Also, a supplementary BLA was submitted for the quadrivalent HPV vaccine in males in December 2008. The HPV Vaccine Work Group is likewise preparing for a potential ACIP vote in October 2009. Workgroup activities throughout the past several months have included a great deal of discussion about the bivalent HPV vaccine and the quadrivalent HPV vaccine. Bivalent HPV vaccine discussions have included ASO4 adjuvant mechanism of action / meta-analysis of adverse events, final Phase III efficacy results and cross protection data, comparative bivalent / quadrivalent immunogenicity, co-administration with other adolescent vaccines, and potential recommendations. Quadrivalent HPV vaccine in males discussions have included safety and efficacy in males, acceptability of male vaccination, cost-effectiveness, and recommendation options. Update on GSK Cervical Cancer Candidate Vaccine (Cervarix®) Including Final Efficacy Results Gary Dubin, MD GlaxoSmithKline Dr. Dubin provided the committee with an update on new clinical data available for the GSK cervical cancer candidate vaccine Cervarix®, including an update on the current regulatory status of the vaccine. The GSK vaccine is formulated with HPV 16 and HPV 18 virus-like particles and the AS04 adjuvant system which includes aluminum hydroxide salts and monophosphoryl lipid A. AS04 is included in the vaccine because in early clinical development, it was shown to enhance immune responses to the virus-like particles. GSK has conducted an extensive clinical development program, including approximately 30,000 women ages 10 years and up. Cervarix® is now licensed in over 95 countries, including the 27 countries of the European Union (EU). In some of these countries, there are on-going post-licensure activities to generate additional information in the real-world use setting. There are new clinical data that were submitted to the FDA in March 2009. The Center for Biologics Evaluation and Research (CBER) review clock is now re-started. The primary new clinical data include final efficacy data from the pivotal trial of HPV-008, which was presented previously as interim data. There were a number of previous ACIP presentations between 2005 and 2009, which included the following: * Phase 2 data: vaccine efficacy, safety and immunogenicity (including long-term follow-up) [Harper DM et al. Lancet 2004; 364:1757-65; and Harper DM et al. Lancet 2006; 367:1247-55] * Interim results of pivotal Phase 3 efficacy trial in 15-25 year olds [Paavonen J et al. Lancet 2007;369:2161-70] * Age bridging data in 10-14 and 26-55 year olds [Pedersen C et al, J Adol. Health 2007, 40(6):564-71; and Schwarz T et al. Vaccine 2009; 27(4):581-7] * Integrated safety analysis from 11 trials involving ~30,000 women (~16,000 receiving active vaccine) [Descamps D et al. Vaccine 2009, 5(5) [Epub]] * Meta-analysis of autoimmune diseases with ~68,000 subjects in clinical trials (~37,000 receiving AS04-containing vaccines) [Verstraeten T et al. Vaccine 2008, 26(51):6630-8] * Adjuvant system mechanism of action The new data upon which Dr. Dubin focused during this session included the following: * Final efficacy analysis of pivotal Phase 3 trial (HPV-008) * Comparative study of immunogencity and safety of GSK vaccine and Gardasil® (HPV-010) [Gardasil® is a registered trademark of Merck & Co Inc.]. The HPV-008 study enrolled over 18,000 women in 14 countries. It was a double blind randomized trial in which subjects received either the HPV vaccine or Hepatitis A vaccine as a control. It was an event-triggered study in that the interim analysis was event-triggered and the final analysis was triggered by the requisite number of cervical intraepithelial neoplasia (CIN)2+ events that were pre-specified in the study protocol. Subjects were followed for 48 months in this study. When the interim analysis was conducted, the mean follow-up time completed at that point had been 15 months for follow-up on average following the first dose of vaccine. With the final analysis, the mean follow-up time was about 39 months following the first dose of vaccine. Thus, there was a considerable amount of additional follow-up time and many more end points accrued that made this analysis much more statistically powerful than the interim analysis. An end-of-study analysis will be conducted when all subjects complete the 48 months of plan study follow-up. The primary objective of the study was to assess efficacy against CIN2+ associated with HPV16 or 18. This was assessed in the according to protocol (ATP) cohort and importantly, the endpoint was evaluated in women who were DNA negative and CR negative at month 0 and DNA negative at month 6 for the HPV type considered in the analysis, so very much an ATP analysis. There are important secondary and exploratory objectives assessed in this study, which included the assessment of efficacy against CIN2+ and CIN3+ lesions, irrespective of the HPV type detected in the lesion; efficacy against persistent infections and CIN2+ lesions associated with non-vaccine oncogenic types; evaluations on the vaccine impact in reducing the need for colposcopy and on cervical excision procedures (including LEEP, laser knife, or cone biopsy); and vaccine safety. The interim analysis was triggered when 23 cases of the primary endpoint were observed in the total vaccinated cohort, which was met in November 2006. The results from that interim analysis were published in 2007 [Paavonen et al, Lancet, 2007;369:2161-70]. The final analysis was to be triggered when at least 36 cases of the primary endpoint, CIN2+ associated with HPV-16 or 18 were observed in the ATP cohort. This trigger was met in October 2008. The CIN2+ endpoint assessments used HPV DNA detection methodology that was published previously. This detection system allows detection of 14 oncogenic HPV types, including HPV16 & 18. Two types of analyses have been performed. One analysis was the pre-specified analysis, which evaluated the association of virus and the CIN2+ lesions just by simple DNA detection. An additional analysis using an HPV Type Assignment Algorithm (TAA) to assign likely causality in cases where multiply infected lesions were detected was also performed. Understanding the cohorts that were evaluated in the HPV-008 trial is important because there are a number of different evaluations. The total vaccinated cohort (TVC) included all women who received at least one dose of vaccine regardless of their baseline cytologic, serologic, or HPV DNA status. This cohort included over 18,000 women and case counting started on day 1. Another cohort evaluated was the according-to-protocol cohort. This cohort included all women who complied with the protocol, received all 3 doses of study vaccines and had normal or low-grade cytology at month 0. An additional cohort evaluated is referred to as the TVC naïve. This is a subset of the TVC, which included all women who received at least one dose of vaccine and who, at baseline, had normal cytology, were HPV DNA negative for all 14 oncogenic types detected in GSK’s assays, and were seronegative for HPV 16 and HPV18 at study entry. These two cohorts are believed to be important because they approximate groups that have public health relevance. The TVC cohort approximates the general population, which includes sexually active young women with prevalent infections and lesions. The TVC naïve cohort approximates the primary target population for universal vaccination programs, mostly young women before onset of sexual activity or before sexual debut. With respect to the results of the primary objective, vaccine efficacy against CIN2+ lesions associated with HPV16 and 18 was high and statistically significant using either the composite endpoint of the two HPV types considered in the analysis, HPV16 or 18, or considering the two types individually. The analysis using the Type Assignment Algorithm (TAA), was to assign causality in lesions with multiple infections, also showed very high level of efficacy—about 98% protection for the composite endpoint. As mentioned earlier, the primary endpoint only considered lesions in women who were seronegative as baseline for the respective type considered in the analysis. GSK, therefore, evaluated the primary objective in women irrespective of their baseline serostatus. This is a larger group of women, including women who were seropositive or seronegative at entry. The high level of efficacy is maintained in this broader cohort with point estimates that are actually quite similar than the estimates seen in the more restricted primary endpoint analysis. Vaccine efficacy was also evaluated against HPV 16 and 18 CIN2+ lesions in the TVC naïve and the TVC cohorts. Vaccine efficacy was very high in the TVC naïve cohort at over 98%. In the TVC cohort, vaccine efficacy was 53%. It should be noted, however, that the CIN2+ lesions in this analysis included lesions associated with pre-existing infections—an important point to consider. Another important analysis in the assessment of vaccine efficacy was evaluating efficacy, not only against CIN2+ lesions associated with HPV16 or 18, but evaluating efficacy against lesions irrespective of the HPV type in the lesions. These analyses are important because they provide perspectives on the overall public health impact that the vaccine is expected to provide against clinically relevant lesions irrespective of whether it is a vaccine type. In the TVC naïve cohort, the vaccine prevented about 70% of CIN2+ lesions and about 87% of CIN3+ lesions overall. An epidemiologic estimate of the proportion of CIN2+ and CIN3+ lesions associated with HPV 16 and 18 suggests that the vaccine efficacy extends beyond what would be expected of a vaccine that would provide protection only against vaccine types. Regarding the results in the TVC cohort, efficacy against CIN2+ and CIN3+ lesions was 30% and 33% respectively. Again, however, it should be noted that the majority of these endpoints were the result of pre-existing infections. That point is emphasized in terms of the cumulative incidence of lesions over time in the TVC. Lesions development occurs at the same rates in both the vaccine and the control groups until about month 18 when there begins to be separation of the curves. This is because most of the lesions that develop early in the trial, during the first 18 months, were derived from pre-existing infections. It is only after there is a wash out of these lesions that the prophylactic affected the vaccine becomes apparent, during the latter part of the follow-up. The efficacy of the vaccine was also evaluated in the prevention of colposcopy referral and cervical excision procedures, which included LEEP, laser knife, or cone biopsy. These endpoints have public health relevance. Additionally, cervical excision procedures may be linked to subsequent issues like cervical incompetence. In both the TVC naïve and the TVC cohort, substantial reductions are observed in these important endpoints. In regard to efficacy data against CIN2+ lesions associated with non-vaccine oncogenic HPV types, efficacy was evaluated using composite endpoints for a number of oncogenic HPV types. Efficacy was also evaluated individually for a few of the most important vaccine types. Vaccine efficacy against HPV 31 and 45, considered as a composite endpoint in the TVC naïve cohort, was 100% and in the TVC cohort was 52%. Again, many of the lesions in the TVC were the result of pre-existing infections. There were substantial and significant reductions in CIN2+ lesions associated with composites of HPV types that constitute the A9 species. The A9 species is the family of viruses that are phylogenetically related to HPV 16. Significant reductions were also seen in CIN2+ lesions associated with viruses in the A7 species, which are viruses phylogenetically related to HPV 18. With regard to the 10 most frequent HPV types associated with cervical cancer, there was a significant reduction in CIN2+ lesions associated with these types, evaluated as a composite endpoint. Pertaining to HPV 31 and HPV 45,, there was a high level of protection against 6 month persistent infection and CIN2+ lesions for HPV 31. For HPV 45, there was a high level of protection against 6 month persistent infection in the TVC naïve. While there were a limited number of CIN2+ cases associated with HPV-45, there were no cases in the vaccine group. In the TVC cohort, there was statistically significant evidence of efficacy against lesions associated with both HPV 31 and HPV 45 CIN2+ lesions and also persistent infection. Most of the safety data from the trial were published at the time the interim analysis was conducted. However, long-term outcomes, such as the occurrence of serious adverse events, medically significant conditions prompting physician visits, new onset autoimmune diseases, and pregnancy outcomes were assessed through the long-term follow up phase of this study. For each of these safety endpoints, the occurrence rates were quite similar between the vaccine (N = 9,319) and the control (N = 9,325) groups. Serious adverse events (SAE) were 7.5% in each the vaccine and control group. Medically significant conditions (e.g., prompted a physician visit) were 31.8% in the vaccine group and 32.4% in the controls. New onset autoimmune disease was 0.8% in each group. In terms of selected pregnancy outcomes, congenital anomalies were 0.7% in the vaccine group and 0.5% in the controls, and spontaneous abortions were 9.1% in the vaccine group and 8.7% in the controls. To conclude on HPV-008, the trial confirms vaccine efficacy against CIN2+ associated with HPV 16 and 18 as a composite endpoint or with the two vaccine types considered separately. The study also showed significant impact on CIN2+ and CIN3+ lesions overall, irrespective of the HPV type found in the lesion, and irrespective of the baseline DNA status of subjects. Efficacy was observed against CIN2+caused by specific non-vaccine types. A significant impact was seen on colposcopy referrals and cervical excision procedures. Consistent with what was observed in the interim analysis of this study, the final analysis confirms a favorable safety profile. Regarding the HPV-010, this is the first head-to-head study comparing the GSK vaccine and Gardasil® with respect to immunogenicity and safety. High efficacy has been observed for both vaccines in the pre-licensure setting. Any differences in the long-term protection between the two vaccines, if they exist, are unlikely to become apparent for many years. Additionally, apparent differences in the cross protection profiles of the vaccines could potentially be related to immunologic responses against vaccine antigens. It is important to note that published immunogenicity data on the two vaccines cannot be compared directly because of differences in study methodologies and differences in serologic assays. This study is the first head-to-head comparative study evaluating the two licensed vaccines. GSK’s vaccine is not licensed in the US, but is licensed in other countries using the same methodology to assess immunogenicity and safety. The composition of the two vaccines is an important consideration in thinking about the results. The GSK vaccine contains 20 micrograms each of HPV 16 and HPV 18 virus-like particles. The antigens are expressed in a baculovirus expression vector system and the vaccine contains the AS04 adjuvant system. Gardasil® contains 40 micrograms of HPV16, 20 micrograms of HPV 18, and additionally the vaccine contains HPV 6 and 11 virus-like particles. The virus-like particles are expressed using a yeast system and the vaccine contains an aluminum hydroxyphosphate sulphate adjuvant. The primary objective of the study was to compare the geometric mean antibody titers (GMTs) for HPV 16 and 18 using seroneutralizing antibodies as the measure at month 7. That is one month after completion of the three-dose series for both vaccines in women aged 18-26 years. This testing was performed at the GSK biologicals labs using a pseudovirion-based neutralization assay (PBNA) developed by the National Cancer Institute (NCI) [Pastrana et al. Virology 2004;321:205-16]. There were some important secondary endpoints assessed in the study, which included serum neutralizing geometric mean antibody titers in month 7 in women in 2 other age strata: 27 to 35 years and 36 to 45 years. Neutralizing antibody levels were assessed in cervico-vaginal secretions (CVS) using PBNA. The frequency of antigen-specific memory T-cells and B-cells were assess, as were reactogenicity and safety. The HPV-010 study was conducted in 40 US study centers using observer blind methodology, which is the highest level of blinding possible given the use of commercial supplies of Gardasil®. Over 1100 women between the ages of 18 and 45 years were randomized to receive vaccine according to the schedules either 0, 1, 6 months for the GSK vaccine or 0, 2, 6 months for Gardasil®. A single dose of aluminum hydroxide placebo was administered either at month 2 in the GSK vaccine group or month 1 in the Gardasil® group to maintain the study blind. Enrollment was stratified into 3 age strata between 18 and 45 years of age. Importantly, statistical criteria to assess immunologic differences between the vaccines, including tests of statistical superiority for the immunogenicity endpoints, were all pre-specified. Regarding the primary and secondary age stratified analyses, in each of the three age strata, the GMT for the GSK vaccine group compared to the Gardasil® group were statistically significantly higher in the GSK group versus the group of women receiving Gardasil®. The HPV 16 neutralizing antibody geometric mean antibody titers, assessed at month 7, were between 2- and 5-fold higher in the GSK vaccine group depending on the age strata. The HPV 18 neutralizing antibody geometric mean antibody titers, assessed at month 7, were between 7 and 9 fold higher. Remember, the antigen content of the two vaccines differs for HPV 16 in that Gardasil® has 40 micrograms of HPV 16 virus like particles and the GSK vaccine has 20. For HPV 18, the two vaccines have the same relative antigen content. Positivity rates at Month 7 for HPV-16 and -18 antibodies measured in cervico-vaginal secretions (CVS) by PBNA (women 18-45 years) was higher with GSK Vaccine than with Gardasil®. The frequency of circulating antigen-specific memory B-cells at Month 7 was 2.7-fold higher with GSK vaccine than with Gardasil® for HPV-16 and HPV-18 . The frequency of CD4+ T-cell responses at Month 7 was significantly higher with GSK vaccine than with Gardasil® for HPV-16 and HPV-18. Turning to the safety evaluations, a higher percentage of women in this study who received the GSK vaccine reported solicited local symptoms within the 7 days after any vaccine dose. Symptoms in both groups tended to be transient, and all of the solicited symptoms resolved within the 7 day observation period. Solicited general symptoms were generally comparable, except for fatigue and myalgia which occurred at a somewhat higher rate in the GSK vaccine group. Again, these symptoms were transient, and resolved. Unsolicited symptoms, including serious adverse events, occurred at similar rates in the two groups. Importantly, when compliance with completion of the three dose course in the two groups was assessed, the compliance levels were high and comparable. Both groups had about 84% of subjects completing the three-dose schedule. In conclusion, in the HPV-010 study in month 7 after vaccination, immune responses were significantly higher with the GSK vaccine compared to Gardasil®. This included parameters such as serum neutralizing antibody responses and antibody positivity rates in CVS, memory B-cell frequencies, and T-cell frequencies. The vaccine safety profiles were consistent with previous studies of both vaccines. The differences observed in reactogenicity did not impact compliance with completion of the 3-dose course. GSK believes that long-term follow-up evaluations in the post licensure setting will be helpful to assess the duration of protection with the two vaccines, and will also help to determine the clinical relevance of the observed differences in immune responses from this study. Overall conclusions and observations are that HPV-008 efficacy data confirm the efficacy of the vaccine against CIN2+ associated with vaccine types, and extends the efficacy profile of the vaccine including demonstration of an impact on the CIN2+ overall and associated with non-vaccine types, including HPV 31 (HPV-16 related) and HPV 45 (HPV-18 related). The HPV-010 data confirmed that the GSK vaccine and Gardasil® induced different immunologic responses. The differences in responses were observed for both HPV 16 and 18 components, although the largest differences observed were for HPV 18 where the two vaccines have the same virus like particle (VLP) dosage. Although the importance of these differences is unknown, they may represent determinants of duration of protection against HPV16 or 18 and / or protection against non-vaccine types. GSK thinks it is important to recognize that disease modeling will help to determine how the observed differences in vaccine profiles might ultimately translate into differences in the public health impact of the vaccines. These data, taken together with long-term data from Phase II efficacy studies, indicate that the GSK HPV vaccine is likely to provide long-lasting protection against cervical cancer. Discussion Dr. Judson asked whether there was any reason to think that the superior neutralizing antibody response in the GSK vaccine was related to a difference in adjuvants. Dr. Dubin replied that although it was difficult to know for sure. most of the evidence suggested that it was the adjuvant that resulted in the difference. This comes from previous studies that have compared different formulations of GSK vaccines using AS04 or aluminum hydroxide as an adjuvant, in which the results were very similar to those observed in the 010 study. Significantly higher neutralizing antibody titers were observed with the AS04 adjuvant compared to aluminum hydroxide, and a slightly higher rate of reactogenicity is observed. It is hard to know whether they are mechanistically related, although they certainly could be. In the analysis of the reduction in CIN2+ due to the non-vaccine serotypes, Dr. Marcy wondered how many of the infections ascribed with non-vaccine serotypes were dual infections with 16 and 18, such that some of that response could be due to the 16/18 response. Dr. Dubin responded that it was now very clear when data from these large studies are evaluated that it is not uncommon to have lesions where multiple HPV types are detected. The analyses shown were pre-specified in which they assessed only the types that were considered in the analysis. That being said, GSK has conducted additional analyses in which lesions that contain HPV-16 or 18 co-infections have been removed and there is still evidence of statistically significant protection against CIN2+ lesions. Some of this data will be available in the public domain soon. It was not presented here because there was limited time to go through the complexity of multiple infections. It is hard to know when there are multiple infections which type is actually is driving the lesions, so an analysis that excludes co-infected lesions is considered to be a very conservative analysis. An analysis that does not exclude them is considered to be the other end of the spectrum. Therefore, the results from these two kinds of analyses represent a range that probably reflects the spectrum of cross-protection. Dr. Meissner noted that the concentration of antibodies necessary to neutralize 31 and 45 presumably was higher than the concentration necessary to neutralize 16 and 18 because those were in the vaccine itself. As time goes by, with waning titers, he wondered whether the ability of those antibodies to neutralize the non-vaccine serotypes may be reduced or even disappear. Dr. Dubin stressed that it was important to point out that, with respect to the mechanism of cross protection, it is not clear whether it is an antibody-mediated phenomenon or whether it is related to induction of T-cell responses. That is one of the reasons that some of the GSK studies not only assessed antibody responses, but also, as in the 010 study, they assessed T-cell reactivity. In the HPV-008 study, there are now data out through 3 ½ years, so what he showed was a cumulative estimate of efficacy over that time period. There are also data, not shown here, from another study in which efficacy has been assessed out through 7.4 years (not using CIN2+ as the endpoint, but in one of the Phase II studies) in which incident infection was an endpoint. There is evidence of sustained protection against both HPV31 and 45 through that entire follow-up period, which GSK believes will predict protection against associated lesions as they continue to engage in follow-up in this program. Dr. Neuzil thought that the best information regarding the public health impact of this vaccine on cervical cancer was the overall vaccine efficacy against CIN2+ and CIN3+ irrespective of HPV type in the lesion [Slide 12]. Dr. Dubin agreed. Two cohorts are analyzed. The broadest is the TVC cohort that includes all women enrolled in this study regardless of their baseline serostatus and regardless of what type was ultimately detected in a lesion. The point estimate of efficacy, again CIN2+ of 30%, is what would be expected if the vaccine were introduced into a population of women that includes women who have pre-existing infections and pre-existing lesions. The TVC naïve cohort is a subset of that cohort and includes only women who had no evidence of oncogenic infection at entry into the study. Other than that, there are no restrictions. Regarding the data on local adverse effects, Dr. Duchin (NACCHO) inquired as to whether Dr. Dubin could show them the data on general adverse effects, which he mentioned was higher in the GSK vaccine for fatigue and myalgia. Dr. Dubin responded that the solicited general symptoms were generally comparable for both vaccines except for fatigue and myalgia Dr. Baker asked about syncope for each group. Dr. Dubin replied that in the larger study there were 18,000 subjects. In that study, there were reports of syncope, but they occurred at the same rates in the two groups. In fact, he thought the numbers were exactly balanced with a total of 11 subjects in the HPV group and in the Hepatitis A control group that had syncope develop after vaccination and one subject in each group who developed pre-syncope. GARDASIL® Update: Safety & Efficacy in Boys and Men Richard M. Haupt, MD, MPH Clinical Research Infectious Diseases & Vaccines Merck Research Laboratories Dr. Haupt reminded everyone that he had presented a lot of these data during the February 2009 ACIP meeting. In addition to presenting data on boys and men from the safety and efficacy study, Protocol 20, designed specifically to assess disease and infection endpoints, Dr. Haupt presented immunogenicity data in 9 to 15 year old males. These data were collected over 5 years ago from an immunobridging study, which was submitted to the FDA with the original biological license application. During this session, Dr. Haupt focused on the immunogenicity data in male subjects 9 to 15 years of age, and the efficacy and safety data in 16-26 year-old men. In the clinical program for men and boys there are two adolescent studies, Protocols 16 and 18. Protocol 16 was an immunobridging and safety study in which immune responses were examined using the Merck competitive Luminex immunoassay. This was assessed in 10 to 15 year old adolescent girls and adolescent boys and compared to a control group of 16 to 23 year old women as a means to bridge the efficacy being observed in women 16 to 23 years of age to that of the adolescent population. Protocol 18 was an immunogenicity and safety study of GARDASIL in 9-15 year-old boys and girls. This protocol also included a saline placebo arm to evaluate reactogenicity. It was a safety study that examined immunogenicity and safety, and included both the aluminum adjuvant as a control arm and a saline placebo only. That study was extended to a 36-month follow-up, and has subsequently been extended to a long-term effectiveness study. Merck is following both girls and boys in that study for 10 years to assess long-term effectiveness and safety. Disease endpoints are being collected over time from that population. Protocol 20 is the male study. It is a randomized, double-blind, placebo-control trial. It was designed to be a 36-month study. Earlier on 2009, based on the very high efficacy demonstrated and the safety profile, Merck’s data and safety monitoring review board recommended that this study be ended early and that vaccination of the placebo recipients be started. Based on that recommendation, the 36-month study plan will be shortened. The study enrolled heterosexual as well as men having sex with men (MSM), for a total of about 4000 subjects of whom about 600 are in the MSM population. For men enrolled in this trial, Day 1 polymerase chain reaction (PCR) and serology result were obtained for the 4 types in Gardasil® (6/11/16/18). Men were excluded who had more than 6 lifetime sex partners, so a lower risk population is represented. However, they could still have had as many as 5 lifetime sex partners. The point is that when men were examined across the board in this study, about 83% were naïve at baseline to all four types. That offers a sense of the susceptibility of a sexually active male population to the vaccine types that are in Gardasil®. There is a great opportunity to prevent infection / disease caused by these four types—even in men who are sexually active. Regarding disease endpoint efficacy, the primary endpoint was a 6/11/16/18 related external genital lesion (EGL). EGL was a composite endpoint that included genital warts and PIN of any grade. PIN is defined as penile, perineal, or perianal intraepithelial neoplasia. Primary endpoint efficacy was very high at 90%, which is highly statistically significant. This is driven predominately by genital warts. There were three cases in the Gardasil® group, 28 for genital warts in the placebo, for vaccine efficacy of 89.4%. There was 100% efficacy against PIN, although there were very few numbers. PIN is a fairly rare condition and this study was never powered to demonstrate efficacy against PIN. It was designed as an extension to examine infection and disease endpoints and to demonstrate efficacy in males for specific disease endpoints. There were two secondary objectives that were infection endpoints. One was efficacy against the persistence of infection. Much like in the women’s studies, that is defined as persistent infection with two or more consecutive positive samples with the same HPV type 6 months apart. There was also an anytime DNA detection, which is a large category that includes any one-time positivity whatsoever (swab, biopsy, et cetera). Persistent infections are very important as a predictor for disease development. There was approximately 86% efficacy. The efficacy against individual types in that analysis was high for all four types, and there was modest efficacy in the endpoint of anytime DNA detection. Immune response was examined measured with Merck’s competitive Luminex immunoassay, which is an assay that measures one specific neutralizing antibody against a known neutralizing epitope. The bottom line is that much like what has been observed in women, the virus-like particles (VLPs) in Gardasil® are highly immunogenic. There was virtually 100% seroconversion as measured in the peak response at month 7. There were very high geometric mean titers (GMTs). As with GMTs in women, over time as measured by Merck’s assay, some individuals reach a point at which their antibody level cannot be measured. However, continued efficacy is observed even in the face of that. In terms of general safety, and much like was seen in women, the most common adverse events observed in men were local injection site reactions. It was the most common vaccine-related adverse event as well. In the boys and men, very rare serious adverse events were seen and none were observed that were vaccine related. Very few men who discontinued, and they certainly had very few discontinued to what was considered to be vaccine related. In addition, Merck examined immune response in 9 to 15 year old adolescent boys. There are times when efficacy studies in certain sub-populations cannot be conducted. This is one of those experiences where it would be unfeasible to conduct an efficacy study because of issues of sexuality and genital sampling. In discussions with the FDA, it was agreed that immunobridging to this population was an appropriate way to infer efficacy in the 9-15 year old population to demonstrate that immune responses to GARDASIL® in 9- to 15-year-olds are non-inferior to those in 16- to 26-year-olds and to demonstrate that GARDASIL® is well-tolerated in 9- to 15-year-olds. The data from 9 to 15 year old adolescents across all four vaccine types demonstrated a non-inferior immune response. In fact, an immune response in the adolescent boys was 2- to 3-fold on average higher than what was observed for adult males. In terms of immune response to HPV 6, there is a higher level in the younger adolescent and then it declines as the boys go through puberty and reaches a similar level across the older age groups studied. This profile is virtually identical for the other three types (11, 16, 18). The same profile has been observed in women as well. There is nothing different about the adverse event profile in the younger adolescent boy populations. The most common adverse event was local injection site reactions to the vaccine. There were very few serious adverse events and very rare discontinuations due to vaccination. In summary with respect to safety and efficacy in boys and men, genital HPV infections lead to a significant burden of disease in men. HPV 16 and 18 are important cancer-causing HPV types in men and are responsible for the majority of HPV-related penile, anal, and oropharyngeal cancers and their associated pre-cancers. HPV types 6/11 cause over 90% of genital warts and RRP. GARDASIL® is highly efficacious against HPV 6/11/16/18-related persistent infections and genital warts in men. This efficacy may also translate to reduced transmission of vaccine type HPV strains between sexual partners. Immune response in 9 to 15 year-old boys is non-inferior to the immune response in16 to 26 year-old men. GARDASIL® was generally well-tolerated in 9 to 26 year-old boys and men. Vaccination of boys and men will contribute to an additional public health benefit of GARDASIL®. Dr. Haupt concluded with the following list of completed and on-going studies: * 018-20 (Adolescent Long-Term Safety & Effectiveness) --> Duration of efficacy of GARDASIL® --> Impact of GARDASIL® on rates of disease caused by non-vaccine HPV types --> Long-term safety & immunogenicity of GARDASIL® * 021(HIV-Infected Children) --> To evaluate the safety & immunogenicity of GARDASIL® in HIV-Infected children --> To determine the impact of nadir CD4 counts (prior to institution of ART) on peak immune responses to GARDASIL® * 024 (Concomitant REPEVAX™ [Tdap-IPV]) * 025 (Concomitant ADACEL™ & MENACTRA™) * 036 (HIV-Infected Men [AMC]) --> Safety & immunogenicity of GARDASIL® in HIV-infected men * 046 – Sub-Saharan Africa --> Safety & immunogenicity study Discussion Dr. Meissner inquired as to whether Dr. Haupt cared to respond to the data that was presented by GSK showing antibody titers 2- to 9-fold higher against 16 and 18 at 7 months follow-up, and what clinical significance he thought this had, particularly in terms of long-term immunity and need for booster doses. Dr. Haupt concluded what it is certainly interesting data, but it is not clear that those differences really correlate with any difference in efficacy or duration of protection. At this point, it is known that both vaccines are highly immunogenic and a lot of antibody is produced by both vaccines depending upon which assay is used and how it is measured. Whether those differences are clinically meaningful is completely unclear at this time. Dr. Marcy inquired as to whether genital warts were divided into circumcised and uncircumcised men. Dr. Haupt responded that they captured circumcision data on male subjects who participated and examined efficacy for all endpoints based on different baseline covariates. Efficacy was assessed based on baseline circumcision, and no difference was observed. It did not appear that circumcision impacted efficacy. There are some other natural history data pertaining to the impact of circumcision and use of condoms. However, from a pure efficacy perspective, the vaccine is highly efficacious no matter what baseline determinant somebody has. Dr. Judson asked whether there had been any demonstrated differences of any type between the Merck and GSK VLPs. Dr. Haupt responded that the vaccines are manufactured very differently. It is very likely that even though they are 16 / 18 VLP’s, there will be some minor amino acid differences. The VLPs of GSK are truncated at the C-terminal end. Dr. Dubin added that the genetic sequences used to express the VLPs are different. Presumably that might translate into some differences in the conformation of the VLPs. There has not been any direct comparison that he was aware of regarding the conformation or epitope mapping looking at the two VLPs. Given the differences in the genetic sequences used to produce the VLPs, he expected that there may be some differences in conformation. Dr. Haupt noted that this was part of the problem. Even if there is known amino acid sequence difference, it is not clear how that translates into the conformation of differences. Conformation is important for immune response. Cost-Effectiveness of HPV Vaccination of Boys in the US Jane J. Kim, PhD Center for Health Decision Science Department of Health Policy and Management Harvard School of Public Health Dr. Kim reiterated that human papillomaviruses (HPV) impose a significant burden on population health. Infections with high risk oncogenic HPV are associated with 100% of cervical cancers, the majority of anal cancers, and a smaller proportion of other anogenital, oropharyngeal, and oral cancers. The majority of these HPV related cases are caused by types 16 and 18. Infections with low risk, non-oncogenic HPV are associated with cervical lesions as well as the vast majority of genital warts, and juvenile onset recurrent respiratory papillomatosis (JORRP), a rare but severe respiratory condition in children. The majority of these cases are attributable to HPV types 6 and 11. The objective of this analysis was to evaluate the cost-effectiveness of including pre-adolescent boys in a routine HPV vaccination program of pre-adolescent girls in the US. The analytic approach was similar to the analysis of catch-up vaccination that was presented to ACIP in June 2008. A series of mathematical models were employed that simulate the natural history of disease. Epidemiological, clinical, and economic data were synthesized from various sources such as cohort studies, clinical trials, and national surveys. Because not all model parameters can be informed directly by the available data, the models were calibrated to achieve good fit to empirical data. Model validation exercises were then undertaken to ensure that the predicted outcomes were consistent with observations from independent data that were not used in model development. The models were used to simulate different interventions and estimate their consequences, such as quality-adjusted life expectancy and costs. The final step was to explore the influence of alternative scenarios, assumptions, and parameter values. Because of the inherent tradeoffs associated with different model types, multiple models were used for this analysis. The first was a dynamic transmission model of HPV type 16 and 18 infection among males and females, which captures the direct and indirect benefits of vaccination. This model was used to calculate the percent reductions in HPV 16 and 18 incidences associated with different vaccination strategies. These estimates of HPV incidence reduction were applied directly to a microsimulation model of cervical carcinogenesis, which captures cervical outcomes associated with all HPV types and detailed screening strategies. This model was used to assess the cost-effectiveness of HPV vaccination and cervical cancer screening in the US. Separate Markov cohort models were developed to simulate the incidence of other HPV 16 / 18 related cancers and HPV 6 / 11 related genital warts and JORRP to capture the potential benefits of the vaccine on other health conditions. Briefly, the dynamic model for females reflects sexual transmission of HPV 16 and 18 only. Those who are uninfected can acquire an HPV 16 or 18 infection, develop pre-cancerous lesions classified as CIN1 and CIN2,3 and over time may develop invasive cancer. Women who clear their infection or lesion develop natural immunity to that same type, and then they can subsequently reacquire the same type of infection at a reduced rate or acquire a new infection with the other type. The history of prior infection is tracked throughout the analysis. Once vaccination is introduced, women enter a corresponding vaccinated state. The model has a similar structure for males reflecting HPV infection only. The dynamic model is age-structured and stratifies the population into four sexual activity levels. Females and males form sexual partnerships over time, depending on age and sexual activity level. HPV incidence is a function of number of sexual partners, HPV prevalence in the population at a given time, and the transmission probabilities of HPV type 16 and 18. The microsimulation model is an individual-based model that has detailed screening and vaccination modules and tracks the history of each individual woman. All HPV types are included in this model, stratified as HPV 16, 18, other high risk types, and low risk types. We leverage the strengths of both models by using the dynamic model to estimate reductions in age-specific HPV 16 and 18 incidence with vaccination, and then applying those reductions to the corresponding inputs in the microsimulation model. This linkage between the two models allows investigators to reflect herd immunity as well as all HPV types, detailed screening scenarios, and individual level heterogeneity. Natural history parameters in both models were from epidemiological studies, cancer registries, and demographic statistics primarily from the US. After initial parameterization, the models were calibrated to ensure a good fit to empirical data using a likelihood-based approach. Selected data on females and males were as follows: The primary analysis included outcomes related to cervical disease as well as other HPV 16- and 18-associated cancers for both females and males relevant to both the bivalent and quadrivalent vaccines. Secondary analyses included HPV 6 and 11 genital warts as well as 6 and 11 associated JORRP, relevant to the quadrivalent vaccine only. Analysis was conducted from the societal perspective, including direct medical and non-medical costs regardless of payer. As recommended for cost-effectiveness analysis in the US, health and economic outcomes were discounted at a rate of 3% per year. Health outcomes were expressed in terms quality-adjusted life years (QALYs), which is life expectancy that is adjusted to reflect diminished quality of life due to disease. Health state utilities, which generally range from 0 reflecting the worst health state to 1 reflecting perfect health for invasive cancer, genital warts, and JORRP were obtained from the published literature. Economic outcomes included lifetime costs of interventions, including direct medical costs such as vaccination, screening, diagnosis, and treatment as well as direct non-medical costs such as patient time participating in the intervention and transportation. Patient time costs due to lost productivity were not included in this analysis. In the base case, it was assumed that the cost per vaccinated individual was roughly $500 inclusive of three doses, supplies, administration, and patient time and transport. Results were expressed as incremental cost-effectiveness ratios measured by the net increase in healthcare costs divided by the net gain in health effect when comparing one intervention to another. These ratios are a measure of value for resources and are used to compare this value across different interventions and diseases. The strategies in this analysis included routine vaccination of 12 year old girls and routine vaccination of 12 year old girls and boys. All strategies included screening with cytology based on current screening rates. The lifetime health and economic outcomes were captured for all birth cohorts over a 10-year period of the vaccination program. With respect to vaccination, it was assumed in the base case analysis that coverage for both girls and boys with the full three dose series was 75%, that efficacy for girls and boys was 100% over the lifetime among those without prior infection with vaccine targeted HPV types, and that the cost per vaccinated individual was $500. Alternative assumptions were evaluated and sensitivity analysis included lower vaccination coverage, lower efficacy, duration of protection and vaccine cost. With respect to cervical screening, the base case analysis assumed cytology screening starting three years after sexual debut, consistent with current guidelines. Screening frequency was based on coverage rates reported by the National Health Interview Survey (NHIS). PAP test sensitivity ranged from 70% to 80% for detecting CIN with a specificity of 95%. The cost of $85 included the test costs, the office visit, and patient time and transport. In secondary analysis, alternative screening strategies were explored including HPV DNA testing for primary screening starting at later ages every 1 to 3 years. In the primary analysis, the cost-effectiveness of including boys in an HPV 16 /18 vaccination program was assumed. These results reflect female outcomes only and the first set of results includes benefits related to cervical disease only. Under assumptions of 75% coverage and complete lifelong vaccine protection, routine HPV vaccination of 12 year old girls who were screened at current rates in adulthood had an incremental cost-effectiveness ratio of $40,310 per quality adjusted life expectancy (QALY) gained compared to screening alone. Adding 12 year old boys to the vaccination program provided benefits for higher costs and had a cost-effectiveness ratio of roughly $180,000 per QALY compared to vaccinating girls only. These ratios decreased or became more attractive when the vaccine’s benefits on other HPV 16 and 18 related female cancers were included. For example, under an assumption of 50% efficacy against non-cervical cancers, vaccinating girls alone decreased to $33,000 per QALY and vaccinated both girls and boys costs $157,000 per QALY. Under a more optimistic scenario of the 100% efficacy against the other female cancers, the ratios decreased to less than $30,000 per QALY for vaccinating girls alone and $140,000 per QALY for vaccinating girls and boys; when including cancer benefits for both females and males, these cost-effectiveness ratios fell to $30,000 per QALY and $131,000 per QALY, respectively, when assuming 50% efficacy against non-cervical cancers, and to $24,000 and $103,000 per QALY when assuming 100% efficacy. To evaluate the quadrivalent vaccine, cervical disease and genital warts only were included. When including genital wart benefits for females only, the ratio for vaccinating girls decreased to $32,000 per QALY and vaccinating both girls and boys decreased to $158,000 per QALY. When including warts benefits for females and males, the ratios decreased even further as expected to roughly $28,000 and $124,000 per QALY for the two vaccination strategies. Scanning the results across the scenarios of other health outcomes, the cost-effectiveness ratio for vaccinating girls alone remains comfortably below $50,000 per QALY even when outcomes include cervical disease only. The ratio for the strategy of including boys, on the other hand, depends on the health conditions included and falls near or below $100,000 per QALY when all cancers or all outcomes are included. When vaccine efficacy was reduced to 75% in boys only, the ratio associated with the strategy of vaccinating boys increased by 80% to 117% depending on outcomes included. For example, when reflecting only benefits associated with cervical disease, the cost-effectiveness ratio of vaccinating both girls and boys increased from $180,000 to $325,000 per QALY when efficacy decreased from 100% to 75% in boys. When reflecting all health outcomes, this ratio increased from $78,000 to $170,000 per QALY. Additional sensitivity analysis included reduced vaccination coverage with scenarios of cervical outcomes alone, all outcomes assuming 50% efficacy, and all outcomes assuming 100% efficacy. When strategies were evaluated in the context of 50% vaccination coverage, the corresponding ratios for both strategies improved due to slightly higher levels of herd immunity benefits. The strategy of including boys in the vaccination program was roughly $100,000 per QALY under an assumption of 50% efficacy and remained below $100,000 per QALY with 100% efficacy. The impact of the vaccine cost, which in the base case was $500 per vaccinated individual, was also examined. Using a vaccine cost of $360, when all outcomes are considered, vaccinating girls and boys decreased to $89,000 per QALY under an assumption of 50% efficacy and $53,000 per QALY with 100% efficacy. In contrast, when the vaccine costs increased to $600, the ratios became less attractive than the base case. In this scenario, the strategy of vaccinating girls and boys remained well above $100,000 per QALY when efficacy was 50% and approached $100,000 per QALY when efficacy was 100%. Results were also sensitive to assumptions of waning vaccine protection; when vaccine protection was assumed to be 10 years, both vaccination strategies had ratios that exceeded $100,000 per QALY. In contrast, changes in screening practice involving less frequent screening with HPV DNA testing and primary screening made vaccination strategies more attractive. Results were insensitive to changes in health state utilities associated with genital warts or duration of warts, and also when a higher proportion of oral and oropharyngeal cancers attributable to HPV type 16 and 18 were assumed. As with all model-based analyses, this analysis had several unavoidable limitations, including uncertainties with respect to natural history, especially the non-cervical diseases. There are also uncertainties with respect to the vaccine properties for females and especially for males. With respect to the analytic assumptions, decrements in quality of life associated with detection and treatment of pre-cancerous lesions that result from screening were not included. Inclusion of these utilities would favor vaccination strategies since HPV vaccination is expected to reduce the prevalence of vaccine type lesions. Conversely, diminished quality of life was also not included due to potential adverse events associated with vaccination, which would favor the screening strategies. Also, this analysis did not evaluate catch-up programs. It is expected, however, that in the context of catch-up vaccination among young females, extending vaccination to boys would be even less attractive than suggested by the current analysis. In summary, provided vaccine efficacy was high and long-lasting, routine HPV vaccination of 12-year-old girls was stably less than $50,000 per QALY across a wide range of assumptions compared to screening alone. This result is consistent with most previous cost-effectiveness studies. Including pre-adolescent boys resulted in higher costs and benefits, and generally had cost-effectiveness ratios that exceeded $100,000 per QALY. This was especially true when vaccine efficacy was differentially lower in males than females. Only when all potential health benefits from the vaccine were included under optimistic assumptions of 100% efficacy, for both females and males over the lifetime, or 50% lifelong efficacy with lower vaccine cost, did vaccinating both girls and boys fall below $100,000 per QALY. Overview of Cost-Effectiveness Models of Male HPV Vaccination in the United States Harrell Chesson, PhD NCHHSTP / CDC Dr. Chesson began with a review of what is known about the cost-effectiveness of HPV vaccination in general. Vaccination of 12 year old girls has been shown to be cost-effective, with cost-effectiveness estimates ranging from $0 to $50,000 per QALY gained. This result has been consistent across a wide range of models. However, there is more uncertainty and less precision in the cost-effectiveness estimates for vaccination of females over the age of 12 and for vaccination of males. He then presented a summary of the published cost-effectiveness studies of male HPV vaccination, and compared and reviewed two unpublished models. In a study by Taira and colleagues (2004), the cost per QALY of male vaccination was about $440,000 in the base case scenario with 70% coverage. However, when vaccine coverage of females was reduced to 30%, the cost per QALY was reduced as well to about $40,000. This finding that the benefits of the male vaccination increase and the cost-effectiveness becomes more favorable with lower vaccine coverage has been found in several models of cost-effectiveness and the impact of male vaccination. It was also shown in the model by Elbasha and colleagues, who in the base case found a cost per QALY of $40,000 at 70% coverage. However, with higher coverage, the cost per QALY increased but with lower coverage of females, the cost per QALY decreased. The Jit study was based in the UK. These investigators found a cost per QALY gained for male vaccination of about $1,000,000 with 80% coverage and lifelong duration of vaccine protection. The key themes from the published studies are that male vaccination has less impact and is less cost-effective as vaccine coverage of females increases. However, vaccine coverage is not the only factor that affects cost-effectiveness. There is considerable uncertainty in the natural history, disease cost and quality of life assumptions, and vaccine characteristics. Because of these uncertainties, there is a wide range of cost-effectiveness ratio across models and within models. The published models have focused on the prevention of cervical intraepithelial neoplasia (CIN) cervical cancer and genital warts; however, the recent trends in the cost-effectiveness models for HPV have been to include additional HPV related outcomes that might be prevented through vaccination such as non-cervical cancers and recurrent respiratory papillomatosis (RRP). Two preliminary models have been expanded to include all of these health outcomes. These include the Kim / Goldie model that Dr. Kim just summarized, as well as the Merck model which looks at adding vaccination of males 9 to 26 years old to a vaccination program for females 9 to 26. Both models examine the cost-effectiveness of adding male vaccination to a female only vaccination program in the context of current cervical cancer screening in the US. To review the Merck model briefly, they assumed effective vaccine coverage by age 18 of about 35% in females and 23% in males. First dose coverage assumptions were higher, but they assumed that only about 50% of those vaccinated with the first dose would complete the series. Vaccine efficacy against infection and disease was based on the clinical trials. They assumed lifelong duration of vaccine protection and assumed that there would be no benefit for those who do not receive all three doses. They assumed the vaccine cost would be $133 per dose, inclusive of administrative costs. They used the US health care system perspective in which vaccine costs as well as disease treatment costs were assessed without regard to who paid these costs. Cost and benefits of vaccination were evaluated over a 100-year time horizon with future cost and benefits discounted at 3% annually. The incremental benefit, in terms of reducing cervical cancer, for male vaccination is quite small and it takes about 40 years to even see this difference. Although the additional benefit of male vaccination is more noticeable for the male anal cancer outcome than for cervical cancer, it still remains that the majority of the benefits that can be obtained from vaccinating both sexes can be obtained from vaccinating females only. In the Merck model, the cost per QALY of female only vaccination was about $2,000. The incremental cost per QALY of adding male vaccination was about $25,000. In terms of the gain and changes in cost and QALYs,per person in the population, adding males costs about $22 as opposed to the incremental cost of female vaccination, which is about $9. The change in benefits was much lower for male vaccination, and was roughly 1/6 the marginal benefit in terms of QALYs gained as compared to female only vaccination. The estimated cost per QALY depends on which health outcomes are included in the model. When including cervical outcomes only, the cost per QALY of male vaccination is over $200,000. However, as more outcomes are included, the cost per QALY decreases to $25,000. When the impact of genital warts on quality of life is reduced by 50% and the duration of genital warts is reduced to three months, these changes in the genital warts assumptions make a fairly big impact on the cost per QALY estimates when including only a few of the health outcomes. However, when all health outcomes are included, the changes in genital warts assumptions do not have as much of an impact. It is important to point out that just focusing on the diseases for which there is evidence of vaccine impact, the cost per QALY of male vaccination is $70,000 per QALY or above and is very sensitive to changes in the model assumptions, such as those related to genital warts. In terms of the results of the two models, when including only cervical outcomes, both models suggest a cost per QALY of male vaccination in the neighborhood of $200,000; however, when including all health outcomes, the cost per QALY of male vaccination is about $25,000 in the Merck model, which is lower than the estimates from the Kim / Goldie model that Dr. Kim just presented in which the cost per QALY of male vaccination can range from $78,000 to $170,000 depending on the vaccine efficacy assumptions. However, this is not really an apples to apples comparison because there are several differences in the questions being addressed by the models. For example, the vaccine coverage is much higher in the Kim / Goldie model and the Kim / Goldie model focuses only on vaccination of 12 year olds. With respect to similarities and differences in the models, both models included a wide range of health outcomes. The only difference is that the Merck model included vaginal pre-cancers. Both models were able to include the indirect effects of vaccination or herd immunity. Both models did incorporate current cervical cancer screening, although the methods they used to do so differed. They also examined a long time horizon, although again, the methods they used to do so differed. Both models assumed at least some degree of natural immunity following HPV infection and clearance. As noted, the effective coverage in the Merck model was much lower than in the Kim / Goldie model. The Kim / Goldie model used a higher cost of vaccination and this is partly because they included patient time and travel costs—not only in their cost of vaccination, but in the cost of the disease treatment. The Merck model included the quality of life impact of CIN, and the Kim / Goldie model did not. The models could be made more comparable by aligning three key assumptions: Cost of vaccination, including administration costs (Merck $400 per series base case, Kim / Goldie $360); vaccine coverage and adherence (Merck 75% coverage / 100% adherence; Kim / Goldie 75% coverage / 100% adherence base case); and ages vaccinated (Merck 9 to 12; Kim / Goldie 12 base case). In the sensitivity analyses, assumptions were changed from the base case. The scenario in which the Kim / Goldie cost was changed to $360 per series was selected for this comparison as it was more comparable to the Merck assumptions. The scenario of the Merck model in which 100% vaccine adherence was assumed was selected for this comparison as it was more in line with the Kim / Goldie model. Under this scenario, the cost per QALY of HPV vaccination, adding males to the female only vaccination program, was about $90,000 in the Kim / Goldie model and about $40,000 in the Merck model. When the models were aligned on these three assumptions, the disparity in the outcomes was greatly reduced, although the estimates are still somewhat different. To summarize, male vaccination costs more than $100,000 per QALY in most scenarios in the Kim / Goldie model. Cost per QALY was < $100,000 only when all health benefits were included with 100% lifetime efficacy, or with 50% lifetime efficacy at lower vaccine cost. Male vaccination cost less than $50,000 per QALY in the most scenarios in the Merck model. Cost per QALY was >$100,000 when including only cervical, vaginal, and vulvar cancers and genital warts in the scenario of 75% effective coverage in females. The differences across these models were reduced, but not eliminated, when selected assumptions were aligned. To conclude, estimates of the cost-effectiveness of male vaccination can vary across models and even within models when key assumptions are changed. This is due to the uncertainty in the influential factors that impact the cost-effectiveness of male vaccination including the HPV diseases included in the model, vaccine coverage and efficacy, and other assumptions. Discussion Dr. Temte thought first time HPV coverage in adolescent females was approximately 25%. From a programmatic standpoint, he wondered whether it was better to push forward to immunize all girls or have a recommendation in which they try to immunize both boys and girls with the idea that perhaps by trying to reach both they would achieve better results than with just the female recommendation. Dr. Kim responded that while she did not have a definitive answer, she could offer a qualitative one. All of the models are consistent in finding that the cost-effectiveness of vaccinating girls is certainly higher than vaccinating boys. Dollar for dollar, the goal would be to achieve coverage in girls based on the data there is currently on vaccine efficacy. To answer the question, it really depends on what the cost is of achieving the increase in coverage in females in terms of whether there is an added cost to that and how that relate to the improvements that might be achieved in health related to boys. Her group has personally not assessed any cost threshold analyses to say that going from 50% to 75% coverage would add X cost for reaching another 25% of girls compared to what it means to go from 0% to 25% coverage in boys. A head-to-head analysis has not been done. Dr. Dasbach (Merck) indicated that Merck has conducted some of those analyses. What they have tried to do with the model that Dr. Chesson just presented was to reflect current coverage levels to at least what is being observed in the US currently, and what would happen if male vaccinations were added on top of that. If coverage levels are low, it makes a lot of sense to increase coverage either by vaccinating more females or more males. Dr. Temte asked whether that was dollar for dollar as female coverage was increased. It looked like the models were pretty consistent in that as female coverage increases, the cost-effectiveness ratio, the cost per QALY for males, skyrockets. This raised a question about what the best value would be. Dr. Kim responded that this is precisely what they were trying to help inform. It is true that the models are consistent in that as coverage is increased in girls, the value of adding boys decreases. However, there might be other reasons that are not included in these models, such as whether including boys actually helps reach more girls or whether opening up vaccination to boys helps gain more coverage in girls. That type of scenario has not been included her their analyses to date. In terms of how things play out in public health protective “bank for the buck” Dr. Judson pointed out that one variation not used was that very often the interventions are gotten into the people who may least need them and are most able to pay for them. Thus, one way of looking at this would be that if 50% coverage is reached in girls at 12, they only account for 10% of all eventual cervical cancer. That is a major public health concern. He also requested clarity on what it cost to prevent a penile wart for one year in a man in terms of quality of life assumptions were used. Dr. Kim responded that they were using consistent results (e.g., the same QALY assumptions as the Merck model). She said she could not personally vouch for the quality of life decrement associated with penile warts. Returning to Dr. Judson’s first question, although they did not look at the impact of disparities in vaccination coverage among females or males in this particular analysis, they did include that analysis in the catch-up analysis and found that their results were very sensitive to correlations between vaccination coverage and screening coverage. If restricting vaccination coverage to women who will eventually get screened, the cost-effectiveness of vaccination at any age becomes highly unattractive and that worsens as the correlation becomes stronger. For genital warts, a decrement in quality of life of .09 was assumed. The scale of health utilities is usually from 0 to 1, 0 reflecting death or the worst health state, and 1 reflecting perfect health. A .09 in theory would be indifferent to a 9% risk of death to get rid of the genital warts at that time period. Dr. Dasbach indicated that the cost of genital warts was about $500 to $600 per episode of care. Just within the US alone, the economic burden is about over $200,000,000 per year in terms of treatment. In terms of the QALYs, a similar estimate is used in terms of the disutility or the quality of life weight associated with warts, and that was also about .09 on a scale of 0 to1. What that means with respect to cervical cancer is that decrement is assumed to be closer to.25 to .5 depending on whether it was local or distal cancer. Also important in terms of looking at this QALY is the duration of the event, so within the Merck model it was assumed that the median length of a genital wart was about 6 months. Dr. Cieslak pointed out that these models were somewhat of a black box because everything that was going into them was not known to the ACIP members. Given that he always thought of the burden of HPV as being a question of the incidence and severity of cervical cancer, he was surprised to see the large decrements in cost per QALY gained as lesser incidence of diseases in males were added. This was counterintuitive to him. He wondered if Dr. Chesson could offer further insight. Dr. Chesson responded that the female vaccination has a major impact on cervical cancer, so that does not leave as much room for the male vaccination to do as much good in terms of reducing the cervical outcomes. Change in cervical cancer was very small by adding male vaccination. Dr. Cieslak said he understood, but as other things were added, there were profound drops in cost per QALY. Dr. Chesson responded that a major reason for the genital warts drop was that even though the cost per case was about $500 when multiplied that by all cases, is was a substantial burden than could be offset. So not only is it a change in the QALYs that is driving this, but also it is a change in the cost associated with the disease outcomes, particularly in genital warts. Dr. Dasbach added that in terms of what they did with respect to male disease as well as female disease, all of the data were calibrated to current levels that are being observed in the US with respect to incidence. They then assessed the reductions that vaccination would provide in terms of the benefits of preventing those diseases. The reason decreases are seem in males is that, as Dr. Chesson was mentioning, there are now direct benefits to males in the female diseases and those are all indirect benefits that male vaccination provides. So in vaccinating males, there are indirect and direct benefits. Dr. Sumaya wondered whether the time and effort of the vaccine process was or could be included. There may be cost differentials on the acceptability of the vaccine with at risk populations. In other words, he thought there would be greater acceptability / interest in the vaccine as opposed to men and he wondered whether there was any cost differentiation with that phenomenon. Dr. Kim responded that this would depend on the level of the coverage actually achieved in both genders. The cost-effectiveness and the value of vaccinating either girls or boys is very sensitive to assumptions of coverage, so they would have to evaluate specific scenarios. Additional cost would be tacked on to implementing or trying to get that coverage for the vaccination strategies. That would differentially disadvantage the vaccination strategies compared to, for instance, screening alone. Dr. Morse pointed out that it appeared that age at immunization would have a major influence on the model, especially as immunization levels increase. Thus, the cost of immunizing an older group of the cohorts 20 to 26 years of age might be much more expensive. HPV Vaccines: Issues for ACIP Consideration Lauri Markowitz, MD ACIP HPV Vaccine Workgroup NCHHSTP / CDC Dr. Markowitz provided a brief overview of issues that ACIP will likely need to consider during the October 2009 meeting. These include the two issues heard during this meeting (e.g., quadrivalent vaccine in males and bivalent vaccine in females). A variety of issues need to be considered for HPV vaccine in males. These include the burden of disease in males, vaccine efficacy, immunogenicity, safety, vaccine acceptability, and impact and cost-effectiveness. It is known that HPV prevalence and incidence are high in sexually active men. HPV incidence in men is similar to that in females. There are still unknowns regarding the transmission and natural history of HPV, particularly in males. In terms of HPV-associated disease in males, HPV types 16 / 18 cause the majority of HPV-associated anal, penile, and oropharyngeal cancers (~7000 invasive cancers / year). HPV types 6 / 11 cause RRP and over 90% of genital warts (.25 -.5 million / year). There are some high risk groups, such as MSM, which has not been discussed with ACIP. This group has high rates of HPV infection and HPV related outcomes. The quadrivalent vaccine is generally well-tolerated in males. There is high efficacy for protection against vaccine-type persistent infection (VE = 86%) and genital warts (VE = 89%). Of note, there are no data yet on efficacy for prevention of pre-cancers in males, although studies on these endpoints are on-going. In terms of the modeling and economic analyses, male vaccination provides little additional benefit for prevention of cervical cancer if there is high vaccine coverage in females. Cost-effectiveness estimates are more favorable as more health outcomes are included. In the Kim / Goldie model, male vaccination cost > $100,000 per QALY in most scenarios. The incremental cost effectiveness was < $100,000 per QALY only when all health benefits were included with 100% lifetime efficacy, or with 50% efficacy and lower vaccine cost. In the Merck model, the cost per QALY was < $50,000 in almost every scenario in which all health outcomes were included. The cost per QALY was in the $75,000 range when including only cervical, vulvar, and vaginal cancers and genital warts. With regard to a recommendation for quadrivalent HPV vaccine for males, several questions must be considered: Should there be data on efficacy for prevention of pre-cancer lesions in males before making recommendations? How much should health economic models impact decisions? What endpoints should be included? What about vaccine coverage in females? Considerations for supporting a recommendation for vaccination of males include the fact that HPV does cause disease in males as well as females. The vaccine has high efficacy for prevention of genital warts and a strong likelihood for prevention of cancers in males. There is also high efficacy for prevention of persistent infection in males. In some models, which included the most favorable assumptions and high efficacy, the cost per QALY was less than $50,000. There are also issues of equity; that is, should the vaccine be made available to males as it is for females? There are also programmatic considerations. Would a gender-neutral vaccination program facilitate vaccine delivery? The work group realizes at the present time there are really no data to support that hypothesis. Considerations for not supporting HPV vaccine recommendations for males include the fact that there are no data on the efficacy for prevention of pre-cancer lesions, and in the Kim / Goldie model, the cost per QALY for male vaccination exceeded $100,000 under most scenarios examined. In the Merck model, the cost per QALY was about $70,000 or $75,000 when focusing only on health outcomes for which we evidence of impact. The options for HPV vaccine recommendations in males that have been discussed in the work group include a routine vaccination at age 11-12 with a permissive recommendation or a catch-up to some older age. The reason a permissive recommendation only was supported by many work group members was the need to wait for more efficacy data against other endpoints and / or the fact that the model showed that the vaccination of males is not cost-effective. There was also discussion of specific recommendations for high risk groups, particularly men who have sex with men. It was recognized that this would be difficult to implement and that many MSM would already have been infected at the time they self-identified. Regarding the work group’s discussions related to the bivalent vaccine in females, considerations were previously presented to ACIP in October 2007. In addition to making specific recommendations for use of this vaccine, there is a need to consider issues related to having two licensed HPV vaccines in the US—the focus of this session. The following table reflects the characteristics of the two vaccines, both of which are L1 virus-like particle or VLP vaccines: Quadrivalent (Merck) Bivalent (GSK) VLP types and Composition 20 µg HPV 6 40 µg HPV 11 40 µg HPV 16 20 µg HPV 18 20 µg HPV 16 20 µg HPV 18 Producer cells Saccharomyces cerevisiae (bread yeast) - expressing L1 Trichoplusia ni insect cell line infected with L1 recombinant baculovirus Adjuvant Alum: 225 µg Aluminum Hydroxyphosphate Sulfate AS04: 500 µg Aluminum Hydroxide 50 µg 3-deacylated Monophosphoryl Lipid A Schedule 0,2,6 months 0,1,6 months Some issues to consider related to having two licensed HPV vaccines for use in females include: Should a preference be stated for one vaccine? Are there differences related to protection against HPV 16 / 18, other oncogenic types, and / or HPV 6 / 11? Are there differences in cost-effectiveness? Can the vaccines be used interchangeably in the vaccination series for protection against HPV 16 / 18? The current understanding of both vaccines is reflected in the following table: Attribute Quadrivalent Bivalent Protection against HPV 16/18 related CIN2/3 and AIS* >98% >93% Protection against HPV 6/11 related genital lesions 100% - Cross-protection against CIN2/3 due to high risk types other than HPV 16,18 Some 16 related types? Some 16 and 18 related types? Seroconversion to vaccine types ~100% ~100% Geometric mean antibody titers bivalent > quadrivalent Duration of protection Unclear if any differences Unclear if any differences Local Reactogenicity bivalent > quadrivalent Cost of vaccine dose** $130 private $105 contract ? Both vaccines may offer some protection against non-vaccine types and there may be differences. Seroconversion to the vaccine types occurred in almost all vaccines, and after a three dose series for both vaccines. The data from the comparative trial illustrates that the bivalent vaccine does produce higher titers than the quadrivalent vaccine, but both vaccines produce titers that are substantially higher than those after natural infection. The implications of this, in terms of differences in duration of protection, are unclear. There is higher local reactogenicity after the bivalent vaccine; however, both vaccines have good tolerability profiles. At present, the cost in the US is only known for the quadrivalent vaccine. In terms of cross protection, based on data from a meta-analysis of HPV types associated with cervical cancers worldwide, HPV 16 and 18 account for 70% of cervical cancers. Some non-vaccine oncogenic types account for a smaller percentage of cervical cancers. Two of the more common types of these non vaccine types are 45 and 31 [Smith J. et al, Int J Cancer 2007]. In terms of protection against type 31 and 45 related CIN2/3 and persistent infection among women who were in the naïve group, they were naïve to 14 types at baseline. There was 100% protection against CIN2/3 or AIS due to 31 or 45 and this was significant for 31. There was also significant protection against 6 month persistent infection with both of these types. For the quadrivalent vaccine, previously published data earlier this year show protection against type 31 related CIN2/3 and persistent infection, but not for type 45. This analysis for the quadrivalent vaccine was among women who were naïve to 12 oncogenic types at baseline. Efficacy has also been examined for CIN2/3 due to groups of non-vaccine oncogenic types. In these analyses, there were some protection from lesions due to types due in the A9 species (these are types related to HPV 16) for the bivalent vaccine and for the quadrivalent vaccine as well. For types related to HPV 18, there is significant protection for the bivalent vaccine but not the quadrivalent vaccine. For a combined endpoint of CIN2/3 due to any of 10 non vaccine types, efficacy was 68% for the bivalent vaccine and 33% for the quadrivalent vaccine [Paavonen et al, presented at IPC, Malmo Sweden (May 2009); Brown et al, JID 2009;199]. A note of caution about these analyses of cross protection is that the analyses shown earlier did not exclude lesions in which there was also infection with a vaccine type, so it is possible that some of the observed protection could have been due to the vaccine types. Also, it is quite difficult to directly compare results from the trials for a variety of reasons in terms of the way the populations were selected and the way the analyses were conducted. Taking into account the available data, the work group has discussed options regarding making recommendations for two licensed vaccines and whether a statement of preference should be made for one vaccine or the other. While there was not complete consensus, the majority of members on the work group felt that a statement should include the following elements: There should be a statement of the differences in protection provided by the vaccines, specifically differences with regard to protection against HPV 6 and 11. The quadrivalent vaccine provides protection against genital warts. There could potentially be a statement about differences in cross protection. There should be an encouragement to providers to understand differences between the two vaccines. For protection against 6, 11, 16, or 18 related outcomes, the quadrivalent vaccine is recommended. For protection against HPV 16 and 18 related outcomes, either the quadrivalent or the bivalent vaccine is recommended. Concerning the issue of interchangeability of the vaccines, it was acknowledged that there would be no data at the time recommendations would need to be made regarding this issue. A possible statement could be, “Whenever feasible, the same brand of HPV vaccine should be used for all doses of the vaccination series. If vaccination providers do not know or have available the type of HPV vaccine previously administered to a female, any vaccine should be used to continue or complete the series to provide protection against types 16/18.” There are many other issues that would need to be addressed for the bivalent vaccine recommendations, which will be addressed during the October 2009 meeting. The future plans for the HPV vaccine work group are to continue to review data, refine the understanding of the cost-effectiveness analyses, discuss options for recommendations for these two issues, and prepare draft recommendations and options for the October 2009 ACIP meeting if there is FDA approval. Overview of Work Group Activities Carol J. Baker, MD Advisory Committee on Immunization Practices Dr. Baker indicated that during this session, the following topics would be presented upon: * Update on immunogenicity and safety of a second meningococcal conjugate vaccine (MenACWY-CRM) for 11 to 55 year olds --> No VFC vote required; no proposed changes to recommendations for vaccination * Early estimate of vaccine effectiveness of meningococcal conjugate vaccine (MCV4) --> 3 years after vaccine implementation: unable as yet to evaluate duration of protection * Proposed revaccination recommendations for persons at high-risk for invasive meningococcal disease With regard to why revaccination needed to be considered, the 2005 ACIP recommendation for revaccination after MCV4 states the following: “ACIP expects that MCV4 will provide longer protection than MPSV4; however, studies are needed to confirm this assumption. More data will likely become available within the next 5 years to guide recommendations on revaccination for persons who were previously vaccinated with MCV4.” Although they are only at the 4-year mark, some considerations need to be made. First, it is likely that the early meningococcal conjugate vaccine (MCV4) vaccinees likely will have been persons in high risk groups for invasive meningococcal disease. They probably received vaccines the earliest, and probably represent a very small part of the total vaccine target. There has also been a shift in thinking about the duration of protection regarding conjugate vaccines, because immunologic memory or boost ability may not actually correlate with protection. To prepare the committee for the future, Dr. Baker reported that the work group would be considering a recommendation for revaccination of adolescents vaccinated 5 years ago who would be entering college. This is a very large cohort of approximately 600,000 students annually. According to the data, a very small proportion of entering college students will have been vaccinated 5 years ago (e.g., coverage <4% in 2005; 11% in Fall 2006). Cost-effectiveness of revaccination of college freshmen living in dormitories needs to be assessed. An additional year may allow for more definitive effectiveness evaluations to be completed. In addition, a recommendation for routine vaccination of infants and / or toddlers with meningococcal conjugate vaccines must be considered. There is a potential for three vaccines to be licensed in 2010-2011: MCV4-D 2-dose series (9,12 months), HibMenCY 4-dose series (2,4,6,12 months), and MenACWY-CRM 4-dose series (2,4,6,12 months). The work group will also continue to evaluate data on the burden of disease and cost-effectiveness of vaccines in infants. The work group anticipates a revision of the 2005 ACIP meningococcal conjugate vaccine statement in the Fall of 2009. The revision is expected to reaffirm the current 2- to 10-year old and adolescent recommendations, which are for high risk 2- to 10-year olds and all adolescents; include additional safety data, especially regarding Guillain-Barré Syndrome (GBS) monitoring; add the MenACYW-CRM vaccine information; include data concerning duration of protection; and include recommendations for revaccination of high risk groups. In 2010-2011, the work group will begin to present data that will lead to a recommendation for infant vaccination. MenACWY-CRM (Menveo®) Clinical Trial and Product Overview Peter Dull, MD Head Development Meningococcal Vaccines Novartis Vaccines Dr. Dull offered a brief, broad overview regarding the Novartis Vaccines Meningococcal Vaccine Program with respect to vaccine characteristics, the overall clinical program, and the specific data on adolescents currently under review. Novartis Vaccines, as a company, has a longstanding interest and scientific expertise in meningococcal disease prevention. The program is intended, rather ambitiously, to control disease in all disease-causing serogroups and all age ranges beginning from two months of age. The history of the Novartis Vaccine Program begins with a monovalent MenC vaccine, which was a CRM conjugate vaccine, which was originally licensed in the United Kingdom (UK) in response to a serogroup C outbreak in late 1999. MenACWY-CRM was built upon the successful MenC-CRM vaccine platform and is a CRM-based conjugate quadrivalent vaccine with initial indication for adolescents through 55 years of age. The goal is to move into younger age groups, with applications forthcoming submissions planned for 2 to 10 year olds and infants. Ultimately, Novartis expects to provide broadly protective MenB infant vaccine. This vaccine is currently undergoing Phase III studies in Europe in >4000 infants. This vaccine would provide the penultimate cornerstone to complete the meningococcal disease prevention goal. With regard to MenACWY-CRM, Menveo® is the trade name that will be used. A unique conjugation process is used utilizing the protein carrier, CRM197. CRM197 is a non-toxic mutant of diphtheria toxin that requires no formaldehyde detoxification, which avoids cross-linking to accessory antigens. It has been used successfully in pneumococcal and Hib conjugate vaccines. Other specific unique features of this vaccine include the conjugation chemistry [Bardotti A et al. Vaccine. 2008;26:2284–2296]. Purified polysaccharides are optimally sized then linked to the CRM197 to produce the conjugates. Standardized polysaccharide sizing allows for consistency in the end product, as well as retention of structural identity. The vaccine has 10 micrograms of MenA with 5 microgram of the C, W, and Y component. It contains no adjuvant and no preservative. The presentation will be “vial-vial”, with the liquid component containing the MenCWY, which is reconstituted into the lyophilized MenA component. The clinical development dates back to about 2002. The clinical trial database is quite extensive, with 24 clinical trials either completed or on-going. Over 16,000 subjects have now received one or more doses of the final formulation. The objectives of the program are to demonstrate immunogenicity across broad range of age groups, persistence of bactericidal antibodies, safety and tolerability, and concomitant use with routine vaccines. Serology using exogenous human complement has been agreed to with the FDA as being the licensure criteria for this vaccine. The data presented during this session is derived using human complement as a reagent. Several Menveo® studies have either completed or are on-going. The following table summarizes the findings of key MenACWY-CRM (Menveo®) Clinical Trials: Age group Doses Phase Comparator Key Results 19–55 y 1 III Menactra® * Well tolerated * Noninferior immunogenicity with statistically higher immunogenicity response for serogroups CWY 11–18 y 1 II Menomune® * Well tolerated * Statistically higher immunogenicity * Persistent immune response III Menactra * Well tolerated * Noninferior immunogenicity for ACWY with statistically higher immunogenicity response for serogroups AWY III Concomitant * Supports co-administration or sequential administration with HPV and adolescent Tdap 2–10 y 1 II Menomune * Well tolerated * Statistically higher immunogenicity III Menactra * Study ongoing 0–2 y 1-2 (toddlers) 4 (infants) II MenC * Well tolerated * Comparable immunogenicity to MenC-CRM III No comparator * Study ongoing The MenACWY-CRM (Menveo®) versus Menactra® in Adolescents Phase III Study is a large study performed in 40 study sites throughout the US, with a primary endpoint of non-inferiority with pre-specified superiority analysis if non-inferiority is first satisfied and approximately 2000 subjects. Adolescents were enrolled with a lot consistency study embedded, and were randomized to receive either one dose of Menactra® or one of three lots of Menveo®. Blood was drawn at baseline and 30 days, and there was a 6-month safety follow-up period. Two-year data of persistence with a subset of approximately 400 subjects from the same cohort has recently become available, which Dr. Dull reported on during this session. Seroresponse was the pre-specified primary immunogenicity endpoint agreed upon with FDA. For a subject with hSBA titer <1:4 at baseline, seroresponse is defined as a post-vaccination hSBA titer ?1:8. For a subject with hSBA titer ?1:4 at baseline, seroresponse is defined as a post-vaccination hSBA titer of at least 4 times their baseline titer. With respect to seroresponse one month post-vaccination, across all four serogroups, the non-inferiority criteria were achieved and statistically significant differences were also observed for the A, W, and Y serogroups. That is the regulatory endpoint, but speaking to the public health endpoint, for those who are protected after vaccination regardless of pre-titer a similar theme emerged. Again, non-inferiority was achieved across all four serogroups A, C, W, and Y, and for the A, W, and Y, there were statistically significant differences between the two vaccines. In another post-hoc analysis among those who are seronegative at baseline, across all measures the same theme emerges: non-inferiority for serogroups A, C, W, and Y, with statistically significant differences for A, W, and Y. Regarding the Y response, unique in the US and among much of the developed world, there has been an emergence of serogroup Y as a serogroup of interest, constituting upwards of 1/3 of disease in recent surveillance data. Regarding hSBA titers ? 1:8 at 22 months post-vaccination in the same subset of approximately 400 adolescents, the same theme emerged. For A, W, and Y a statistically significant difference was maintained between the two vaccines. In terms of local reactogenicity within 7 days of vaccination, both vaccines were well tolerated, with comparable reactogenicity and incidences of local injection-site reactions were similar between groups. With respect to systemic reactogenicity within 7 days of vaccination, rates of systemic symptoms were similar between groups. No serious adverse events were assessed as vaccine-related, and there were no study withdrawals due to adverse events. Concomitant administration was examined in a large Phase III study conducted in Latin American to examine Menveo® administered alone versus Menveo® co-administered with Tdap and HPV vaccines. There was also an analysis of sequential administration with diphtheria-containing vaccines such as MenACWY-CRM given one month before Tdap. There was no incremental increase in reactogenicity of two diphtheria-containing vaccines. This has been observed in other studies and is not completely surprising. That is, the safety profile was comparable whether given alone, sequentially, or concomitantly with the other study vaccines. Non-inferior immunogenicity was measured by percentage with hSBA ? 1:8 for all meningococcal serogroups; percentage with diphtheria and tetanus antibody concentrations ? 1.0 IU/mL; and percentage with HPV seroconversion and GMTs. There were robust responses to all pertussis antigens, and the non-inferiority criteria were met for PT. From an immunogenicity standpoint, non-inferiority was achieved for the meningococcal serogroups for the diphtheria, tetanus, and HPV. With regard to pertussis antigen responses, non-inferiority was achieved for pertussis toxin. Robust responses were achieved across all three antigens, but there was a decrement in the response to filamentous hemagglutinin (FHA) and pertactin (PRN). In summary, the Menveo® program seeks to provide protection beginning from 2 months of age, and there are data from Phase II that support infant vaccination with a 2-4-6 schedule. There is favorable immunogenicity compared with the currently licensed quadrivalent meningococcal conjugate vaccine, MenACWY-D (Menactra®), in adolescents. The percentage of seroresponders and hSBA ? 1:8 is statistically significantly higher for serogroups A, W-135, and Y. GMTs are statistically significantly higher for serogroups A, C, W-135, and Y. There is a statistically significantly higher percentage of those who maintain hSBA ? 1:8 at 22 months post-vaccination. Menveo® is well-tolerated in all age groups. Data support concomitant use with routine adolescent vaccines. Phase III studies are in progress to support licensure in infants beginning from 2 months of age. Estimate of Effectiveness of Meningococcal Conjugate Vaccine (MCV4) Ms. Jessica MacNeil, MPH Division of Bacterial Diseases National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Ms. MacNeil presented an analysis that provided an early estimate of the effectiveness of meningococcal conjugate vaccine (MCV4), as well as a description of cases of meningococcal disease in persons vaccinated with MCV4. Regarding the timeline for MCV4 recommendations, MCV4 was licensed in January 2005 for use in 11 to 55 year olds. In May 2005, ACIP recommended vaccination of adolescents at three time points, at 11 to 12 years of age, or at high school or college entry if not previously vaccinated. Expected shortages limited the use of MCV4 in 2005 and 2006. During that time, vaccination focused primarily on persons entering high school and college, while 11 to 12 year olds were asked to defer vaccination until a later time. As supply improved, ACIP revised their recommendations to call for a routine vaccination of all 11 to 18 year olds at the earliest opportunity in June 2007. MCV4 was licensed on the basis of safety and immunogenicity, and was demonstrated to be non-inferior to meningococcal polysaccharide vaccine (MPSV4), the vaccine then licensed for use in the US. Previous studies have shown that polysaccharide vaccine is 85% effective against serogroup C meningococcal disease [1Rosenstein N, Levine O, Taylor J, et al. “Efficacy of meningococcal vaccine and barriers to vaccination.” JAMA 1998;279:435-9]. In pre-licensure clinical trials with MCV4, 92% of subjects demonstrated seroresponse to serogroup C, while 82% seroresponded to serogroup Y. The incidence of meningococcal disease was at a historic low prior to the implementation of MCV4, and this has delayed efforts to conduct a vaccine effectiveness analysis using case-control methodology. However, through efforts to conduct a case-control study, CDC became aware of a number of cases of meningococcal disease in MCV4 recipients. The cases Ms. MacNeil presented during this session all occurred between January 2005 and December 2008, and were identified by Active Bacterial Core Surveillance Sites (ABCs) and MeningNet sites, which are participating in an on-going MCV4 effectiveness case-control study. Surveillance for meningococcal disease in these sites is a mixture of both active and enhanced passive surveillance. Data were collected for each of these cases through case report forms and medical record reviews. The following map reflects the ABCs and the MeningNet sites included in this analysis. Together, the ABCs and MeningNet sites cover 54% of the US population: Cases were included in this analysis if they had isolation of a vaccine preventable serogroup of Neisseria meningitidis (serogroup A, C, Y, or W-135), or detection of DNA from a vaccine preventable serogroup in a clinical specimen taken from a normally sterile site, more than 10 days after vaccination with MCV4. From 2005 to 2008, 14 cases of meningococcal disease were identified in MCV4 recipients. Of these, 13 (93%) were culture confirmed, 1 case was polymerase chain reaction positive (PCR+) with clinically compatible illness, 8 (57%) cases were caused by serogroup C, and 6 (43%) cases were caused by serogroup Y. All 14 cases had received MCV4, and no common lot of vaccine was identified among the cases. The median time from vaccination to disease onset was 395 days (range 43 to 1,021) and cases in vaccinated persons were identified in 6 of the 20 participating case-control study sites. Of these, 7 (50%) cases were male, 7 (50%) cases were attending college, and 2 (14%) cases were military recruits. The median age at vaccination was 18.4 years (range 12.6 to 20.5), the median age at time of disease was 19.9 years (range 15.2 to 21.6 years). Nearly half of the cases occurred within the first year following vaccination, with other cases occurring 1 to 2 years or more 2 years post-vaccination. In interpreting these data, it is important to note that MCV4 coverage was low in 2005 and 2006. Only cases who were vaccinated early had time to be observed 2 to 3 years post-vaccination. With time, this distribution is expected to change. With regard to the clinical description of the cases, 13 (93%) cases were hospitalized. The median hospitalization time was 3 days (range 0 to 46 days). There were 3 fatal cases (21% case fatality). Meningitis was reported in 6 (43%) cases and bacteremia in 8 (57%) cases. Regarding underlying conditions, Case 1 had a pulmonary embolism and deep vein thrombosis; Case 2 had Type 1 diabetes and mitro valve prolapse; Case 3 had irritable bowel syndrome and eczema; Case 4 was a current smoker; Case 5 had a history of pyelonephritis; Cases 6, 8, 10, 11, and 12 had no reported underlying conditions, Case 7 had seasonal allergies; Case 9 had a prior history of bacterial meningitis and recurrent infections; Case 13 was taking a medication that inhibits complement; and underlying medical conditions were unknown for Case 14. It is expected that cases of meningococcal disease would occur in vaccinated persons; however, as CDC began to receive reports of cases in vaccinated persons, they wondered whether the 14 observed cases were within the range of what would typically be expected. To estimate the expected number of cases in vaccinated persons, a simulation approach was used. The simulation approach is useful for modeling phenomena with significant uncertainty in inputs such as MCV4 coverage in the analysis. The simulations rely on repeated random sampling. The estimates of vaccine effectiveness were varied in the simulations to determine how likely the observed outcome of 14 cases in vaccinated persons was. Because the population under surveillance included only ABCs and MeningNet sites, the calculation of expected number of cases was limited to this population as well. In the analysis, an incidence rate of .38 per 100,000 was used, which was the incidence of serogroup C and Y disease among 13 to18 year olds. It was calculated using 2002-2006 ABCs data, and was estimated to the US population. This incidence rate is similar to the observed rates in the unvaccinated that were calculated using data from the 20 participating case-control study sites. National immunization survey (NIS) teen estimates for MCV4 coverage were used when they were available. NIS teen provides coverage estimates for 13 to 17 year olds and at this time is complete for 2006 and 2007. In the analysis, CDC was interested in estimating cases for 2005-2008. For 2005 and 2008, coverage had to be estimated based on the limited distribution and claims data available. In 2005, estimated coverage for 13 to 17 year olds was 4%. In 2008, coverage was estimated to have increased to approximately 50% in this age group. Because NIS Teen only provides coverage estimates for 13 to 17 year olds, coverage also had to be estimated for 18 year olds. For the primary analysis, CDC used the best estimates of what coverage actually was in 18 year olds and increased coverage over time from 2005 to 2008. Because there was greater uncertainty in the estimates for 18 year olds, a sensitivity analysis was also done for varying coverage estimates among those 18 years of age or older. Determining the coverage in 18 year olds was the most challenging aspect of this analysis because it was complicated by the fact that coverage among all 18 year olds is very different than coverage among college freshmen. Coverage also likely varies between colleges. The following table summarizes the coverage estimates used in the primary analysis: These coverage estimates represent the best estimate as to what coverage actually was in each year and each group. The way these coverage estimates are applied also accounts for the fact that those over 18 will not continue to be vaccinated with MCV4 and, therefore, maintains the coverage level reached at 18 years of age for that birth cohort. These 18 year olds are also maintained in the populations, so the total population in the analysis increases over time. Regarding the methodology used in the simulations, a record was created for each person in the birth cohort. A vaccination status was then assigned to each person, which was determined by a uniform random number in the coverage assumptions for that birth cohort. The disease status was then assigned to each person, which was also determined by uniform random number along with vaccine effectiveness and incidence rate assumptions. Each simulation was run 1,000 times. When it was complete, it produced a range of expected values given the assumptions used. The results of the simulations were used to determine the probability of seeing 14 or more observed cases by determining the area under the curve on the right tail of the histogram. Based on best estimate of coverage in 18 year olds, if MCV4 was 90% effective, a median of 7 cases would be expected, and the probability of observing 14 or more cases of meningococcal disease in vaccinated persons would be 2.9%; therefore, based on the best estimates of MCV4 coverage, vaccine effectiveness appears to be greater than 80%. It is unlikely to be 90% effective. Regarding the sensitivity analysis of the probability of seeing 14 or more cases based each coverage assumption and level of vaccine effectiveness tested, 18 year old coverage was held constant for each birth cohort. If there was 50% coverage (coverage was held constant at 50% for all persons 18 years of age or older during 2005-2008) and MCV4 was 90% effective, there would be a 5% chance of observing 14 cases in vaccinated persons. If MCV4 were 85% effective, there would be a 47% chance 14 cases would be observed. Even with high estimates of coverage in the sensitivity analysis, MCV4 appeared to be between 80% and 90% effective. To summarize, this is the first estimate of vaccine effectiveness for MCV4. The results of this analysis suggest that effectiveness of MCV4 is between 80% and 90%, which is similar to polysaccharide vaccine. It is also important to consider that all of the observed cases of meningococcal disease in MCV4 recipients occurred less than 3 years since vaccination therefore this estimate of vaccine effectiveness applies to persons less than 3 years since vaccination. The ACIP Meningococcal Working Group expects more data to be available in 1 to 3 years to further evaluate vaccine effectiveness. Plans are to expand the MCV4 effectiveness case-control study to additional sites with the hope that this analysis will allow CDC to determine separate estimates of vaccine effectiveness for serogroup C and serogroup Y. Additionally, with the introduction of new conjugate vaccines, vaccine-specific analyses will be conducted. At this time, CDC is unable to evaluate duration of protection using this early data; however, they will continue to monitor for cases of disease in vaccinated persons through the case-control study and ongoing surveillance in the US. Discussion Dr. Neuzil requested further rationale for why, with respect to effectiveness estimates, a straight case-control study using the ABC and MeningNet sites was not done. Ms. MacNeil responded that CDC is in the process of conducting that study, but it is not complete. It has been slow because the incidence has been so low in the last few years. What was presented was simply an early estimate using that data. Eased on the case-control study are anticipated within the next year or two. Dr. Pickering requested clarification between what was recognized and what was actually tested for. That is, were the 12 people who did not have an apparent immunity deficiency tested for terminal complement deficiency or any of the other conditions known to be associated with this disease? Ms. MacNeil replied that the records reviewed were of the actual hospitalization for meningococcal disease. There were no additional indications of other cases that had complement deficiencies at the time of disease; however, CDC did not have any follow-up records regarding whether they were tested for complement deficiencies later. Rationale and Proposed Recommendations for Revaccination of Persons at Increased Risk for Meningococcal Disease Amanda Cohn, MD Division of Bacterial Diseases / NCIRD Centers for Disease Control and Prevention Dr. Cohn presented the rationale and proposed recommendations for revaccination of persons at increased risk for meningococcal disease. She acknowledged and thanked sanofi pasteur for providing CDC with much of the data to be presented during her presentation. She then explained the working group rationale for recommending revaccination with quadrivalent meningococcal conjugate vaccine (MCV4) for high risk groups, clarifying that at this time, there is still a single licensed vaccine, MCV4, to which she would be referring. However, these proposed recommendations are intended to apply to any quadrivalent conjugate vaccine used, and the language will be adjusted as new vaccines are licensed. In addition, she defined the group of persons at increased risk, reviewed the available data on safety and immunogenicity of revaccination, and reviewed the proposed recommendations. In 2005, ACIP recommended that persons aged 2 to 55 years who are at increased risk for meningococcal disease be vaccinated with MCV4. MCV4 was licensed in 2005 only for a single dose, and there were no recommendations made for revaccination made at that time. There was an expectation that conjugate vaccines would provide longer lasting protection than polysaccharide vaccine. Since that time, it has become clear that data on duration of protection from primary vaccination and the safety and efficacy of revaccination are limited, and it is unlikely there will be more data available. Given that many individuals in this high risk group are at much greater risk for severe disease, the mortality among these high risk groups can be high. Therefore, the working group believes that protection should be optimized for these high risk groups. There is a precedent for revaccination with meningococcal vaccines as the recommendation to revaccinate with polysaccharide states: “Revaccination might be indicated for persons previously vaccinated with MPSV4 who remain at increased risk for infection. – Children (age <4 years) should be considered for revaccination after 2-3 years – For older children and adults, revaccination might be considered after 5 years” This recommendation was also made in the setting of limited data on duration of protection, and even some concern about blunted response of revaccination; however, revaccination of these groups has become a standard of care. Therefore, the burden of proof needed to be that conjugate vaccines provide substantially greater protection than polysaccharide vaccine five years after vaccination not to recommend revaccination. While these individuals may continue to be protected beyond five years, immunogenicity data are not strong enough for the working group to be assured. With respect to why the working group believes high risk groups should be revaccinated, the group evaluated data on circulating antibody, but memory and herd immunity are also important benefits of conjugate vaccines. Serum bactericidal activity (SBA) is a measure of functional antibody or the ability of sera to kill a strain of Neisseria meningitidis in the presence of complement. Baby rabbits were used as the complement source. SBA is an accepted marker of immunogenicity, but no there is no clear cut off that indicates long-term protections for individuals after vaccination. Dr. Cohn presented the percentage of persons with SBA titers greater than 1:128, because this was the cutoff that was used for licensure trials for MCV4. However, this may be an over-estimate of titers needed for protection. Additionally, the assays are highly variable across laboratories. There are also properties of conjugate vaccines, such as the ability to mount a memory response, that are not quantitated in SBA titers. The contribution to protection of these conjugate properties versus levels of circulating antibody is not well-understood, but there is evidence from the meningococcal group C conjugate vaccine (MenC) experience in the UK that memory alone is not enough to protect against meningococcal disease, perhaps because there is not enough time to mount a memory response before infection becomes overwhelming. Finally, there is not high enough coverage with MCV4 that reduced transmission can be expected, so no additional protection can be presumed through herd immunity at this time. SBA-BR seroresponse ?1:128 post-vaccination at years 3 and 5 post-vaccination, serogroup C, Dr. Cohn presented data from studies of subjects in the initial clinical trials. The total number of subjects tested 3 and 5 years out is very small. The 3-year subjects were initially vaccinated at 11 to 18 years of age, and the 5-year year subjects were initially vaccinated at 2 to 10 years of age. Three years after vaccination, the subjects vaccinated with MCV4 had substantially higher titers than those vaccinated with MPSV4 in naïve controls. At five years, only 50% of those vaccinated with MCV4 has titers at or above 1:128, which is greater than the 42% seen in the other two groups, but is still low. There is similar data at 5 years among subjects initially vaccinated at 11 to 18 years of age, but Dr. Cohn did not show that data because the number of subjects in that study was very small. However, the data is comparable and is very similar to the 2 to 10 year olds who were vaccinated 5 years previously [Data courtesy of sanofi pasteur, 3 year follow-up of MTA02 (11-18 year-olds), 5 year follow-up of 603-02 (2-10 year-olds)]. In terms of the GMTs of the SBA, there is better persistence of SBAs in subjects vaccinated with MCV4 compared to MPSV4 and at 5 years. Titers are higher than age matched controls, which is not the case for subjects who were previously vaccinated with MPSV4, but the absolute values of these titers is still low. In the smaller study of 11 to 18 year olds at 5 years, the GMTs were similarly low. To summarize, the 5-year SBA persistence data do not convince the working group that protection, as measured by circulating antibody at 5 years, is substantially higher in subjects vaccinated with MCV4 than in unvaccinated individuals or in subjects who received MPSV4,[ Data courtesy of sanofi pasteur, 3 year follow-up of MTA02 (11-18 year-olds), 5 year follow-up of 603-02 (2-10 year-olds)]. The proposed 2009 definition for persons recommended for revaccination includes the following: * Those at increased risk of infection – Persistent complement deficiency – Anatomic or functional asplenia * Those with suboptimal response to vaccination – Anatomic or functional asplenia * Those with prolonged or frequent exposure – Microbiologists who are routinely exposed to isolates of N. meningitidis – Frequent travelers to or people living in areas with high rates of meningococcal disease (Meningitis belt) Previous ACIP language implied that only persons with terminal complement component deficiencies are at increased risk. To clarify, the working group would like to change this language to state that persons with persistent deficiencies in the complement pathway are at increased risk, and those deficiencies would be listed in the recommendations. Late complement pathway deficiencies are highly associated with recurrent disease, but other deficiencies put persons at risk as well. For example, 70% of children with primary C3 deficiency have an episode of invasive bacterial disease in a median age of 2 years, and 55% of this disease is caused by Neisseria meningitidis. There is a high risk for recurrent disease. In comparison, C1, C2, and C4 deficiencies are rarely associated with invasive disease. Properdin, factor D, and terminal complement deficiencies also cause a high rate of infections (50-60%). These occur in the teenage years, and almost all of this disease is caused by Neisseria meningitidis. Complement-independent, antibody-mediated phagocytic killing can occur with high levels of antibody. Therefore, maintaining high levels of antibody in this population is important. The data on the risk of disease in persons with asplenia is from older case series and studies that showed risk for all encapsulated organisms, including, but not specifically for Neisseria meningitidis. So while the working group was unable to offer a precise risk for disease among asplenics, it is widely accepted that persons with asplenia are at risk for invasive infection from Neisseria meningitidis. There are also data to suggest that persons with asplenia have a suboptimal response to vaccination. A group of 130 persons with asplenia had a significantly lower response to one dose of MenC vaccine in the UK. Their SBA GMTs were 157 compared to 1448 among non-asplenics, and only 80% of those individuals had titers greater than 1:8 SBA [Balmer, P et al. Infection and Immunity, Jan 2004, 332-337]. In terms of exogenous exposures putting a person at increased risk, microbiologists exposed to isolates of Neisseria meningitidis are at increased risk with an estimated attack rate of 13 per 100,000 microbiologists exposed to an isolate of Neisseria meningitidis during 1996-2001, compared to a rate of .3 per 100,000 among US adults. There is also a high risk of mortality, which was 50% among a small group of laboratory workers with an n of 16, which is possibly related to this group being exposed to a high bacterial load [Sejvar et al, J. Clin Micro, 2005]. The disease risk in travelers or to persons living in areas with the epidemic meningococcal disease, such as the African Meningitis Belt, is not known. It is likely to only be higher if that person is living in or working with local population; however, given the potential for limited access to medical care while traveling, the working group felt that this was important to include in these recommendations. Additionally, vaccination has a small, but possible ability to reduce risk of colonization and spreads to household contacts of travelers upon the return, such as occurred after the W 135 Hajj outbreak. In terms of how many people would be included in this recommendation, based on private claims data provided to the working group by sanofi, approximately 20,000 doses annually are given to groups for which vaccine is recommended only for high risk persons. Over the course of five years, this would be about 100,000 persons in total who received vaccination, but not all of these individuals would necessarily need to be revaccinated. Travelers may not be included in these estimates, as vaccination is an out-of-pocket cost for travelers, but most travelers will unlikely be traveling five years after to the African Meningitis Belt, so they were unable to estimate how many travelers would be included. Although there are about 60,000 persons with sickle cell anemia in the US, the prevalence of complement deficiencies and other types of asplenia is unknown. So the working group recognizes that this recommendation is off-label use of the vaccine, but they are comfortable with this given the targeted and small number of individuals at increased risk included in these groups. The working group discussed at length their preference not to include college freshmen living in dorms and military recruits in the groups recommended for revaccination at this time. This is a much larger cohort of individuals, more than 600,000 / year with much broader policy and programmatic implications. In 2009, very few persons in these groups were vaccinated greater than five years prior and coverage in the fall of 2006 was only 11%, so it was likely to even be lower. For the upcoming college year, the number of adolescents vaccinated more than five years ago will be very low. In most colleges, there is relatively high vaccination coverage among college freshmen, and there is close to 100% coverage among military recruits. Therefore, individuals no longer protected by vaccine may be protected by the potential for herd immunity in these institutions. The working group agreed that more time should be taken to assess the degree of transmission in these highly vaccinated populations, and the need for revaccination in these groups. There are limited safety data available on revaccination. Dr. Cohn reported on data from two studies. The first was from subjects initially vaccinated at 11 to 18 years old and the second was in subjects initially vaccinated at 2 to 10 years of age. The proportion of subjects with local and systemic adverse events was similar whether they received MCV4 or they were vaccine-naïve prior to this initial vaccination. The reactions were similar and there were no serious adverse events in any of the groups. A strong boost response was observed with revaccination for both serogroup C and serogroup Y. In terms of the percentage of seroresponders after revaccination compared to age matched controls, 100% of subjects previously vaccinated with MCV4 had titers at or above 1:128. A strong boost response was also demonstrated by high GMTs among subjects previously vaccinated, compared to vaccine-naïve subjects. The same was true for serogroup Y. More subjects were able to retain titers at or above 1:128 five years after initial vaccination with serogroup Y, compared to serogroup C. A large portion of the vaccine-naïve individuals also had antibody titers above or at 1:128. This may be due to natural immunity due to nasal pharyngeal carriage or it may be related to the assay used. Nevertheless, a boost response to revaccination was clearly demonstrated for serogroup Y compared to the previously vaccine naïve group [Data courtesy of sanofi pasteur, 5 year follow-up of 603-02 (2-10 year-olds at dose 1)]. To summarize, even with the small number of individuals in these studies, the ACIP working group was convinced that revaccination would be safe and would induce a boost response. The working group also evaluated this five year interval for revaccination among the young children aged 2 to 6 years. Regarding the SBA GMTs by single year of life for 2 to 10 year olds, there are very few persons in each of the age years where it is clear that the initial immune response in the very young children is similar to polysaccharide vaccine. It is known that protection in young children vaccinated with polysaccharide vaccine is not long-lasting [Pichichero M et al. Pediatr Infect Dis J. 2005;24:57-62]. Limited antibody persistence data with MCV4 suggests children vaccinated at age 2 to 3 years are not as well-protected three years post vaccination. Of children vaccinated at age 2-3 years, 14.6% (n=48) had an hSBA titer >1:4 3 years after vaccination [Granoff, D et al. PIDJ 2005:24, 132-136]. Children at increased risk in this age group are also likely to be asplenic or have complement deficiency, and may have a suboptimal response to vaccine. The working group agreed that an additional dose of vaccine three years after the first MCV4 may benefit this small group of children. Thus, the working group was proposing revaccination for high risk persons out of an abundance of caution. In the setting of demonstrated disease risk, which is very high in some of these age groups, and a low risk for serious adverse events, the working group felt that it would be useful to have limited off-label use in this small targeted group. There is evidence of waning functional antibody, which may or may not indicated lack of protection; however, it is known that high levels of circulating antibody is important for persons with complement deficiencies. Persons at increased risk are not protected at this point by herd immunity in the population. There is also strong evidence of a boost response. Therefore, the proposed recommendation is: “Persons aged 2-55 years who remain at increased risk for meningococcal disease 5 years after vaccination with MCV4 or MPSV4 should be revaccinated with MCV4. This includes: – Persons with persistent complement component deficiencies* – Persons with anatomic or functional asplenia – Microbiologists who are routinely exposed to isolates of N. meningitidis – Frequent travelers to or people living in areas with high rates of meningococcal disease (African meningitis belt) *inherited or chronic deficiencies such as C3, properdin, factor D, or late complement components” Two additional components of this recommendation would be stated as follows: “At this time, college freshmen living in dorms who were previously vaccinated against meningococcal disease at age 11-18 years are not recommended to be revaccinated with MCV4. Children who received their first MCV4 or MPSV4 at age 2-6 years and remain at increased risk for meningococcal disease should be vaccinated with an additional dose of MCV4 3 years after their first meningococcal vaccine.” Discussion Referring to the safety of revaccination [slide 15], Dr. Neuzil said it would be ideal to see a larger number of subjects who had received a repeat vaccination in the 11 to 18 year old group (n=17). Based on a power calculation, that would not be high enough to detect a difference. She wondered whether Dr. Cohn could tell them anything more about local reactions, even though the total number was close, in terms of whether there was any trend toward greater severity, et cetera. Dr. Cohn responded that there is one additional study that she did not include in adolescents 11 to 18 years of age who were revaccinated at three years rather than five years. The n in that study was greater and the proportions were similar. She requested that someone from sanofi further discuss the reactions as she did not have specific information beyond whether they fell into one of the specified categories. Dr. Hosbach (sanofi pasteur) responded that they have larger numbers at three years which he agreed to provide to the group, although he did not have it with him. There was nothing remarkable. Dr. Marcy expressed concern about the data Dr. Dull presented for Menactra®, given that subjects barely made it at 1:8 in some cases. Now they were viewing 1:128, and the levels were very high. He was trying to understand the difference, because simply attributing it to different assays was not sufficient. Dr. Cohn responded that human complement was used in the other assays, while the sanofi and UK studies had used baby rabbit complement for the most part. There are also differences in assays in various laboratories. The level needed for licensure was based on baby rabbit complement, which seems to have changed in the process in that she believed human complement would be required for all future studies. She inquired as to whether anyone from FDA wanted to comment. Dr. Hosbach (sanofi pasteur) responded that baby rabbit complement was utilized initially in comparing what was licensed for Menomune®, the polysaccharide vaccine. That was utilized as a standard. For studies in infants and toddlers, human complement was used as well. Referring to the second component of the proposed recommendation, James Turner (ACHA) thought they would find that there would be students coming to school who received polysaccharide when they were teens. The proposed recommendation seemed to state that no revaccination would be recommended if they had been vaccinated against meningococcal disease. He suggested an amendment to read, “Those who were previously vaccinated with MCV4, would not need to be revaccinated with MCV4.” Dr. Cohn responded that the change could be made to reflect MCV4, and a line could be added to indicate that persons with polysaccharide vaccine should be revaccinated if they have not been vaccinated in five years. Amy Middleman (SAM) noted that the proposed recommendations indicated that persons aged 2 to 55 who remained at increased risk from meningococcal disease should be immunized again five years later. However, the second component of the recommendation separated out 2 to 6 year olds and indicates revaccination at three years. She wondered whether the first part should actually read “7 to 55 year olds.” Dr. Cohn said that consideration was given to changing that, but the caveat is that if children are initially vaccinated at age 2 and then they are vaccinated at age 5, by the next time they would be over 7 years old. They did not want people to think that they continually needed to be vaccinated at three years. She agreed that they could change it if it seemed confusing. Dr. Baker pointed out that the dashes needed to be replaced with “through.” Dr. Sawyer was not clear whether the working group was proposing multiple revaccinations or a one-time revaccination. Dr. Cohn answered that as currently written, the recommendation was that persons continue to be vaccinated every five years. This can be readdressed in the future, but the group was thinking that to simplify the recommendations, this language would work well. For this particular group of individuals, this may have to be revisited every five years and would likely require the same recommendation given the high risk of disease. Dr. Baker agreed that it was frustrating, given the limited data. There is a tremendous risk for the individuals to be included. The population and costs are small. Microbiologists are already covered by the Occupational Safety & Health Administration (OSHA) for vaccine, and travelers or their employers pay for the vaccine. The risk of not having protective immunity drove this recommendation. The poorest response in is ages 2 through 4 year. They are more likely to be vulnerable as they turn 5 or 6, depending upon when they have been vaccinated. The Red Book used to say 3-5, but people were confused about whether this meant 3 or 5. Moving to a five-year recommendation as routine for adolescents, but a three-year for children younger than that is consistent with the Red Book. With regard to the lack of specific safety data, Dr. Sawyer wondered whether Vaccine Adverse Event Reporting System (VAERS) data were assessed to determine whether those who had been following this practice without recommendations had generated any reports to VAERS. Dr. Cohn responded that there is a VAERS analysis of people who are vaccinated with MCV4 at all. There has not been a specific analysis to examine people who may have received two doses. Aside from the reports of Guillain-Barré Syndrome (GBS), there is nothing specifically about syncope in adolescents. In children who received many other vaccines, the adverse events are similar (e.g., local reactions in other vaccines). Dr. Cieslak indicated that he had not seen any data on breakthrough cases because of waning immunity, nor had he seen data on the efficacy side suggesting that that population they were proposing to revaccinate was likely to be protected after the second dose. If I had to guess, because they did not respond to the first dose, they would probably be less likely to respond to the second dose. Dr. Baker responded that the data Dr. Cohn summarized on asplenics led to the UK recommendation that adult asplenics receive two doses two months apart. They immunized and bled subjects one month. It is known that asplenics do not have a good primary response, so revaccinating them may be similar to giving them two doses, which is routine health policy in the UK. Even if one or two microbiologists died of meningococcal disease at five years, she did not want to be the one to find out. While there are very limited data regarding safety, this is driven by the incredible risk for these patients. The difference is 13 per 100,000 for microbiologists compared to .3 per 100,000. Nancy Messonnier added that the working group discussed balance: Do you wait for breakthrough cases to occur before you make a recommendation? Part of the conclusion that the working group came to was that the standard of care was actually the polysaccharide vaccine recommendation for revaccination, which appeared to be based on a similar lack of data on breakthrough cases. As discussed in the working group, there was not convincing evidence that the conjugate vaccine behaved substantially differently in these age groups than polysaccharide vaccine such that a different recommendation would be warranted than would be made for polysaccharide vaccine. Dr. Englund noted that there were some data showing that college freshmans’ re-immunization was not very robust. She wondered whether the working group was happy with that part of the recommendation. Dr. Cohn responded that there are some data to show that individuals who initially received polysaccharide vaccine and were then give conjugate vaccine were able to overcome and boost. Though not to the same extent as persons who previously received conjugate vaccine, it was better than an additional dose of polysaccharide vaccine. Dr. Judson inquired as to whether this would have to go back through the FDA for a change in indications or labeling, given that they were making a recommendation based on inadequate efficacy data that the FDA might not approve. Dr. Cohn responded that the recommendation was for off-label use. Dr. Baker replied that the current label is for one dose. There is no re-immunization labeling at this time, as has been the case for polysaccharide vaccine for years. The initial efficacy was in the military where human complement was used. In the military polysaccharide was developed because of the tremendous outbreaks and the high mortality. There was a great efficacy study in which efficacy was correlated with bactericidal activity in recruits. That was the history of a very bad disease versus a very safe vaccine. With regard to Dr. Englund’s question regarding whether the working group was happy, Dr. Baker said she was not happy but this was all the data they had and she was concerned about individuals at high risk. Dr. Englund felt strongly that the lack of data was very concerning. This is a major problem that will affect a large segment of children who received the polysaccharide vaccine. There are mechanisms to get it funded that ACIP should be encouraging. Dr. Baker thought the assumption that there is a large population of children who received polysaccharide vaccine who will need to be revaccinated was a tremendously wrong assumption. Dr. Cohn thought that most children who received polysaccharide vaccine would have received it prior to going to college unless they were in one of the high risk groups. If they were in a high risk group, they would fall under the recommendation to continue to be revaccinated with MCV4. The polysaccharide recommendations were only made for children who were entering college and were living in dorms. Dr. Hosbach (sanofi pasteur) stated that this is not in the package insert. The older package insert does indicate that the ACIP recommendation says to immunize these populations every three to five years. They do intend to generate additional data. Motion: MCV4 Revaccination for Persons at Prolonged Increased Risk Dr. Sawyer moved to approve the revised recommendations as stated in the presentation. Dr. Sumaya seconded the motion. The recommendation will include clarification again MCV4 and dashes with be changed to “through.” The motion passed with 13 affirmative, 1 negative, and 1 abstention. VFC Resolution Update: Meningococcal Vaccines Jeanne M. Santoli Immunization Services Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Dr. Santoli indicated that the purpose of this proposed resolution was to update the revaccination recommendations discussed during this session and to streamline the resolution through the use of links to published documents. The MPSV4 Component of the VFC Resolution, I are: * Eligible groups --> All children 2-18 years of age. * Recommended Meningococcal Polysaccharide Vaccine Schedule --> The recommended schedule for meningococcal polysaccharide vaccine can found at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm --> See Section B. Conjugate Vaccine to Prevent Meningococcal Disease for potential, limited use of MPSV4 for revaccination. * Dosage Intervals for Meningococcal Polysaccharide Vaccine --> http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm --> See Section B. Conjugate Vaccine to Prevent Meningococcal Disease for potential, limited use of MPSV4 for revaccination. * Recommended dosage --> The recommended dosage can be found in the package inserts available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 * Contraindications and Precautions --> Contraindications and Precautions can be found in the package inserts available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 MCV4 Component of the VFC Resolution, I are: * Eligible groups --> All children 2-18 years of age. --> Recommended Meningococcal Polysaccharide Vaccine Schedule --> The recommended schedule for meningococcal conjugate vaccine can found at: * http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm * http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5631a3.htm * http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5648a4.htm * Revaccination is recommended for children at increased risk of meningococcal disease, including: --> Persons with persistent complement component deficiencies (inherited or chronic deficiencies such as C3, properdin, factor D, or late complement components ) --> Persons with anatomic or functional asplenia --> Persons infected with HIV --> Microbiologists who are routinely exposed to isolates of N. meningitidis --> Frequent travelers to or people living in areas with high rates of meningococcal disease (African meningitis belt). * Dosage Intervals for Meningococcal Conjugate Vaccine --> http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm --> http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5631a3.htm --> http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5648a4.htm * Children through age 18 years who received their first dose of MCV4 or MPSV4 at ages 2-6 years and remain at increased risk for meningococcal disease should receive an additional dose of MCV4 at 3 years after their first dose. * Children through age 18 years who received a dose of MCV4 or MPSV4 after age 6 and remain at increased risk for meningococcal disease should receive an additional dose of MCV4 at 5 years after their previous dose. * MCV4 is preferred for revaccination, but MPSV4 is an acceptable substitute for persons with precautions or contraindications to MCV4 vaccine. * Recommended dosage --> The recommended dosage can be found in the package inserts available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 * Contraindications and Precautions --> Contraindications and Precautions can be found in the package inserts available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 The underlined group, persons infected with HIV, was not a group that was discussed. However, that group was previously included in the VFC resolution for vaccination by the ACIP, so it was brought forward into this VFC resolution to give providers who are treating these children the flexibility of vaccinating VFC eligible children with this vaccine. Then the resolution concludes with the following statement about making updates based on published documents: “If an ACIP recommendation or notice regarding meningococcal vaccination is published within 12 months following this resolution, the relevant language above (except in the eligible groups sections) will be replaced with the language in the recommendation and incorporated by reference to the publication URL. Motion: VFC Resolution Update for Meningococcal Vaccines Dr. Baker moved to approve the revised recommendations as stated in the presentation. Dr. Sawyer seconded the motion. It was noted that all dashes should be replaced with “through.” The motion passed with 14 affirmative, 0 negative votes, and 1 abstention. Introduction Paul Cieslak, MD Chair, ACIP JEV Vaccines Workgroup Dr. Cieslak offered gratitude to the technical advisors the workgroup was able to obtain from the outside including, Christina Greenaway (International Society of Tropical Medicine), Tony Marfin (Washington Department of Health), David Shlim (ASTMH), and Tom Solomon (University of Liverpool). He explained that the JEV Vaccines Workgroup was charged with reviewing safety and immunogenicity data for the new inactivated Vero cell-derived JEV vaccine, tradename Ixiaro ®; updating and revising the 1993 ACIP recommendations for the use of JE vaccines among US travelers; monitoring the availability of JEV vaccines for US travelers and working to mitigate possible supply issues (BIKEN’s production of JE-VAX ®); and addressing the availability of JEV vaccines for US children, with the new vaccine being labeled only for persons 17 years of age and above. Revised Recommendations for the Use of Japanese Encephalitis Virus Vaccines Marc Fischer, MD, MPH Arboviral Diseases Branch DVBID, NCZVED, CDC Dr. Fischer reminded everyone that Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus. JEV is the leading cause of encephalitis in Asia, with an estimated 35,000 to 50,000 annual cases. Of these, 20%-30% of patients die and 30%-50% of survivors have significant sequelae. There are no specific antiviral therapies, and treatment consists of supportive care. JEV is transmitted in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds. JEV is transmitted to humans through the bite of an infected mosquito, but less than 1% of infected people develop symptomatic disease. Humans are a dead-end host and do not develop a level or duration of viremia sufficient to infect mosquitoes. Japanese encephalitis occurs primarily in rural agricultural areas, often associated with rice production and flood irrigation. The mosquitoes that transmit JEV feed primarily outdoors during the evening and night. In endemic countries, most adults have protective immunity and JE is primarily a disease of children. However, since travelers from non-endemic countries usually do not have JEV antibodies, travel-associated Japanese encephalitis can occur among persons of any age. In most temperate areas of Asia, JEV transmission is seasonal, and human disease usually peaks in summer and fall. In the subtropics and tropics, transmission patterns vary and human disease often peaks during the rainy season, but may occur year round. From 1973 to 2008, there were 55 cases reported in the literature of travel-associated Japanese encephalitis among people from non-endemic countries, including the US. The median age of these cases was 34 years, patients ranged from 1 to 91 years of age, 53% of the patients were male, 34 of the travel-associated cases were tourists, 9 were expatriates living in Asia, and 6 were soldiers or military personnel. The type of travel was unknown for another 6 cases. Ten of the reported cases were fatal, and 24 of the survivors had sequelae.  None of these patients had received JEV vaccine.   For 37 of the 55 travel-associated cases, more complete information was available regarding their itineraries and activities. Duration of travel for these cases ranged from 10 days to 34 years, and 65% of the cases were traveling for a month or longer. Of the 13 short-term travelers, 10 had a trip duration of 2 to 4 weeks, and 3 had traveled for 10 days to 2 weeks. Among these shorter-term travelers, 3 had known extensive rural exposures, and 8 stayed in resorts or coastal hotels with shorter trips into more rural areas. Two cases did not have any risk-related itinerary information available. No cases were reported among short-term travelers who visited only urban areas. From 1943 to 1972, there were more than 300 cases of JE among U.S. military personnel. Between 1973 and 1992, 11 cases were reported among US citizens, including 5 among civilian travelers. Since December 1992, when a JEV vaccine was first licensed in the US, only 4 cases of Japanese encephalitis have been reported among US citizens, all among civilian travelers or expatriates. Three of these cases occurred among returning immigrants or travelers visiting family in Asia. Estimating the incidence of Japanese encephalitis for travelers to Asia is difficult. Extrapolating from the rates of disease among unimmunized US military personnel or resident children in endemic areas, the risk of Japanese encephalitis for travelers with prolonged stays in rural areas with active JEV transmission may theoretically be as high as 10 to 200 cases per 1 million travelers per week. However, most travelers do not have this type of itinerary or risk, and between 1973 and 2008, there were only 15 cases of JE reported among US travelers to Asia. In 2004, there were an estimated 5.5 million entries of US travelers into Japanese encephalitis endemic countries. Using these figures, for all travelers to Asia, an overall risk of less than 1 case per 1 million trips would be estimated. Based on the available data, the workgroup concluded that the overall risk of Japanese encephalitis for most travelers to Asia is very low, but that the risk varies based on destination, duration, season, and activities. The risk of Japanese encephalitis among expatriates and travelers who stay for prolonged periods in rural areas with active JEV transmission, are likely similar to that of the susceptible resident population. Travelers on brief trips may be at increased risk if they have outdoor or nighttime exposures in rural areas, especially during periods of active transmission. Short-term travelers, whose visits are restricted to major urban areas, are at minimal risk for Japanese encephalitis. Two JEV vaccines are currently licensed in the US. JE-VAX®, an inactivated mouse brain-derived vaccine, has been licensed since 1992 for use in travelers one or more years of age. In March 2009, the FDA approved IXIARO®, an inactivated Vero cell-derived vaccine, for use in travelers 17 years of age or older. The inactivated mouse brain-derived vaccine was first developed in the 1960s. It has been administered to millions of people worldwide and has been used effectively to control Japanese encephalitis disease in several Asian countries including Japan, Taiwan, South Korea, and Thailand. In December 1992, a formulation of this vaccine was first licensed in the US. The vaccine was manufactured by BIKEN in Osaka, Japan and is distributed in the US by sanofi pasteur. However, in 2006, BIKEN discontinued production of JE-VAX®, and remaining supplies are now limited. JE-VAX® is a formalin inactivated vaccine derived from wild-type Nakayama-NIH JEV strain grown in mouse brains. The final preparation is lyophilized and contains gelatin as a stabilizer and thimerosal preservative. The primary immunization series consists of three doses administered subcutaneously on days 0, 7, and 30. Efficacy of the mouse brain-derived vaccine was demonstrated in a randomized, controlled trial conducted among 65,000 Thai children. Study participants were randomized to receive two doses of JEV vaccine or tetanus toxoid. After 2 years, the vaccine had an efficacy of 91% [Hoke 1988]. The current 3-dose primary immunization series for travelers was established based on immunogenicity studies performed in adults from non-endemic countries. Mouse brain-derived JEV vaccine results in mild injection site reactions in about 20% of recipients. Mild systemic side effects such as fever, headache, or diarrhea have been reported in approximately 10% to 30% of vaccinees. This vaccine has also been associated with allergic hypersensitivity reactions and rare, but serious neurologic adverse events. Allergic hypersensitivity reactions, including generalized urticaria and angioedema of the face and oropharynx, have been reported primarily among adult travelers and military personnel. The reported frequency of allergic reactions range from 10 to 260 cases per 100,000 vaccinees, and these risks vary by country, year, case definition, surveillance method, and vaccine lot [Plesner 2003; Takahashi 2000; Berg 1997; CDC 1993]. The study with the highest incidence of allergic hypersensitivity reactions included active follow-up of over 14,000 US Marines in 1997 in which 38 allergic reactions were identified, including 27 patients with urticaria, angioedema, and / or wheezing, and 11 patients with generalized pruritis. Two patients were hospitalized for observation. Although most of these reactions occurred within the first 24 hours after the first dose, when they occurred following a subsequent dose, symptom onset was often delayed with a median of 4 days and a range of up to 2 weeks [Berg 1997]. Gelatin, which is used as a vaccine stabilizer, may be responsible for some of these allergic reactions. In one study among Japanese children who received mouse brain-derived JEV vaccine, 10 children who developed an immediate hypersensitivity reaction all had measurable immunoglobulin E (IgE) antibodies against gelatin. By contrast, only 1 of 28 children developed a delayed hypersensitivity reaction, and none of 15 controls who had no allergic reaction had evidence of anti-gelatin IgE antibodies [Sakaguchi 2001]. The incidence of neurologic events reported following receipt of mouse brain-derived JEV vaccine has ranged from 0.1 to 2.6 per 100,000 vaccinees [Takahashi 2000; Plesner 1998]. These neurologic events have included paresthesia, seizures, encephalopathy, gait disturbance, and Guillain-Barre syndrome. In addition, there have been case reports of children in Japan and Korea with acute disseminated encephalomyelitis (ADEM) following vaccination. In 2005, in response to these cases, Japan suspended routine immunization with mouse brain-derived JEV vaccine. In reviewing this decision, the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety determined that a causal link had not been demonstrated. The committee recommended that, although current use and policies should not be changed, the mouse brain-derived vaccine should be gradually replaced by new generation JEV vaccines [Matsukura 1980; Ohtaki 1992; Ohtaki 1995; Sohn 2000; Takahashi 2000; Matsui 2002; Ferguson 2007; Plesner 2000; Plesner 2003]. The recently licensed inactivated Vero cell-derived JEV vaccine is manufactured by Intercell Biomedical and distributed in the US by Novartis Vaccines. This vaccine is now available in the US, Europe, and Australia, and the manufacturer anticipates having adequate supplies to meet US civilian traveler needs. IXIARO® is a formalin inactivated vaccine derived from the attenuated SA 14-14-2 JEV strain propagated in Vero cells. The final liquid preparation contains aluminum hydroxide as an adjuvant. It does not contain gelatin or thimerosal. The primary immunization series consists of two doses administered intramuscularly on days 0 and 28. The vaccine is not licensed for use in children less than 17 years of age. Due to the availability of several effective JEV vaccines in Asia, randomized, controlled efficacy trials to evaluate new vaccines would now be logistically difficult and potentially unethical. As a result, there are no efficacy data for the new Vero cell-derived JEV vaccine. Instead, the vaccine has been licensed based on its ability to induce JEV neutralizing antibodies as a surrogate for protection, and based on safety evaluations in almost 5,000 adults [Hombach 2005; Markoff 2000]. The pivotal non-inferiority study compared people randomized to receive two doses of the new Vero cell-derived vaccine to three doses of the existing mouse brain-derived vaccine. The study was performed among adults in the US, Austria, and Germany. The primary outcome measure was the proportion of vaccinees who developed JEV neutralizing antibodies based on a 50% plaque reduction neutralization test or PRNT50. The immunogenicity analysis was performed on 735 subjects who met all protocol criteria, including having no JEV neutralizing antibodies prior to vaccination. The safety analysis was performed on 863 subjects who had received at least one dose of either vaccine. Of the Vero cell-derived vaccine recipients, 98% developed a neutralizing antibody titer of 10 or greater, compared to 95% of the mouse brain-derived vaccine recipients, at 56 days after the first dose. This met the study criteria for non-inferiority. The geometric mean titers (GMTs) were significantly higher among recipients of the Vero cell-derived vaccine. However, it is important to note that this study used SA 14-14-2 as the target strain in the neutralizing antibody assay and GMTs were higher for the mouse brain-derived vaccine when the Nakayama JEV strain was used in the assay. In this study, severe pain or tenderness at the injection site was uncommon and occurred in less than 2 percent of recipients of either vaccine. However, severe redness or swelling at the injection site was significantly less common among recipients of the Vero cell-derived vaccine. The frequency of systemic adverse events was similar between the two groups [Tauber 2007]. The pivotal safety study compared 1,993 subjects who received two doses of the new Vero cell-derived JEV vaccine to 657 subjects who received two doses of a placebo adjuvant composed of phosphate buffered saline and aluminum hydroxide. Adverse events were monitored for 56 days following the first dose. The proportion of vaccinees who reported any adverse event, medically attended adverse events, serious adverse events, or an adverse event that resulted in termination from the study, were similar between the two groups [Tauber 2008]. Among the 12 (0.6%) subjects in the Vero cell-derived vaccine group who terminated the study prematurely due to adverse events, 2 (0.1%) of the events were classified as severe, including one case of gastroenteritis and one rash. Of the adverse events leading to termination, 8 (0.4%) were considered possibly related to the study vaccine, including two subjects with headaches, and one subject each with influenza-like illness, injection site pain, nausea, fatigue, rash, and dermatitis. One case of generalized urticaria was reported in a patient at 8 days after she had received her 2nd dose of the Vero cell-derived vaccine. The urticaria was described as being of moderate intensity. It was treated with an antihistamine and resolved within 3 days. Angioedema was not observed. The event was assessed by the study investigator as being unlikely related to the vaccine and the subject completed the study. Overall, the new inactivated Vero cell-derived JEV vaccine is a very promising vaccine for use in adult travelers, given its favorable immunogenicity and reactogenicity profile after a two dose primary series. In addition, because the vaccine does not contain gelatin or murine proteins, there are likely to be fewer vaccine-associated hypersensitivity or neurologic adverse events compared with the mouse brain-derived vaccine. However, because the new vaccine has been studied in less than 5,000 recipients, the possibility of these or other rare adverse events cannot be excluded. Post-licensure surveillance data will be important to further evaluate safety in a larger population. The new Vero cell-derived JEV vaccine is currently approved for use in adults 17 years of age or older. As a result, the mouse brain-derived vaccine is the only JEV vaccine that is approved for use in children in the US. Although the mouse brain-derived vaccine is still approved for use in adults, sanofi pasteur will now restrict purchase of their remaining inventory of JE-VAX® for use in children 1 to 16 years of age. All remaining doses of JE-VAX® will be available through this pediatric stockpile. One pediatric clinical trial with IXIARO® has been completed and others are planned, but it will likely be several years before the vaccine is approved for use in children in the US. Recommendations regarding the use of JEV vaccine for travelers must weigh the risks of travel-associated Japanese encephalitis, with the benefits and potential risks of JEV vaccine. The overall risk of Japanese encephalitis for most travelers to Asia is very low, but again varies based on destination, duration, season, and activities. When Japanese encephalitis does occur, it has a high morbidity and mortality, and there is no specific treatment. Safe and effective vaccines are available. However, the possibility of rare serious adverse events cannot be excluded. Given these considerations, the workgroup developed the following general recommendations for the prevention of JE among travelers: 1. Travelers to JE endemic countries should be advised of risks of JE disease and the importance of measures to reduce mosquito bites 2. JEV vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JEV transmission season 3. JEV vaccine should be considered for short-term travelers to endemic areas during the JEV transmission season if they will travel outside of an urban area and their activities will increase the risk of JEV exposure 4. JEV vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or times outside of a well-defined JEV transmission season With regard to recommendations for the prevention of JE among travelers, the following language was crafted: “Travelers to JE endemic countries should be advised of the risks of JE disease and the importance of personal protective measures to reduce the risk of mosquito bites. For some travelers who will be in a high risk setting based on location, duration, season, and activities, JEV vaccine may further reduce the risk of infection.” “All travelers should take precautions to avoid mosquito bites to reduce the risk of JE and other vector-borne infectious diseases. These precautions include using insect repellent, permethrin-impregnated clothing, and bed nets, and staying in screened or air conditioned rooms. Additional information on protection against mosquitoes and other arthropods can be found at [CDC Yellow Book website].” Recommendations for the use of JEV vaccine are as follows: “JEV vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JEV transmission season. This includes longer-term travelers, recurrent travelers, or expatriates who will be based in urban areas but are likely to visit endemic rural or agricultural areas during a high risk period of JEV transmission.” “JEV vaccine should be considered for the following: * Short-term travelers (<1 month) to endemic areas during the JEV transmission season if they plan to travel outside of an urban area and have an increased risk of JEV exposure. Examples of higher risk activities or itineraries include: 1) Spending substantial time outdoors in rural or agricultural areas, especially during the evening or night; 2) Participating in extensive outdoor activities (e.g., camping, hiking, trekking, biking, fishing, hunting, or farming); and 3) Staying in accommodations without air conditioning, screens, or bed nets. * Travelers to an area with an ongoing JE outbreak. * Travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel.” “JEV vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or times outside of a well-defined JEV transmission season.” Dr. Fischer also presented the draft recommendations for laboratory workers, reporting that at least 22 laboratory-acquired JEV infections have been reported in the literature. JEV may be transmitted in a laboratory setting through needle sticks or theoretically through aerosol or mucosal exposure. Work with the wild-type JEV is restricted to laboratories with Biosafety Level 3 (BSL-3) containment and select agent registration. Some well-characterized attenuated JEV strains may be handled safely at BSL-2. Based on this information, the workgroup developed the following recommendations, which he noted differed slightly from the original handout: “JEV vaccine is recommended for laboratory personnel who work with live, wild-type JEV strains. Vaccinated, at-risk laboratory personnel should receive appropriate booster doses of JEV vaccine or be evaluated regularly for JEV-specific neutralizing antibodies to assure adequate titers.” Discussion Dr. Marcy inquired as to what had been the previous use annually of this vaccine, thinking about the 2500 to 4000 doses left in the stockpile and how long that was expected to last. Dr. Fischer responded that this had varied over time and partially depended upon how much has gone to the military. Dr. Hosbach (sanofi pasteur) replied that while it was difficult to predict how long the stockpile was anticipated to last, based on their estimates, it probably would last approximately 2 to 3 years. It was very difficult to calculate how many children were actually receiving the vaccine. In total, just over 100,000 doses were used annually, and about 80% to 90% of that went to the military. Thus, there was not a major marketplace for the use of this vaccine. Dr. Marcy inquired as to whether Intercell planned to move along quickly to amass more data and whether the FDA would seek a fast track. He expressed concern that the vaccine supply would be depleted before the new one was available. Dr. Katrin Dubischar-Kastner (Intercell) indicated that Intercell, the manufacturer and license holder of the vaccine, is progressing with its pediatric development plan. They are currently starting trials and expect them to begin in the 4th quarter of 2009. Pediatric licensure is expected within the next 2-3 years. Dr. Fischer mentioned that the possibility had been discussed with FDA of setting up an investigational new drug (IND) that could be used in the event that the JE-VAX® supply was completely exhausted but no licensure had been issued on the new vaccine. That is the way this vaccine was administered in Europe for years. They did not have a licensed JE vaccine. They do believe that the supply should last for approximately 2 years. The number of children is small and the regimen is 3 doses. In terms of global warming, Dr. Marcy wondered whether attention was being given to changes in patterns of the viruses. For example, there have been changes in the dengue season. Dr. Fischer responded that there has definitely been a change in the geographic area that JEV covers over the past few decades. It is unclear how much of that is a surveillance artifact versus actual change. There has probably been change in agriculture practices, herd migration, and other things. There is no clear evidence of global warming or climate change playing a role in that. For vector-borne diseases, it is really very complex as to what global warming or climate change affects, because there will be changes in rainfall as well as warming. Therefore, it is very unclear for most vector-borne disease what the effect of climate change would be. With regard to season, it is less certain whether there have been changes. There has certainly been more recognition of classic outbreaks that occurred in Northern Asia where this disease was first recognized in the early 1900s, in which there are high peaks in very short periods of time (July through September) as is observed with West Nile Virus. There is certainly more recognition moving into South Asia and the Western Pacific that the disease occurs even more sporadically or year round. It is not clear whether that reflects a change over time or merely recognition of the disease. Dr. Hosbach (sanofi pasteur) indicated that the doses stockpiled are due to expire in May 2011. Dr. Stanley Gall (ACOG) said he did not hear anything about use of this vaccine during pregnancy, although this is bound to occur. He wondered whether the assumption could be made that because it was non-live virus vaccine it would be safe during pregnancy. Dr. Fischer responded that this would differ for the two vaccines. One vaccine is considered a category C, one a Category B. For the new vaccine, there have been some studies in rodents so the category is a little different. Basically, it is considered for both the vaccines to be a precaution; that is, because it is not a live vaccine, there is no known risk, but data are limited. Thus, the wording basically states that vaccination should be deferred unless the person has to travel to a high risk area and the risk of the disease outweigh the risks of the vaccination. Dr. Meissner pointed out as a working group member that the group did discuss that the Vero cell-derived vaccine appears to be a significant improvement over the mouse brain-derived vaccine. Although it is still early, at least at this stage, it appear to have significant advantages. He thought that was a tribute to Intercell Biomedical for their production of this vaccine and Novartis for their plan distribute this vaccine. This vaccine does not have gelatin as a stabilizer, will not have nervous tissue proteins from the mouse brain, and appears to be more immunogenic. He thought that should be acknowledged. There have been only 4 cases of JEV in 15 years since the first set of recommendations were issued in 1993, which also weighed heavily on the working group deliberations. Christine Hahn (CSTE) noted that this recommendation relied heavily upon knowing when JEV transmission season is. She wondered whether this appeared on the CDC travel site for quick reference. Dr. Fischer responded that there is a table that has transmission seasons by country and areas that are endemic. The table is included in the current recommendations. The working group agreed that it could be updated more readily and changed to refer to the Yellow Book website, and would then be updated in the Yellow Book every other year. There is also a cautionary statement that there are limits to surveillance data, and that there are changes from year to year. A general idea is given of the seasons and the locations where JE occurs, but people must be careful in interpreting that data. Those caveats are included in the document. An inquiry was posed regarding what the new vaccine product insert would say about revaccination for those who have continuing exposure over the years, and how often revaccination should occur. Dr. Fischer responded that for the new vaccine, there are really no recommendations with regard to booster doses or revaccination. There are some data on the ration of neutralizing antibody, which cites two different studies, one which is published and one which has been presented at a meeting, in which Intercell is examining duration of neutralizing antibodies. One study shows as many as 83% of vaccinees having neutralizing antibodies at 12 months. The other study went out as far as 24 months and had a little less than 60% at 12 months, and 48% at 24 months. Currently, in both the package insert and the ACIP recommendations, there are basically no recommendations similar to what was done initially for meningococcal conjugate vaccine with regard to booster doses. It simply states that this will need to be determined. Dr. Beck noted that at one point, the DoD had a back-up stock of JE-VAX®. He wondered whether that still existed and could serve as a potential back-up for the civilian population. COL Cieslak (DoD) responded that he believed that stock was sold back to the company in advance of the Beijing Olympics. The DoD basically relinquished that supply. What is currently being held for pediatrics is in part some of that stock that was sold back by DoD. Dr. Hosbach (sanofi pasteur) expressed gratitude to the military, the cooperating agencies, and Dr. Gellen for helping arrange this. A couple of times sanofi pasteur was able to buy back material from the military to supply to the private sector. However, the military still has a stockpile of JE-VAX®, of which sanofi recently repurchased another 5,000 doses to keep going so until IXIARO® is licensed. Regarding cost considerations, Dr. Chilton indicated that there was a statement in the committee’s packages that were received prior to the meeting indicating that those who travel to rural areas or expatriates living in rural areas probably have roughly the same exposure to this disease as those who live in those areas, which is listed in that material at 0.1 to 2 cases per 100,000 persons per week in those areas. He wondered if that was correct. Dr. Fischer responded that those data are extrapolated significantly from military population data primarily during the Korean Conflict and Vietnam War. It seemed to Dr. Chilton that for those traveling to or living in one of these rural areas, preventing one case of JE would cost $5 to $100 million at the price quoted for this vaccine. That seemed high to make a recommendation as strong as the one pending a vote. Dr. Fischer replied that two things needed to be taken into consideration. First, all of the cases reported have been in the context of vaccination. It is not clear exactly who is being vaccinated, but it is assumed that the vaccine is being somewhat appropriately targeted such that cases are being prevented. Second, the numbers presented were of cases reported in the literature. There are likely more cases that are not diagnosed and / or reported. He cautioned against making too many assumptions. While the disease is believed to be rare, he would not try to put a specific number on it. The working group did engage in discussions about cost, but this is a travel vaccine. Dr. Sumaya pointed out that Recommendation #2 states that “JEV vaccine should be considered.” He wondered whether there was a reason it did not say “recommended,” particularly when one of the items is travelers to an area with an on-going JE outbreak. Dr. Fischer responded that this was similar to the current recommendations, and they have the strongest evidence that these are the people at greatest risk. More thought really needs to be placed on the individual traveler and their itinerary. Dr. Cieslak said he thought the incidents cited were 100,000 per year and not per week, and the week extrapolation was different. He thought it was as high as 1 per 5000 per week. Dr. Fischer replied that they were per week for the highest risk populations. Motion: Revised JE Vaccine Recommendations Dr. Meissner moved to approve the revised recommendations as proposed. Dr. Sawyer seconded the motion. The motion passed with 12 affirmative, 1 negative, and 0 abstentions. Introduction Dr. Mark Sawyer, Chair Hepatitis Vaccines Work Group Dr. Sawyer indicated that the terms of reference for the Hepatitis Vaccines Work Group were to: * Determine the advisability and extent of hepatitis A vaccination recommendations for families adopting children from other countries * Review data from recent hepatitis B outbreaks among diabetics in institutional care to determine whether vaccination is appropriate * Review data related to long-term immunity of hepatitis B vaccine to determine if additional vaccine doses are necessary; if so, what dosage and schedule * Review hepatitis A vaccine long-term immunity to see if updating recommendations is warranted The first term of reference regarding hepatitis A recommendations was dealt with in the past. During this session, an update was presented on the work group’s deliberations pertaining to the second term of reference regarding recent hepatitis B outbreaks among diabetics in institutional care to determine whether vaccination is appropriate for this population. Hepatitis B among Residents of Long-Term Care Facilities Nicola D. Thompson, PhD Division of Viral Hepatitis NCHHSTP, CDC Dr. Thompson presented a summary of information the hepatitis vaccine work group has discussed in recent months with respect to the role of hepatitis B vaccine use among residents of long-term care facilities, specifically those with diabetes. While seemingly unrelated, these three issues had arisen which the work group was charged to address (e.g., hepatitis B virus, diabetes, and long-term care). During this session, she discussed hepatitis B virus transmission during delivery of health care, summarized hepatitis B virus infection outbreaks among people with diabetes, discussed diabetes epidemiology in the US, addressed long-term care, and raised possible prevention strategies for consideration. There has been a dramatic decline in the incidence of acute HBV infection in the US last few decades. Much of this decline can be attributed to the implementation of vaccine recommendations for infants and children, and targeted high risk groups, such as injection drug users, persons with high risk sexual behaviors, healthcare workers, and chronic hemodialysis patients. The decline observed has been much more striking in younger age groups when compared to older adults when incidence is stratified at 50 years of age. In 2007, about 4500 cases of acute HBV infection were reported, and the acute HBV infection fatality rate was 1.5%. It is important to note that due to under-reporting and the high proportion of asymptomatic acute infections, it is estimated the actual number of new cases in 2007 was around 43,000 [National Notifiable Diseases Surveillance System (NNDSS)]. There is an inverse relationship between the age at infection and the development of chronic HBV infection. The risk of developing chronic HBV is highest in those who are infected as infants and children, compared to healthy adults. [Shepard et al. Epidemiologic Reviews 2006;28:112-125]. However, older adults and immune suppressed individuals are also at high risk for developing chronic HBV infection Studies have shown that this risk may be as high as 59% in older adults [Kondo. Hepatology 1993;18:768-74], between 40% and 45% for hemodialysis patients [Hyams CID 1995;20:992-1000], and up to 22% for HIV-infected individuals [Alter MJ J Hepatol 2006; 44:S6–9]. The CDC estimates that between 800,000 and 1.4 million persons in the US have chronic HBV [CDC MMWR 2008;57 No. RR-8]. Other estimates suggest that it may be higher at around 3 million, and that immigration plays an important role in chronic HBV infection in the US, with estimates indicating that approximately 46,000 cases are imported each year [Welch et al. Estimating Prevalence of chronic hepatitis B in Foreign-born persons in the US. Abstract OP059. ISVHLD 2009; Mitchel et al. Increasing burden of imported chronic hepatitis B – US, 1973-2007. EIS Conference 2009]. Chronic carriers are central to the epidemiology of HBV, as they may be asymptomatically infected for many years and unknowingly provide a risk of transmission to susceptible persons. Chronic carriers are at increased risk of cirrhosis and liver cancer. It is thought that between 2000 and 4000 people die each year from HBV-related chronic liver disease [CDC MMWR 2008;57 No. RR-8]. The primary modes of HBV transmission are perinatal, sexual, and by percutaneous and permucosal exposures. This includes injection drug use, non-sexual household contact with HBV infected persons, and healthcare related transmission. While healthcare related transmission due to occupational exposures and through the receipt of blood and blood products has been decreasing, patient-to-patient HBV and hepatitis C (HCV) transmission during the delivery of healthcare has been increasingly recognized in the US [1:Thompson et al. Nonhospital health care–associated hepatitis B and C virus transmission: United States, 1998–2008. AIM 2009;150:33-39]. With respect to the number and cause of HBV and HCV outbreaks that have been reported since 1998 in the US, all of these outbreaks have involved patient-to-patient transmission during the delivery of healthcare due to poor infection control practices. Both hepatitis B and C outbreaks have occurred in a variety of settings, including endoscopy clinics, nuclear imaging clinics, pain remediation clinics, oncology clinics and physician offices. One area of particular concern is the multiple and continuing outbreaks of HBV infection among long-term care residents that have repeatedly been associated with poor practices during diabetes care, specifically during blood glucose monitoring [Thompson, Perz. JDST 2009;3:283-89; Thompson et al. AIM 2009;150:33-39]. While the prevalence of chronic HCV infection is higher in the US than chronic HBV infection, there are some important features of HBV that help facilitate its transmission; the high viral titer and high environmental stability. A virus can be present in tiny or invisible amounts of blood, and due to the environmental stability, dried blood on surfaces, equipment or devices can remain viable for at least seven days [Beltrami et al, Clin Microbio Reviews, 2000. MMWR 2001;50(No. RR-11); Bond et al. Lancet 1981; 8219:550-1. Shikata et al. J Infect Dis 1977;136:571–76; Shikata et al. J Infect Dis 1977;136:571–76; Kamilli et al. ICHE 2007;28:519-24]. Together these characteristics play an important role in healthcare-related HBV transmission and specifically during diabetes care when equipment used for finger stick procedures and monitoring blood glucose levels are shared among multiple persons. HBV transmission has been associated with blood contamination of the end and barrel of spring-loaded finger stick devices, with blood contamination of blood glucose testing meters, and with failures by staff to wear or change gloves or perform hand hygiene between performing finger-stick procedures. Preventing this type of transmission relies on consistent adherence to standard infection control recommendations. In 1990, CDC and the FDA published recommendations clearly stating that spring loaded finger stick devices should be restricted for individual use. Later, guidance on this issue came from the American Association of Diabetes Educators. In 2005, CDC again reinforced the 1990 recommendations and made specific recommendations for prevention of blood borne pathogen transmission during diabetes care in long-term care settings. This issue is also addressed in the 2007 Healthcare Infection Control Practices Advisory Committee (HICPAC) Isolation Guidelines, which are applicable to all settings were healthcare is delivered. Just a few months ago, the FDA issued a health alert for the appropriate use of insulin pens in healthcare settings. This alert was issued after it was discovered that these devices, designed for individual use, were found to have been used on multiple patients in two US acute care hospitals. In the US, the first recognized outbreak of hepatitis B associated with diabetes care was reported in 1990. Since then, and despite multiple comprehensive prevention recommendations, these outbreaks have continued to occur. A notable shift from acute care hospitals to the long-term setting appears to have occurred, first in nursing homes and then in assisting living facilities. In total, 19 outbreaks of HBV infection among diabetic persons have been reported since 1990, with 6 outbreaks occurring in the past 2 ½ years. Given that most newly infected adults will be asymptomatic and that the diagnosis of acute hepatitis B is often not suspected or missed in older adults, it is likely that these outbreaks under represent the true number that have occurred. From combined data from 13 seroprevalence surveys conducted during investigations of these outbreaks, in which 1308 persons were tested for HBV infection, persons with diabetes had a high prevalence of both past and chronic infection compared to those without diabetes. In these outbreaks, acute HBV infections occurred predominantly among persons with diabetes, 30.5% compared to 0.9% among those without diabetes. Overall, the prevalence of ever being infected with HBV (including those with past, chronic, and acute infection among non-diabetics) was 5.6%, but was 42.9% among persons with diabetes. The median age of people with acute HBV infection from these outbreaks was 75 years with a wide range from 42 to 92 years. The vast majority with acute HBV infection (92%) had diabetes and were monitoring their blood glucose levels. A small number of secondary cases have been reported in non-diabetic roommates and family members of infected individuals, and among non-vaccinated staff members. About 1/3 of those with acute infection were symptomatic, and among those that were symptomatic, 37% were hospitalized. The acute HBV infection fatality rate was 5% among all people infected and was actually as high as 15% among those with symptomatic acute hepatitis B. Those who died from acute HBV infection had a median age of 85 years and ranged from 64 to 92 years [CDC. Unpublished Data 2009]. Among 29 people who were re-tested at least six months after their initial diagnosis of acute infection, 50% had developed chronic infection. As already noted, this is similar to rates that have been reported in the literature for older adults and immune suppressed individuals, such as hemodialysis patients, and is higher than that for HIV infected individuals [CDC Unpublished Data 2009; Kondo. Hepatology 1993;18:768-74; Hyams CID 1995;20:992-1000; Alter MJJ Hepatol 2006; 44:S6–9]. It has been well reported that the prevalence of diabetes has been and continues to increase rapidly in the US. Only about 5-10% of those with diabetes have Type 1, the vast majority have Type 2 diabetes. In 2006, just under 18 million people in the US had been diagnosed with diabetes [CDC available at: www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm]. This equates to about 5.8% of the total US population, but the prevalence is highest among people 65 years of age and older [Cowie et al., Diabetes Care 2009;32:287-94. CDC available at http://www.cdc.gov/diabetes/statistics/prev/national/tprevage.htm]. As the population continues to age, the number of people with diabetes will also continue to increase. By 2050 it is estimated that 29 million people will have diabetes, with most of them being older than 65 years of age and our colleagues in the division of diabetes translation tell us that this 29 million is an underestimate of what the actual burden will be [Boyle et al. Diabetes Care 2001:24:1936-40]. Daily blood glucose monitoring is a common practice among those with both Type 1 and Type 2 diabetes. Approximately 60% of all people with diabetes are estimated to self-monitor their blood glucose level at least once a day. This is in line with the Healthy People 2010 goal of 61% [CDC. Behavioral Risk Factor Surveillance System. MMWR 2007;56:1133-1137]. Long-term care provides both medical and non-medical care to people with chronic illnesses or disabilities. Long-term care is provided in many settings, but there are two main categories of residential long-term care and they have very different philosophies. Nursing homes provide care to people who cannot be cared for at home or in the community setting. They provide a wide range of personal care and health services that are medically oriented. Regulation and oversight of nursing homes occurs at the federal level. Assisted living is a group living arrangement that provides residents help with activities of daily living, such as eating, bathing, using the bathroom, and medication administration, this includes diabetes care. Social and recreational activities are usually provided and these facilities operate under a social model. There is no federal definition of assisted living and facility licensing and oversight occurs at the state level. It is important to point out that the data for nursing homes is much more robust than it is for the assisted living facilities. The nursing home data largely comes from the National Nursing Home Survey conducted by CDC. The data from assisted living comes from a couple of different sources, some of which is from 2002, and some of which is more recent data from non representative samples. In both nursing homes and assisted living facilities, the majority of residents are female and the median age is between 84 and 85 years. In both settings, a substantial number (10-12% or around 270,000 persons) of residents are less than 65 years of age. Memory and mental health disorders are common among residents of long term care. In nursing homes, it is estimated that about 25% of residents have diabetes, and between 15 and 20% in assisted living. Other common health conditions among residents include stroke and COPD or emphysema. About 2/3 of nursing home residents are considered to be in fair or poor health, compared to 50% of those in assisted living [National Nursing Home Survey, 2004, NCHS/CDC; US Dept of HHS Assistant Secretary for Planning and Evaluation Office of Disability, Aging and Long-Term Care Policy. November 2002; Overview of Assisted Living, 2006. NCAL]. In long-term care settings, there are relatively few professional, licensed medical staff: 32% of direct care staff in nursing homes and only 15% in assisted living. The duties of licensed nurses include resident assessment, medication reviews, care plan development, staff monitoring, wound care, vital sign readings, oxygen administration, blood glucose monitoring, and delivery of injections. In some states, these activities can be delegated to unlicensed, paraprofessional staff that comprises the majority of direct care staff in both of these settings. Few states have minimum staffing ratios for assisted living. Some require that a registered nurse (RN) be available 24 hours a day, but they do not have to be on site, or they only have to come in when medications are administered. Few states require paraprofessional staff, such as personal care aides, to be certified. Most paraprofessionals have no formal healthcare or medical training and learn while they are on the job [American Health Care Association. Estimates of Current Employment in the Long-Term Care Delivery System and Bureau of Labor Statistics; National Nursing Home Survey, 2004, NCHS/CDC; Overview of Assisted Living, 2006. NCAL]. Recruitment and retention of staff is recognized as a major challenge in long-term care settings. The average annual staff turnover rates range from 36-41% for registered nurses, 44-50% for licensed practical nurses, and between 45-66% for paraprofessional staff. Compared to other healthcare workers, long-term care staff earns the lowest salaries, receive the fewest benefits, are less likely to have employer sponsored health insurance, and have few advancement opportunities. In one recent HBV outbreak investigation, when the public health department staff returned to the facility 6 months after the initial investigation to conduct follow-up assessments, the new nursing director and staff were unaware that hepatitis B outbreak had even occurred. The impact of training and education initiatives is hampered in settings with such high staff turnover [Sikorska-Simmons. Gerontologist 2005;45:196-205; Zimmerman et al. J Am Geriatr Soc 2002;50:1987-95; 2007 American Healthcare Association Survey: Nursing Staff Vacancy and Turnover in Nursing Facilities; 2007 AAHSA National salary and benefit surveys]. In addition, high nursing turn over and low staffing rates have been associated with incident of infections in long term-care. In this setting, infections have been recognized as the leading cause of morbidity and mortality among residents. This increase in risk is due to the vulnerable resident population and the institution environment where residents share bedrooms and bathrooms and group activities are encouraged [Zimmerman et al. J Am Geriatr Soc 2002;50:1987-95; Richards. Infections in Residents of LTC Facilities: An Agenda for Research. Report of an Expert Panel. JAGS 2002;50:570-576]. Infection prevention and control programs have been poorly implemented in long-term care. Few resources or personnel are devoted to infection control activities, and there are no dedicated infection control staff. Staff charged with infection control duties often have many other duties and spend few hours on infection control issues. About half of the staff who are charged with infection control have no training in infection control themselves [Goldrick. Infection Control in skilled nursing LTC facilities: An Assessment. AJIC 1999;27:4-9]. There are few data on the effects of infection control interventions on resident outcomes and cost. This limits the uptake and implementation of infection control programs and dedication of resources to this issue [Richards. Infections in Residents of LTC Facilities: An Agenda for Research. Report of an Expert Panel. JAGS 2002;50:570-576]. Two surveys have been conducted by CDC to assess routine diabetes care in non-outbreak situations. These surveys were used to assess the standard of diabetes care in these long term care facilities. Selected results from those surveys showed that, among facilities using spring loaded finger stick devices, between 16 and 24% of were sharing these among their diabetic residents despite there being recommendations in place since 1990. Among facilities sharing blood glucose testing meters among residents, 50-72% were not cleaning meters between each use. In both these surveys, the facilities were aware that the public health authorities had a planned visit to review diabetes care at their facility. In Virginia, the state health department had mailed educational packets and CDC safe diabetes care recommendations to each facility ahead of their visit. It is, therefore, likely that the prevalence of unsafe diabetes care practices may be higher than reported here [Virginia data: Patel et al. ICHE 2009;30; Florida data: CDC Unpublished Data 2008]. Currently, it is estimated there are about 2.5 million people residing in long-term care facilities in the US. Most of these residents are in nursing homes, although most growth in long-term care residency has occurred in the assisted living arena. This sector of long-term care has the least regulation and oversight, and the fewest medically trained staff [US Dept of HHS. Office of Disability, Aging and Long-Term Care Policy. November 2002; Overview of Assisted Living, 2006. NCAL and National Nursing Home Survey, 2004, NCHS/CDC]. As the US population is aging and living longer, there will be an increasing demand for long-term care services among adults with disabilities. It is expected that over the next 30 years, there will be a doubling of the number of people with moderate or severe disability [Johnson et al. Meeting the LTC needs of the Baby Boomers: How Changing Families will affect paid helpers and intuitions. 2007. The Urban Institute]. In summary, the reported incidence of acute HBV has been declining dramatically in the US; however, this decline has been much less dramatic among people greater than 50 years of age. Patient-to-patient HBV and HCV transmission due to poor infection control practices during the receipt of healthcare has been increasingly recognized in the US. This type of transmission has occurred in a variety of healthcare settings. However, persons receiving diabetes care in long-term care facilities have emerged as one risk group. In these settings, multiple people undergo daily and often multiple daily percutaneous exposures during blood glucose monitoring. Despite long-standing and comprehensive prevention recommendations, HBV infection outbreaks continue to be reported in long-term care. These outbreaks have shown that HBV is not an insignificant disease in this population of older adults with diabetes, with a high rate of acute HBV deaths and chronic infection being reported. Improving infection control, oversight, and regulation of long-term care is an increasing public health priority, although many challenges remain. Without change, the number of people placed at risk for infection will increase as the prevalence of diabetes and utilization of long-term care both increase. CDC is addressing the prevention of hepatitis B among diabetics in three ways: 1) by improving the implementation and adherence to existing infection control recommendations; 2) by working with equipment manufacturers to develop technology and safety engineered devices to help prevent sharing of equipment, by developing and designing and marketing equipment for institutional use, and by developing equipment that reduces or eliminates blood borne pathogen transmission; and 3) by assessing the role of hepatitis B vaccine in prevention, which is the current charge of the Hepatitis Vaccines Workgroup. Future workgroup meeting topics include examining the epidemiology of HBV infection, focusing on older adults without traditional risk factors; reviewing data on hepatitis B vaccine immunogenicity and safety by age, focusing again on older adults and people with diabetes; and assessing feasibility, programmatic issues, and cost-effectiveness. Discussion Dr. Judson found it amazing that 50% of the facilities surveyed were not following even the most basic or reasonable prevention techniques. He thought states regulated these facilities closely. His 92 and 94 year old parents live in such a facility and tell him that state inspectors come by to review practices, and everyone is very tense. Dr. Thompson replied that most people who work with infection control in this area would agree that oversight and regulation is sorely missing in long-term care facilities, particularly assisted living facilities. While surveys are conducted, these may only be done once every three years and often they are assessing non-infection control issues. Dr. Baker indicated that inspections are every three years in Texas, and facilities are notified in advance. Because facilities are forewarned, they look great on paper for one day. Dr. Judson wondered whether facilities were directly violating the regulations that pertain to them or were simply undertrained with no one really in charge. Dr. Thompson thought the latter was the case most of the time. While she did not know whether there specific regulations were in place for this issue, there are certainly recommendations from CDC. Unfortunately, there are 50 states with 50 different sets of regulations, oversight, and licensing. For example, in Pennsylvania, to work in an assisted living facility and perform blood glucose monitoring and administer insulin injections, you would only need to have to have a high school diploma and attend a four-hour training class. Under-training and under-staffing are definitely issues, and there are very few professional staff. There are infection control recommendations that some facilities follow, but this is certainly not happening in all of them. Dr. Judson thought that from a public health standpoint, this situation ought to be fixable with the proper regulations and enforcement. Dr. Thompson agreed. The working group plans to address infection control in terms of implementation of the existing recommendations, technology (e.g., safe devices), and vaccines. Ken Schmader (AGS) noted that nursing homes are highly regulated by various federal and state organizations; however, infection control practices are not addressed amongst all the quality measures and regulations. Many issues need to be addressed (e.g., delirium, pressure sores, weight loss, depression, et cetera) within quality measures. Quality infection control can occur in the nursing home, for which there is evidence from the VA. The Department of Veterans Affairs is the largest single provider of nursing home care in the US, with over 130 nursing homes and 11,000 patients. The VA has put into practice infection control training practices, practitioners, programs, et cetera. There is very good evidence that this works. In fact, in the American Journal of Infection Control in 2008, there was an article published on that, which could serve as a model for the work group. Dr. Chesley Richards of CDC is one of the authors [Prevalence of nursing home-associated infections in the Department of Veterans Affairs nursing home care units; AJIC: American Journal of Infection Control. 36(3):173-179, April 2008]. Dr. Thompson added that the Study on the Efficacy of Nosocomial Infection Control (SENIC) study was instrumental in showing that there is a cost benefit to implementing infection control, and that savings can be made by the facility. However, there is no such equivalent study or data for long-term care. Alexis Elward (HICPAC) emphasized that infection control implementation is very resource-intensive and requires a considerable amount of education—repeatedly. There is a large proportion of paraprofessional staff, as high as 65%-85% in some of these facilities. This raises further challenges. With the lack of consistent regulatory oversight and dedicated resources, the problem is further compounded. Hepatitis B vaccination would only be one arm of a comprehensive program to address this issue. Dr. Baker thought it would be beneficial to have some data pertaining to immunity. She agreed that infection control is extremely labor-intensive and education must be repeated regularly. Even certified nursing assistants who require more than four hours of training do not know anything about infection control and blood borne precautions. They are paid $8 an hour in most assisted living facilities with no benefits, so the minute there is a better place down the street, they move on. It is all about money. Introduction Carol J. Baker, MD, Chair ACIP Yellow Fever Work Group Dr. Baker indicated that the Yellow Fever Work Group was charged to update and revise the 2002 recommendations based on new evidence. Many organizations were involved in the process of a rigorous review of the literature. The following Yellow Fever Work Group meetings were held, with the topic areas addressed shown for each: * September 16, 2008 --> Introduction and background YF disease and vaccine * November 10, 2008 --> Vaccine presentation, dose and booster --> Simultaneous Administration of Other Vaccines * December 9, 2008 --> General Safety --> Requirements for vaccination before international travel --> Upcoming changes to yellow fever risk areas * January 12, 2009 --> Hypersensitivity --> Yellow fever vaccine-associated viscerotropic disease * February 9, 2009 --> Thymic disease and use of vaccine --> Yellow fever vaccine-associated neurotropic disease * March 9, 2009 --> Travelers and individuals living in endemic areas --> HIV --> Elderly * April 14, 2009 --> Pregnancy --> Breastfeeding --> Young children * May 11, 2009 --> Cancer and cancer treatments --> Immunomodulatory drugs --> Additional topics The resulting proposed revisions were reported to the full committee during this session for the purpose of information. Proposed Updates to the ACIP Yellow Fever Vaccine Recommendations J. Erin Staples, MD, PhD CDC / CCID / NCZVED / DVBID During this session, Dr. Staples reviewed yellow fever disease, the vaccine used to prevent it, and the proposed updates to the 2002 yellow fever recommendations the work group is considering. Yellow fever disease is caused by yellow fever virus which is the prototypic flavivirus. It is transmitted to humans predominantly by Aedes mosquitoes, though other mosquitoes are involved in rural settings. However, in urban areas, Aedes aegypti mosquitoes can effectively spread the disease from human to human leading to large outbreaks of the disease. Yellow fever disease is endemic to 47 countries in equatorial Africa and South America. It can cause a range of disease in humans from mild illness to jaundice and hemorrhage. The WHO estimates there are approximately 200,000 cases and 30,000 deaths per year due to yellow fever; however, most cases go unrecognized by the current surveillance systems. Yellow fever vaccine was developed in the 1930s. It is a live-attenuated viral vaccine produced in eggs (e.g., chicken embryos). From 1937-2008, over 500 million doses have been given to humans. Currently, one vaccine licensed for use in the US, YF-VAX®, produced by sanofi pasteur. It is derived from 17D-204 vaccine strain, so it is often referred to as a 17D vaccine. There are two primary reasons to vaccinate someone against yellow fever, which are to: 1) protect travelers and endemic populations against the disease; and 2) limit the introduction and spread of the disease into new areas. Many countries require proof of vaccination for all travelers. Yellow fever vaccine is the only vaccine exclusively covered under International Health Regulations, which were updated in 2005. Countries have the right to detain a traveler without proof of yellow fever vaccine for up to 6 days (e.g., the incubation period of the disease). Multiple factors must be weighed when deciding whether to vaccinate someone against yellow fever (e.g., country requirements, risk of disease, and risk of vaccine adverse events). The risk of illness and death for yellow fever in an unvaccinated traveler traveling 2 weeks to endemic area in West Africa is 50 and 10 per 100,000 population, respectively. For South America, that risk is estimated to be about 10 times lower at 5 illnesses and 1 death per 100,000 population [Monath Clin Infect Dis. 2002;34:1369-1378]. Risk for vaccine adverse events must be taken into consideration as well. Risk for general adverse events is approximately 43 per 100,000 doses and for serious adverse events is approximately 4.7 per 100,000 doses [Based on US VAERS data 2000-2006; Lindsey et al. Vaccine. 2008; 26: 6077-6082]. The potential serious adverse events following yellow fever vaccination fall into three categories. The first is anaphylaxis. Individuals who are allergic to eggs, chicken proteins, and gelatin are at increased risk at a rate of 1.8 per 100,000 doses. Neurotropic disease / neurologic disease is a conglomerate of various presentations that are due to one of two mechanisms. The first is direct vaccine viral invasion of the central nervous system resulting in encephalitis or meningitis. The other is autoimmune-mediated phenomenon such as Guillain-Barré Syndrome (GBS) or acute disseminating encephalomyelitis. The rate for all neurologic disease following yellow fever vaccination is 0.8 per 100,000 doses. Another serious adverse event is viscerotropic disease in which the vaccine virus, as a live attenuated virus, proliferates and causes a disease similar to natural infection with multi-system organ failure. This occurs at a rate of 0.4 per 100,000 doses, with a case fatality of over 50%. The Yellow Fever Work Group took two general approaches for revising the yellow fever recommendations that were published in 2002. The first was that the group wanted to provide more specific information when possible based on published literature, unpublished reports, or expert opinions. They also wanted to further clarify the risks of disease versus the vaccine to help better guide travel practitioners in advising their patients about whether to be vaccinated. The work group also wanted to align the yellow fever ACIP recommendation with other ACIP documents. For example, there are pregnancy and breastfeeding guiding principles, so that language would be used to help unify the way breastfeeding and pregnancy are put forth. When there is a lack of evidence for yellow fever vaccine specifically, the group plans to adhere to the general recommendations for live viral vaccines with respect to timing intervals and Immunocompromised individuals. Anticipated revisions to the 2002 recommendations for the upcoming 2009 recommendations fall into broad categories, which are to: update the epidemiology of yellow fever disease, include information on International Health Regulations (2005), update vaccine safety data, add / improve wording for vaccine precautions and contraindications based on new data; and outline research priorities. In terms of the updated epidemiology of yellow fever disease, a new risk map was created in 2008 which harmonizes the WHO and CDC areas at risk: Disease activity has been increasing in the last couple of years in terms of the areas affected, specifically for South America where areas in which yellow fever disease has been dormant for the last 30 years now have disease activity. That includes Northern Argentina, Paraguay, the Eastern edge of the endemic area for Brazil, and Trinidad. In Africa, there has been an increase outside of their normal endemic area of West Africa in the central African countries. In terms of vaccine safety data, the work group wants to update the incidence rates. This information will come from more recent VAERS data, which includes the serious adverse event rate of 4.7 for all comers. Specific age group incidents will also be highlighted, particularly for serious adverse events. For individuals 60-69 the rate will be 6.3 serious adverse events per 100,000 doses, and for those greater than 70 the rate goes up to 12.6 per 100,000 doses. More information will also be provided on serious adverse events. When the last recommendations were published in 2002, viscerotropic disease had just been recognized. There have been more cases, so those data will be summarized to present key clinical characteristics that are observed. The neurologic disease observed will also be characterized. Specific testing that can be conducted for vaccine adverse events will be described to assist in determining whether the event that is noted is potentially related to the vaccine. Potential treatments will as be discussed which would apply for events such as GBS. More information will also be provided on yellow fever vaccine precautions. For breastfeeding, updated information will be included on transmission and vaccine-associated adverse events. For those ? 60 years, the risk of the disease versus serious adverse event will be clarified. For HIV, risk will be further defined based on CD4 counts and anti-retroviral therapy. In terms of contraindications, in 2004 thymic disease was recognized as a risk factor for viscerotropic disease. Language was subsequently added to package inserts. Thus, language needs to be added to the ACIP recommendations to clarify thymic conditions that will place someone at risk. Immunomodulatory drugs are a relatively new class of drugs that alter immune response. There are many different groups of immunomodulatory drugs, some of which include tumor necrosis factor-alpha (TNF-?) blockers, Interleukin1 (IL1) blockers, and monoclonal antibodies (Mab). Many of the package inserts contraindicate the use of live viral vaccines, so that language will be added to the 2009 yellow fever recommendations. During the next couple of months, the work group plans to craft specific language for the revised yellow fever vaccine recommendations. It is anticipated that final recommendations will be presented for an ACIP vote in October 2009, with the final document expected to be submitted to the MMWR in November 2009. Discussion Dr. Temte inquired about the methodology for doing conducting assessments, noting that VAERS had been mentioned a couple of times. In his experience, many patients receiving yellow fever vaccines are typically receiving several other vaccines simultaneously. In addition, increasing numbers of patients in older age groups are travelling internationally. Thus, it seems that it would be extremely difficult to determine adverse events caused by yellow fever vaccine versus other vaccines, and / or the potential synergistic effects of yellow fever vaccine co-administered with other vaccines. Dr. Staples responded that in the VAERS analysis, the work group examined whether other travel vaccines were co-administered. For the cases specifically classified as the most serious adverse events being considered (e.g., viscerotropic disease and neurotropic disease), many of the cases had diagnostic testing to confirm that yellow fever vaccine was the source of their adverse event. This issue can be further considered. Dr. Baker added that the statement will include information about how to test to confirm whether there is an association with yellow fever vaccine. In terms of safety, Dr. Neuzil pointed out that this vaccine is frequently given in other countries as part of campaigns. They may be able to acquire additional safety data from some of these sources. She also inquired as to whether any other vaccines are available or in development. Dr. Staples responded that as far as she knew, there were no other vaccines available or in development. There are other routes of administration, and there have been some preliminary studies examining inactivation of the current vaccine. Until recently, when viscerotropic disease was discovered to have been a risk of the vaccine, it was considered to be very safe and effective. It is still a fairly safe and effective vaccine, particularly for endemic areas. Dr. Katz (IDSA) asked what was known about boosters and what the International Health Regulations state says about them. Dr. Staples responded that the International Health Regulations, as well as the WHO, state that boosters should be given every 10 years. Most of the serious adverse events observed have been reported after primary vaccination, so it is not believed that boosters increase the risk of serious adverse events. There are some data to suggest that immunity lasts longer, but when the WHO conducted a comprehensive review about the booster interval, they still thought that 10 years was a reasonable timeframe for this vaccine. Ms. Stinchfield (NAPNAP) inquired as to whether it was correct that special certification was required to serve as a yellow fever vaccine clinic, and if so what the rationale was for that requirement. Dr. Staples responded that a certificate is regulated through CDC’s Division of Migration and Global Quarantine (DMGQ). However, much of the regulation also requires state health department involvement. This was linked to the International Health Regulations, which prior to the 2005 recommendations, emphasized yellow fever disease as one of the immediately notifiable diseases considered important. However, the specific regulations for yellow fever vaccine and proof of yellow fever vaccine have been sustained in the 2005 regulations. She believed that it was the International Health Regulations and the requirements for proof of vaccination that supported detainment for lack of proof of vaccination. No public comments were offered during the first day of the meeting. June 25, 2009 Call to Order Dr. Dale Morse Chair, ACIP Dr. Larry Pickering Executive Secretary, ACIP, CDC Dr. Dale Morse welcomed the group to the second day of the meeting. He turned the floor over to Dr. Larry Pickering to address unfinished business. Dr. Pickering offered a few comments about Dr. Morse on the occasion of his final meeting serving as an ACIP member and Chair of ACIP. He reflected on the time and energy that Dr. Morse had spent on ACIP and with CDC, and enumerated Dr. Morse’s many accomplishments as Chair of ACIP. Dr. Pickering expressed appreciation to Dr. Morse for his many contributions to the committee, which include the following ACIP recommendations made during his chairmanship: CDC. Prevention of Rotavirus Gastroenteritis Among Infants and Children; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2009;58 (No. RR-2) Recommended Adult Immunization Schedule—United States, 2009. MMWR 2009;57 Recommended Immunization Schedules for Persons Aged 0 Through 18 years --- United States, 2009. MMWR 2009;57 CDC. Prevention and Control of Influenza; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008;57 (No. RR-7) CDC. Prevention of Herpes Zoster; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008;57 (No. RR-5) CDC. Prevention of Pertussis, Tetanus, and Diphtheria Among Pregnant and Postpartum Women and Their Infants; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008;57 (No. RR-4) CDC. Human Rabies Prevention - United States, 2008; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008;57 (No. RR-3) Dr. Morse thanked Dr. Pickering and those present, offering a wrap-up of his time with ACIP. He noted the rapid growth that ACIP saw during Jon Abramson’s leadership from 2005 to 2007, including: 1) voting to recommend rotavirus vaccine for children and the HPV vaccine for young females; 2) recommending a second dose of the varicella vaccine; 3) zoster vaccine for adults; 4) conjugated meningococcal vaccine for adolescents and college students; 5) Tdap vaccine for adolescents and adults; 6) expanded adult recommendations for hepatitis B vaccine and expanded recommendations for hepatitis A vaccine for all children over 12 months; and 7) expansion of use of influenza vaccine to include children age 24 through 59 months. Dr. Morse then turned to 2007 to 2009, when ACIP entered a maintenance phase. This phase did not bring less work for the committee, however. Vaccine guidelines were updated for children, adolescents, and adults; anthrax; meningococcal; HAV for prophylaxis; HAV for foreign adoptee contacts; pneumococcal; combination vaccines; and second dose of rotavirus. Further, ACIP has prepared for October 2009 votes on PCV 13, bivalent HPV for females, quadrivalent HPV for males, and novel H1N1 influenza. He noted that 12 votes were pending for this June meeting: rabies, polio, JE, MMR, influenza antivirals, meningococcal, MMRV safety, and combination vaccines. Dr. Morse noted the important progress toward universal flu immunization, with expansion of recommendations for children through 18 years of age. While flu recommendations for adults have not yet been completed, he anticipated that these recommendations could be achieved in the near future. He pointed out that a change in leadership is a good time to assess where the committee has been, where it is currently, and where it is going. It is also a good time for the committee members to share in their combined accomplishments and to recognize the individual contributions of their colleagues. In particular, he recognized the efforts of Jean Smith, Antonette Hill, Larry Pickering, and all ACIP staff. Further, Dr. Morse acknowledged the importance of science in ACIP’s work. He cited David Axelrod, former New York Commissioner of Health who said, “We must remain devoted to the canons of science that are so much part of the practice of medicine and the practice of the allied arts. To do otherwise would be to build public policy on quicksand.” Knowledge without application is useless. ACIP must also remember the faces behind the numbers and the people who are served by their work, as Dr. Jules Richmond, Former Surgeon General, said: “statistics are people with their tears wiped dry. As Xenophon in Cryopaedia, 400 BC said, “As there are persons who mend torn garments, so there are physicians who heal the sick; but your duty is far nobler and one befitting a just person – namely to keep people in health.” Collectively, they have been able to accomplish more than they could individually. The cause of keeping people healthy is noble, and Dr. Morse thanked ACIP for allowing him to be part of the process. General Recommendations on Immunization Dr. Andrew Kroger CDC.CCID/NCIRD/ISD Dr. Morse asked Dr. Andrew Kroger to present revised language for the General Recommendations on Immunization for the committee to consider. Dr. Kroger reminded the group of Option Two from the previous day’s discussion, which stated: “The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines if licensed and indicated for the patient’s age, but depends on the vaccination status of the patient, provider preference, patient preference, the potential for adverse events, and vaccine availability.” Discussion regarding this option led to a consensus that it was the best of those offered, but the language needed streamlining. The term “licensed” is redundant, and concern was expressed about describing vaccines as recommended for a specific age. There was an affirmative vote by ACIP for this option. The General Recommendations Working Group of ACIP met and discussed how best to incorporate feedback from the general group into the recommendation. Their deliberations resulted in the following clarification: “The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment*, patient preference, and the potential for adverse events,” with a footnote to state: “*Provider assessment should include storage costs, number of injections, vaccine availability, vaccination status, likelihood of improved coverage, and likelihood of patient return visits.” Discussion: Dr. Englund felt that storage cost was not the most important thing for practitioners to consider, so she suggested that the order of the items in the superscript list be revised. She commended the working group on this clarification. Dr. Neuzil said that the potential for adverse events is part of the provider assessment, and she wondered about the rationale for putting that element in the first part of the statement rather than in the second part. Dr. Kroger replied that from a public health point of view, the potential for adverse events is important to add because vaccine safety stakeholders play an important role along with providers and patients and this issue will be revisited in future decisions about combination vaccines. Dr. Temte added that in current practice situations, the largest barrier to immunization is concern over adverse events. Placing it in the first statement highlights its significance and the degree to which ACIP considers it to be an important issue. Dr. Sumaya said that the working group debated whether to include the issue in the body of the recommendation or in its annotation. Because the issue will be critical in monitoring, they concluded that it should be in the body of the recommendation. Dr. Baker asked for clarification about where the annotated text would be placed. Dr. Kroger answered that in recent history of MMWR publications, this information has gone at the bottom of the page. Dr. Stinchfield noted that storage and cost are two different issues, so they should be separated by a comma. She agreed with rearranging the order of the items. Dr. Ehresmann commented that some of the issues fall under “patient preference,” and she wondered whether providers consider patient preference in their assessment. The phrasing could state, “considerations should include provider assessment and the potential for adverse events” and note patient preference as part of the assessment. Dr. Judson agreed that patient preference is a subset of the provider assessment. Dr. Englund disagreed, stating that physician offices do not carry every vaccine combination, so the language should remain as written. Dr. Cieslak said that the general recommendation stated too much. He suggested “the use of combination vaccines generally is preferred,” leaving physicians to consider what they usually consider. Motion: General Recommendations on Immunization Dr. Chilton made a motion to approve the recommendation of the work group to accept the newly-written clarification for Option Two as written, with the exception of moving “storage” and “cost” to the end of the statement and to separate them with a comma. Dr. Judson seconded the motion. The motion carried with 14 affirmative votes, 0 abstentions, and 1 negative vote. Centers for Disease Control and Prevention Dr. Anne Schuchat presented updates on CDC’s work in international use of vaccine. The WHO recently recommended global use of rotavirus vaccine. CDC is part of a consortium working to provide scientific and technical support to introducing both rotavirus and pneumococcal conjugate vaccines around the world. CDC is also completing the Hib Initiative, a four-year Global Alliance for Vaccines and Immunization (GAVI)-supported initiative, with the mandate to promote evidence-informed decisions in resource-poor countries about the use of Hib vaccine. More than 90% of the birth cohort in developing countries is now living in countries that have decided to use this vaccine. This initiative has the potential to reduce global deaths substantially. The last part of CDC’s major global effort regarding vaccines is the Measles Initiative. Last January, CDC announced a 74% reduction in worldwide measles deaths since 2000. The work that ACIP does on these vaccines has a direct link to these global efforts. Center for Medicare and Medicaid Services (CMS) Dr. Linda Murphy reported that in February 2009, the Children’s Health Insurance Program Reauthorization Act (CHIPRA) and the American Reauthorization and Recovery Act (ARRA) were approved. As a result, many programs and changes are anticipated. Grants under CHIPRA will be announced in July 2009, and the funds will be awarded by September 30, 2009. These grants are aimed at schools and a range of local and religious groups, which are not typical outreach groups. The groups include coalitions and other agencies that will reach rural and tribal children that state and federal entities may not be able to reach. Six million children are uninsured, and grants are available to reach out to them to enroll them in CHIP or Medicaid. Once the children are reached, the states must be able to take the new enrollments. When the grants are posted on www.grants.gov, applicants will have 30 days to submit grant proposals. CMS is focusing on outreach and enrollment, quality, and information technology as they work to improve healthcare to Medicaid- and CHIP-eligible children. CMS is always seeking to improve in the area of pandemic planning. They are considering ways to be flexible with Medicaid, given the H1N1 situation. As it stands, Medicaid works well in an epidemic situation. CMS will work with each individual state when new plans are written. The Vaccines for Children (VFC) rates were put on hold in the absence of a Secretary of Health and Human Services (HHS) or a Director of Medicaid. Now that Cindy Mann has been named the Director of Medicaid and Kathleen Sibelius as Secretary of HHS, they are able to rewrite and update the Federal Register notice for VFC, with more developments on the horizon. Department of Defense (DoD) Dr. Wayne Hatchey explained that DoD is focusing on influenza. A mandatory influenza immunization requirement is in place for active duty service members. They began mandatory immunization for healthcare workers providing direct patient care last year. This year, services must report compliance with the program. DoD is preparing for two simultaneous (or overlapping) influenza immunization programs with seasonal influenza and novel H1N1. They are collaborating with CDC and FDA to track vaccine effectiveness through the Armed Forces Health Surveillance Center (AFHSC), as well as vaccine safety through the Military Vaccine Agency (MVA). DoD is developing an immunization strategy that is based on variable disease virulence. The strategy will be adjusted by target groups, based on the epidemiology of novel H1N1. Department of Veterans Affairs (DVA) Dr. Linda Kinsinger reported that on April 25, 2009, the DVA activated an operations center to coordinate communications to and from the field. They instituted case reporting for the VA based on CDC policies. Reporting occurred daily at first, and then occurred weekly as of mid-May. Based on evolving CDC recommendations, and with input from VA subject matter experts, DVA issued seven clinical advisories to the field. They held a series of five VA-wide teleconferences over a three-week period to allow the field to ask questions, and they have participated in a number of inter-agency working groups and policy committees. Food and Drug Administration (FDA) Dr. Norman Baylor noted that most of FDA’s activity updates involved H1N1 work; therefore, he presented an update later in the meeting agenda. Heath Resources and Services Administration (HRSA) Dr. Geoffrey Evans updated the group on the autism hearing. Decisions were made regarding the Theory One combination of MMR vaccine and thimerosal. Theory Three was also decided upon, as there was no new evidence for the MMR vaccine-only theory. Decisions for three cases are in, and are under appeal. The first-level appeal decisions should be in later in the year. Theory Two, the thimerosal-only decision, is awaiting the end of briefing. He expressed hoped that the briefing would end in the next few months, with decisions later in the year. The Institute of Medicine (IOM) contract project to review vaccines and adverse events, which started in September 2008, held an organizational meeting in April and a Biologic Mechanisms Workshop in Washington the previous day. The committee is adding varicella vaccine, influenza vaccines, HPV, and hepatitis B. If additional funding is obtained, then four additional vaccines will be added. Indian Health Services (IHS) Ms. Amy Groom reported that IHS instituted influenza-like illness surveillance using its electronic health records system. The system receives daily feeds from approximately 300 facilities, and compile the data weekly for their sites and administrative areas. The trends of influenza-like illness in Indian Country mirror national trends. They are, however, investigating a cluster of severe H1N1 disease resulting in hospitalizations in a group of Indians in Arizona. IHS will determine whether this is an unusually high hospitalization rate or a result of widespread transmission in the area. National Institutes of Health (NIH) Dr. George Curlin stated that influenza research advances in seasonal influenza as well as in novel H1N1. He assured them that seasonal influenza has not been forgotten, despite concerns regarding H1N1. Enrollment has begun in a study of influenza vaccines for pregnant women, and basic research also continues. National Vaccine Advisory Committee (NVAC) Dr. Gus Birkhead presented an update on NVAC’s recent accomplishments: 1) input into draft National Vaccine Plan; 2) RAND study of the effectiveness of NVAC; 3) completion; 4) Adult Vaccination Report release in June 2009; 5) Vaccine Safety Working Group Report on the CDC ISO Scientific Agenda in June 2009; and 6) NVAC’s role in the H1N1 vaccination program. The National Vaccine Plan is being updated for the first time since 1994. The IOM and NVAC have both been involved. Over 450 public comments have been received, and five public sessions have been conducted by IOM. NVAC has provided comments directly to IOM. NVAC held three public engagement sessions in St. Louise, Missouri; Syracuse, New York; and Columbus, Ohio. A public stakeholders’ meeting was held in Washington, DC. These sessions examined population values pertaining to vaccinations. The final report is due in November. Additional information is available at: http://www.hhs.gov/nvpo/vacc_plan/. Dr. Birkhead described the RAND Corporation’s study of the effectiveness of NVAC. A draft report of the study was presented during ACIP’s last meeting. The report consisted of a literature review, reviewing past recommendations to NVAC, and interviews with key stakeholders. The report concluded that NVAC has a broad mission and there may be confusion in the minds of the general public and of healthcare professionals regarding the mission of each of the HHS advisory committees relating to vaccines. There are at least four other agencies in addition to NVAC. Further, the report states that NVPO is under-resourced to fully support its broad mission. The study highlighted gaps in representation on the group, including public members, economists, communication experts, and others. The report’s recommendations focus on these areas and on engaging in more active follow-up and seeking feedback from the Assistant Secretary of Health (ASH). The Adult Vaccine Working Group completed the first part of its charge to review federal agency activities relating to adult immunizations. The working group created the following recommendations: 1) Better assess immunization coverage; 2) Conduct health services research; 3) Emphasize adult immunization with grantees; 4) Update immunization guidance; 5) Health care worker immunization; 6) Secure funding support, in particular including all ACIP vaccines in Medicare Part B; 7) Develop incentives; 8) Conduct outreach and promotional campaigns; and 9) Improve safety monitoring. Regarding the fourth recommendation, it was noted that many federal programs do not operate on the current ACIP guidelines, so the group recommended that all federal agencies dealing with adult immunization examine their internal program guidance. The report will go to the ASH and will be posted soon. The working group is moving to its second charge, which is to broadly consider vaccine financing in the public and private sectors. In June 2009, NVAC’s Immunization Safety Working Group issued a report on its review of the CDC Immunization Safety Office Scientific Agenda. The report contains advice on the content of the research agenda, adding draft topics and providing a framework for prioritizing research topics. The report also details possible barriers to implementing the research agenda and suggestions for addressing them. It was adopted during the June 2009 meeting, and a draft is available on the NVAC website. The process of reviewing the agenda was extensive, and included community meetings and keystone and stakeholder meetings. The Vaccine Safety Working Group’s second charge is to review the current federal vaccine safety system. Over the next year, they will review the current federal vaccine safety system. Further, the working group will develop a White Paper describing the infrastructure needs for a federal vaccine safety system, which are to: 1) fully characterize the safety profile of vaccines in a timely manner; 2) reduce adverse events whenever possible; and 3) maintain and improve public confidence in vaccine safety. The membership of the working group has expanded. Its three chairs are Andy Pavia, Marie McCormick, and Tawny Buck. Three new members have been added to the group: Vicky Debold, PhD, RN, Health Administration and Policy Department at George Mason University, VRBPAC Public Representative; Robert Beck, JD; ACIP Member Public Representative; and Bill Raub, PhD, Former Deputy Director of the National Institutes of Health and Science Advisor to the Secretary, Department of Health and Human Services. Current plans for NVAC include a kick-off working group meeting on July 15 – 16, 2009, in Washington, DC. The meeting will include presentations and discussion on five panels: 1) Principles and policy alternatives for a robust vaccine safety system; 2) Identifying innovative ways of overcoming gaps in vaccine safety science infrastructure; 3) The ideal system to meet the needs of the public, public health, and healthcare professionals for confidence in vaccine safety; 4) Lessons from other safety arenas; and 5) Enhancing the adoption and implementation of the NVAC white paper. Dr. Birkhead also described NVAC’s role in the response to novel H1N1 influenza. The June 2, 2009 NVAC meeting included informational presentations from a number of advisory committees and partner organizations. He emphasized that NVAC’s role in the response includes maintaining partner input. NVAC will focus on the implantation of a vaccination program; ensuring stakeholder input; maintaining coordination among vaccine advisory committees; and contributing to vaccine safety and post-marketing. They plan to hold two public teleconferences and to submit recommendations to the ASH. A subgroup of the Safety Working Group will work with CDC and ISO concerning surveillance and vaccine safety issues. NVAC made a series of recommendations to the new ASH regarding response to novel H1N1. The recommendations include accelerating the urgency of the response. While response has begun, state and local planning must begin before it is too late. Further, resources are needed at the state and local levels, where health departments have lost 10,000 staff in the past year and expect similar losses this year. State and local health departments will bear the brunt of H1N1 response, and pandemic response will be occurring simultaneously with response to seasonal influenza. Further, pandemic influenza funding for state and local entities was terminated in 2008, and other preparedness funding has declined. NVAC’s recommendations noted that while the $350 million in supplemental funding was helpful, at a cost per dose of $15, the vaccination program will cost $9 billion dollars. Finally, vaccine safety monitoring is a critical piece of the response effort. National Vaccine Program Office (NVPO) Dr. Bruce Gellin noted that Dr. Howard Koh had been confirmed as the ASH. Before he came to HHS, he was the Harvey Feinberg Professor of the Practice of Public Health. Introduction: Overview of Session Abigail Shefer, MD Immunization Services Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Dr. Shefer reported that a nationwide shortage of Hib vaccine began in December 2007 when several lots of the vaccine produced by Merck were recalled voluntarily and production was temporarily suspended. To address the limited supply of Hib vaccine, CDC recommended that the Hib booster dose at 12 to 15 months be temporarily deferred for healthy children. Since then, there has been enhanced surveillance for Hib disease to identify any increase in incidence of cases. Using sentinel site registry data in select states, there has been some indication that the third dose of the primary series may have declined due to programmatic issues as well as a mismatch between local supply and demand, she said. Some information on both of these issues has been presented at past ACIP meetings. The shortage has been on-going for approximately 1.5 years. Glaxo-Smith Kline (GSK) Monovalent Hib Vaccine Remon Abu-Elyazeed MD, MPH, PhD Head, Pediatric Vaccines Clinical and Medical Affairs, North America GlaxoSmithKline Dr. Abu-Elazeed thanked ACIP for the opportunity to present clinical data highlights of GSK’s Hib conjugant vaccine. GSK has been working closely with CDC and FDA to make HIBERIX®, its Hib vaccine, available in the US as quickly as possible to help alleviate the Hib vaccine shortage that has become a public health concern. HIBERIX® is reconstituted at the time of use before intramuscular administration. Each 0.5mL single dose contains 10 micrograms of purified capsular polysaccharide conjugated to approximately 25 micrograms of inactivated tetanus toxoid. It contains no thimerosal and is latex-free. HIBERIX® was first licensed in Germany in 1996 and is currently licensed in 98 countries. From its launch until November 2008, approximately 55 million doses of HIBERIX® have been distributed worldwide. A Biologic License Application (BLA) was submitted to the FDA on March 17, 2009, and it is being reviewed under accelerated approval. License of HIBERIX® in the US will provide an additional source of vaccine to the US market for booster dose. The proposed indication under review by the FDA is active immunization as a booster dose for the prevention of invasive disease caused by Hib in children ages 15 months through 4 years of age, and prior to their first birthday. The clinical package to support approval of HIBERIX® contains data from nine studies. Seven studies provide core data when HIBERIX® was administered as a booster dose. These include 1008 subjects. Two additional studies focus on administration of HIBERIX® as a primary vaccination series. These studies provide supportive safety data and include 1396 subjects. The studies were chosen in consultation with FDA as the most relevant to evaluation of HIBERIX® use in the US. In all of the trials, HIBERIX® was administered to children between 11 and 25 months. All seven studies support the safety of HIBERIX®. Six studies support immunogenicity, and three of them study administration of HIBERIX® as a booster in children who received primary vaccinations with HIBERIX® according to a 2-4-6 month schedule, or according to a 3-4-5 month schedule. Four studies provided data on the interchangeability when a booster dose of HIBERIX® was administered to children previously vaccinated with another vaccine. These four studies provided safety and immunogenicity data of HIBERIX® following priming with other Hib vaccines that are licensed in the US. Polyribosyl ribitol phosphate (PRP) immune responses after a booster dose of HIBERIX® following priming in infancy with HIBERIX® were studied in children aged 14 to 23 months. They received HIBERIX® co-administered with a combination DTaP-HBV or DTaP-IPV vaccine. In a series of studies after booster vaccination with HIBERIX®, 100% of the subjects achieved seroprotection at both 0.15 microgram per mL and at 1 microgram per mL cutoffs. In all three studies, HIBERIX® elicited a marked increase in GMCs from pre- to post-vaccination. In three additional studies, children were primed in infancy with either HIBERIX®, ActHIB®, HibTITER®, or PedvaxHIB®. After a booster vaccination with HIBERIX®, 100% of the subjects achieved protection at the 0.15 microgram per mL cutoff. Further, between 96.4% and 100% of subjects achieved anti-PRP antibodies concentration greater than or equal to 1 microgram per mL. In all three studies, HIBERIX® elicited a marked increase in GMCs from pre- to post-booster vaccination. Regarding the immunogenicity of co-administered vaccines, in one study a booster dose of HIBERIX® was co-administered with DTaP and OPV. In the second study, a booster dose of HIBERIX® was co-administered with DTaP-HBV-IPV. The studies are not meant to be comparative, but both measure immunogenicity with co-administered vaccines. All subjects in both studies achieved seroprotective antibody levels against diphtheria, tetanus, and polio. At least 95% of the subjects demonstrated pertussis vaccine response. The group who received the Hepatitis B vaccine achieved seroprotective antibody levels against Hepatitis B, demonstrating that HIBERIX® does not interfere with immune response to concomitantly administered vaccines. In terms of safety, solicited local and general adverse events were reported in all seven studies within four days after the booster dose was administered. Two representative studies include Study DTaP-HepB-IPV 010 and Study DTaP-IPV 026. In one study, children 12 to 25 months of age received HIBERIX® and a combined DTaP-HepB-IPV vaccine. This study included 371 subjects. The second study included 65 children aged 15 to 19 months of age who received HIBERIX® and DTaP. In both studies, HIBERIX® was administered concomitantly at a separate site. Relatively few local and general adverse events were reported, and there were very few cases of Grade 3 symptoms. Three serious adverse events were reported in 1008 subjects in the seven booster studies. All subjects recovered with no sequelae. No deaths were reported in any of the seven clinical studies. It was concluded that the safety of HIBERIX® was clinically acceptable. From the launch of HIBERIX® in 1996 until 2008, approximately 55 million doses have been distributed worldwide. Evaluation of post-marketing adverse events reports since the product launch have not revealed safety concerns, and HIBERIX® has not been withdrawn in any country due to safety concerns or regulatory issues. Regarding immunogenicity, a booster dose of HIBERIX® provides strong immune response in children previously primed with Hib vaccine, regardless of the priming vaccine or the priming schedule. HIBERIX® is immunogenic when administered following primary vaccination with another US-licensed Hib conjugate vaccine. Further, HIBERIX® is immunogenic when co-administered with other commonly-used pediatric vaccines. Dr. Abu-Elazeed reiterated that the BLA was submitted on March 17, 2009 and is awaiting accelerated approval. As a post-license commitment, GSK plans to conduct a confirmatory trial for the booster dose in US infants, with HIBERIX® given at months 2-4-6 and 15 to 18 months as scheduled. This trial will include co-administration with commonly-used pediatric vaccines. Discussion Dr. Ehresmann asked about the timeframe for an accelerated FDA review. Dr. Abu-Elazeed replied that the maximum time is six months from the submission date. Dr. Baylor added that there is no specific time for accelerated review. Priority review timeframes are six months, where the criteria for accelerated approval allow for vaccine approval on a surrogate, which in this case is immunogenicity. A confirmatory study is required post-licensure. FDA’s goal is to complete this process as soon as possible. Hib Surveillance Michael L. Jackson, PhD, MPH Meningitis and Vaccine Preventable Diseases Branch National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Dr. Jackson reported on Hib surveillance during the Hib vaccine shortage. In October 2008, when Merck announced that they would not be able to return to market until mid-2009, CDC began enhanced surveillance for Hib. They worked to raise awareness among clinicians and laboratorians of the on-going vaccine shortage, the need for testing of suspected H. influenzae cases, and for reporting to local health departments. CDC disseminated messages through a number of venues, including an MMWR report; notices through organizations such as PIDS and NACCHO and the Epi-X system; and presentations at national meetings. Since November 2008, CDC has actively followed up with state health departments on all reported cases of invasive H. influenzae in children less than five years of age. This follow-up is to make sure that CDC has the best available information on serotype, vaccination history, and disease outcome. For this evaluation, the focus is on invasive Hib, defined as isolation of Hib from a normally sterile site such as blood or cerebrospinal fluid. Using enhanced surveillance data, CDC began testing for an increase in Hib incidence. The pre-shortage baseline was defined as the years 2000-2007, as these were years during which the incidence of Hib in the US was relatively stable. Fairly good surveillance data are available for that timeframe. Using the 2000-2007 data, the expected number of annual cases of Hib during the baseline period were calculated, with 95% confidence intervals. Starting from January 2009, each month the number of Hib cases reported in children less than five years for the past twelve months is compared with the upper confidence limit of the expected cases from baseline. This analysis tests whether the cases have exceeded the expected counts. These analyses were conducted for the US as a whole and for each state or jurisdiction individually. For the US as a whole, the expected cases of Hib for each calendar month, with confidence limits, were also calculated. They then compare the monthly number of reported Hib cases with the upper confidence limit of the expected monthly cases. This calculation is repeated for Hib plus untyped H. influenzae. The analysis of Hib plus untyped H. influenzae is needed to account for possible differences in the proportion of cases that were serotyped during the shortage compared to the baseline period. Another question of interest is whether the population at risk for Hib has changed as a result of the Hib vaccine shortage. In particular, it is important to learn whether there have been shifts in the age distribution or the vaccination history of Hib cases among children less than five years of age. To address this, CDC compared Hib cases occurring since November 2008, when the active follow-up started, with Hib cases reported through the ABC system from 1995 through 2007, prior to the vaccine shortage. For the twelve month period of May 2008 through April 2009, a total of 43 cases of invasive Hib in children less than five years were reported to CDC. For comparison, the annual average during the baseline period was 31.4 cases per year. Although somewhat higher than average, this difference was not statistically significant. Hib cases reported in each state or jurisdiction from May 2008 through April 2009 in children less than five were compared with the state-specific annual averages. Overall, 32 states or jurisdictions reported as many or fewer cases than average during baseline. Twenty states or jurisdictions reported more cases than average during baseline. Despite media reports of clusters of Hib in a few places, none of the increases were statistically significant. Hib case counts for the US as a whole exceeded the historical limits during February of 2009, but not in the subsequent months. Dr. Jackson reminded the group that the period from November 2008 through April 2009 represented a timeframe during which CDC worked to enhance Hib surveillance, so some of this increase may be a surveillance artifact. The combined counts of Hib and untyped H. influenzae have remained within the historical limits during the shortage. Age and vaccination histories for Hib cases during the vaccine shortage were compared with cases from the pre-shortage era for whom age and vaccination history are available. During the shortage, cases tended to be younger and were more commonly un- or under-vaccinated than pre-shortage cases. However, the differences were not statistically significant. Dr. Jackson concluded that CDC has not observed a sustained, statistically significant increase in Hib cases in children less than five years of age either for the US as a whole or for any individual state, despite enhanced surveillance efforts. In addition, there has been no apparent change in the population at risk for invasive Hib. Hib cases in children less than 5 years of age during the shortage are not significantly different from cases prior to the shortage in terms of age distribution or vaccination history. There has not been a substantial impact on invasive Hib in children less than five years of age in the US during the Hib vaccine shortage. CDC will continue to monitor Hib incidence as the booster dose is reinstated and as new Hib vaccines are introduced. Discussion Dr. Schuchat found the data to be reassuring. When the shortage began, they discussed a “cushion of protection,” given the herd effect of the vaccine. She expressed her hope that people would not interpret these data to mean that the shortage has not been a concern or that additional cases are not possible. They have learned from other countries with similar difficulties that problems can emerge over time. They are probably in the “cushion of protection” and a long delay for booster doses would present a problem. Dr. Pickering asked for clarification on the untyped cases and how typing rates might be improved, as well as what the demographic differences were between untyped cases and Hib cases. Dr. Jackson replied that the enhanced surveillance efforts have included contacting the states to verify serotype information. They have better serotype information available now than they did prior to the shortage. An average of 40% of cases were untyped before the shortage, and now about 12% of cases are untyped. He did not have information regarding distribution of age among untyped influenza cases since the start of the shortage, though he noted that these were a small proportion of the Hib cases. Dr. Ehresmann confirmed that these cases are untyped, not untypable. Dr. Jackson agreed. Vaccine Supply Jeanne Santoli, MD Immunization Services Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Dr. Santoli presented information regarding the anticipated 2009 supply to support reinstatement of the Hib booster dose. Sanofi pasteur will supply at least 18 million doses of Hib-containing vaccine, including both monovalent and combination product, to the US market during 2009. The increased supply will be available beginning in July 2009. This volume will support return to the fourth dose and to begin catch-up efforts. GSK has applied for licensure of their monovalent Hib vaccine, HIBERIX®. They have the capacity to produce more than 4 million doses for the US during 2009. The regulatory review response is anticipated no later than mid-September, and the indication sought is for the booster dose. Merck is working with FDA toward the following goals: 1) a limited supply of PedvaxHIB® to be available in the fourth quarter of 2009; and 2) full availability of PedvaxHIB® is expected in the first quarter of 2010. The return of COMVAX®, the combination with hepatitis B and PedvaxHIB® will be dependent upon the supply situation for both the Hib and hepatitis B vaccine components. Hib Vaccine Implementation Plan Abigail Shefer, MD Immunization Services Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Dr. Shefer presented plans for the implementation of the Hib booster dose. The currently available Hib-containing vaccines include monovalent Hib (ActHib®) and DTaP-IPV/Hib (Pentacel®). Both are manufactured by sanofi pasteur. An increased number of doses of both vaccines will be available starting July 1, 2009. The increased number of doses will be sufficient to reinstate the booster dose of Hib vaccine to be administered on time at 12 to 15 months for all children who completed the primary three-dose series. However, there will only be enough supply for limited catch-up at this time. Limited catch-up means that older children whose booster dose was deferred should receive a dose of Hib vaccine at their next routinely scheduled visit or medical encounter. Supply constraints do not permit mass recall of all children whose booster dose was deferred. This means that CDC does not recommend that practices institute an active notification process to contact all children with deferred booster doses at this time. Rather, CDC recommends that practices target children presenting for their next scheduled appointment or who have a medical encounter for any reason. The current availability of Hib vaccine means that providers will be able to order some additional doses of Hib vaccine each month based on previous purchasing patterns or on practice birth cohort and estimates of additional needs. This applies to both private and public vaccine supplies. Practices need to develop a tailored plan that best suits their office environment, taking into account such elements as staffing, responsibilities, and clinic setup. The plan will likely include a review of electronic or paper records or registries or IIS prior to a physician encounter; screening children during scheduled visits; and discussing and sharing immunization schedules with parents. Most of the challenges at the practice level are related to the use of combination products and the goal of minimizing extra immunization. This might lead to a mismatch between patient vaccination needs and the available stock of different vaccine formulations available in a local provider’s office. For example, practices using Pentacel® for Hib vaccination need to ensure that adequate supplies of monovalent Hepatitis B vaccine are available to complete the Hepatitis B vaccine series. Further, children who have already received four doses of DTaP should be prioritized to receive monovalent Hib vaccine. In collaboration with several partners, CDC has prepared a number of educational materials about reinstating the booster dose and limited catch-up. The June 26, 2009 MMWR will include an article on the topic. Q & As for providers and patients are in the clearance process and may be ready for posting in early July 2009. Additionally, a one-page provider letter will be placed in all McKesson vaccine shipments and will alert providers to the reinstatement of the booster dose and limited catch-up. Another resource is an algorithm table on “Protecting Infants against Hepatitis B Virus Infection When Using Pentacel® Vaccine during the Hib Vaccine Shortage.” It outlines the issues and thinking that a practice needs to undergo when considering Hepatitis B and Hib-containing vaccines. It is posted on the CDC website: http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm. Plans for monitoring the situation are under discussion. They will continue to monitor Hib vaccine use through the registry sentinel sites. These registries are located in eight states throughout the country that have higher-quality data and are able to provide more timely data. This information will give CDC an idea of provider compliance with the recommendation. They are also considering conducting a provider survey to assess knowledge and practices related to administration of the booster and catch-up. The survey can be targeted through the registry sentinel sites, which will allow validation of actual vaccine delivery. A national survey of pediatricians and family physicians is also possible. The monitoring plans will depend on several factors, including vaccine supply and any new Hib-containing vaccines that come to market and affect that supply. Discussion Dr. Morse complimented all of the individuals who worked to manage the shortage. A tremendous amount of work took place, from surveillance to allocation and education. Professional agencies and manufacturers worked to help increase supply. Dr. Ehresmann clarified that the booster will be reinstated as of July 1, 2009. Dr. Shefer confirmed that the recommendation will be to reinstate the booster dose on time for children 12 – 15 months old, with limited catch-up for children during a regular visit or other encounter. Dr. Ehresmann shared comments from a listserv of state grantees, who expressed concern regarding vaccine supply and concerns pertaining to the reinstatement of the booster dose. She was encouraged to hear about the GSK product. Dr. Leonard Friedland (GSK) said that all manufacturers need to adequately plan for vaccine supply. He asked about sanofi pasteur’s distribution plans for July between monovalent Hib and combination Hib vaccines as they reintroduce additional supply. This information will help them at GSK understand their supply constraints. Dr. Phil Hosbach (sanofi pasteur) replied that while he could not share that information in this forum, they have shared detailed information with CDC so they have a month-by-month supply for Pentacel® and Hib. They are pleased to have kept supply in place for at least three doses for the last year and one half. They have been able to adjust their supplies to provide a fourth dose. Dr. Shefer said that AAP and AFP will communicate with their members about the reinstatement of the booster dose in various ways. An inquiry was posed regarding why HIBERIX® is indicated for 15 months and why it could not be given at 12 months. Dr. Schuchat replied that GSK would need to submit infant information. Dr. Abu-Elazeed said that the clinical package submitted for approval of HIBERIX® as a booster dose includes children less than 15 months, but the numbers are not sufficient to expand the indication for less than 15 months. Dr. Pickering requested further information about plans to expand HIBERIX® in the future. Dr. Abu-Elazeed answered that GSK has committed to a post-approval study. The primary series will be administered at two, four, and six months with a booster at 15 to 18 months. Nancy Messonnier (NCIRD) said that the indication for Hib, the ACIP recommendations, and the Red Book start at 12 months for the booster dose. However, sanofi pasteur’s vaccine is not licensed for 12 to 15 months. The only vaccine with this licensure is produced by Merck. Because sanofi’s vaccine is not licensed for 12 to 15 months, GSK’s vaccine, which is based on a comparison with sanofi’s, will have the same indication as Sanofi’s—only 15 months. Physicians are likely to administer it anyway. Dr. Friedland (GSK) added that GSK is in late development with a combination HiB- meningococcal-CY vaccine for infants. The fourth dose in that schedule will be at 12 months. They look forward to presenting data on that vaccine during the October 2009 ACIP meeting. Claire Hannon (Association of Immunization Managers) echoed concerns that grantees have about the supply of Hib. She has heard from programs that are waiting for supplies to maintain the 3-dose series. The supply for July has only recently been sent, and it is difficult for grantees to know where they will be in the middle of July. They are happy to get additional vaccine in July and glad to have details about monovalent and combination products, but not knowing how much will be in the future is difficult. Some providers use a combination of a different type, so they need monovalent and need information about the future. Dr. Santoli said that they have given grantees quarterly information about their allocation, recognizing the need for them to plan ahead. They were not able to give that information the first time because of a need to understand reactions to the first allocations. They adopted a different approach to be more equitable across states. She agreed that grantees need as much information as possible in advance. Tom McCubbins (Merck) announced that Merck has restarted its Hib process. The data are very promising, and they should have supply available in the fourth quarter of 2009. They anticipate a return to full supply in 2010. Dr. Mark Netoskie (AHIP) said that AHIP supports these recommendations. A survey of their member organizations indicated that they would not require changes to their current vaccine policies. Dr. Jeanne Santoli CDC/CCID/NCIRD/ISD Dr. Santoli offered updates on the supply of vaccine for pediatric and adult hepatitis B, hepatitis A, and MMR-V. In February 2009, CDC analyzed available pediatric supply data from both United States manufacturers of pediatric hepatitis B to assess sufficiency over the remainder of 2009. This assessment would help them understand the situation and how to proceed. In conjunction with the Vaccine Supply Stakeholder Group, which includes representatives from AAP, AAFP, ASTHO, NACCHO, AIM, FDA, and ACIP, CDC determined that there was no need to adjust routine pediatric vaccine recommendations. Following that analysis, in March 2009, CDC and its partners communicated broadly to encourage providers to continue routine ordering practices and to avoid placing larger-than-normal orders or stockpiling. Some delays had occurred in January and February, which could have caused ordering behavior to change and therefore create a situation that they hoped to avoid. Both manufacturers and CDC’s 64 immunization grantees are currently managing provider orders to support judicious vaccine ordering. This endeavor takes a great deal of work, but the process is critical to moving forward without issuing interim recommendations for this vaccine. The analysis showed that the summer months of June, July, and August were anticipated to have the tightest vaccine supply. At this point, both manufacturers are supplying vaccine to the United States market. GSK will supply additional product to the United States beginning in September 2009 to assure sufficient supply. Merck expects supplies to be limited during the remainder of 2009, although supplies are still forthcoming, and they do not expect to return to full supply until 2010. She then addressed adult hepatitis B vaccine. Merck is not currently distributing its adult or dialysis hepatitis B vaccines. These products will not be available for the remainder of 2009, but will return to full supply in 2010. Fortunately, the supply of GSK’s adult hepatitis B vaccine and adult hepatitis A/hepatitis B combination vaccine is sufficient to meet national demand at this time. The supply will meet increased demand that comes from CDC's High Risk Adult Hepatitis B Initiative. Regarding adult hepatitis A vaccines, Merck is not currently distributing this product currently and does not anticipate doing so during 2009. Merck will provide additional information regarding the availability of adult hepatitis A vaccines when it becomes available. GSK’s production and supply of adult hepatitis A vaccines and adult hepatitis A/hepatitis B combination vaccine are currently in good supply to meet national demand, said Dr. Santoli. MMR-V vaccine has not been, and will not be, available during the remainder of 2009. Merck expects MMR-V to return to the United States market with full availability in the first half of 2010. Finally, she addressed monovalent vaccines for measles, mumps, or rubella. Merck is not distributing these products at this time. They plan to resume production of these monovalent vaccines in the future, based on available resources and capacity. However, Merck does not expect that these vaccines will be available for at least two years. They are making customers who inquire aware of that longer time frame. Discussion Mr. John T. McCubbins (Merck) thanked his colleagues at GSK and sanofi for helping with the shortage issues that Merck has experienced. They understand the shortages’ significance to public health. He offered apologies to ACIP, public health providers, and patients for Merck’s difficulties. They have a two-fold plan to resolve their issues. An acute plan will address issues with specific vaccines that are in short supply, and long-term infrastructure issues will be addressed so that when temporary issues arise, they are not translated into supply issues. Progress has been made on that front. For example, Merck has produced 25% more varicella-containing product in the first five months of 2009 than they have produced in any previous year. They have restarted Pedvax, and the supply should be available at the end of 2009 and the beginning of 2010. Merck has been producing its hepatitis B product, and they expect full supply in 2010. Additionally, they are investing in expanding infrastructure and in building new facilities in Ireland and North Carolina. They anticipate licensure for the North Carolina facility in 2010, which will improve the supply situation. They are investing in the future to ensure that they will get where they want to be and not have a recurrence of this situation. Merck is in the vaccine business for the long haul, and they commit to greater transparency on their supply situation, including progress and setbacks. He understood that the only appropriate apology was to put these vaccine products back on the market, and Merck is committed to that effort. Dr. Sawyer asked for comments from Merck regarding the rationale for returning to production of monovalent measles, mumps, and rubella, given that there are no recommendations from ACIP to use those vaccines. Mr. McCubbins replied that the monovalent M, M, and R have been given a lower priority than the combination product. This prioritization is due to a capacity issue and the belief that better coverage is achieved with the combination product. Merck will return to monovalents, but not for at least two years. Margie McGlynn (President, Merck Vaccines) responded that Merck has heard mixed feedback from the marketplace. There is no clear, good answer regarding production of monovalent M, M, and R. They feel that if providers are interested in using the monovalent vaccines, it is their obligation not to make that decision on behalf of the providers. They understand the on-going public health debate and the feelings of physicians who believe in using monovalents because of fears of problems with co-administration of combination vaccines. The concerns are not valid, but could affect penetration rates and utilization rates of the vaccine. They also appreciate that some providers and patients want monovalent products. For these reasons, Merck decided not to make the choice. At the same time, MMR has priority to immunize the greatest possible number of children on a global basis. They welcome additional input. She stressed that this decision was one of her most difficult as President of Merck Vaccines. Dr. Birkhead stated his belief that Merck had made a mistake by proceeding with monovalents. Dr. Temte said that the Wisconsin Council on Immunization Practices (WCIP) has heard that various hospitals and health systems have been using the pediatric hepatitis B vaccine off-label, giving two doses to adult employees for cost savings. He asked about broad communication efforts to avoid this practice. Dr. Santoli answered that CDC is in the process of clearing a set of hepatitis B Q & As about supply challenges on the pediatric and adult sides. This Q & As will state clearly that to make the best use of pediatric vaccine supply during a time when supply is limited, that supply should not be used to vaccinate adults. She agreed that the cost incentive may cause people not to heed that guidance. Dr. Sumaya asked about communication or agreement between the pharmaceutical companies that supply the vaccines and the information that reaches providers via a number of advisory groups that make decisions and plans. He wondered whether the pharmaceutical companies have strategic plans for the next few years, and whether CDC has a sense of time frames and the availability of vaccines. Mr. Phil Hosbach (sanofi pasteur) replied that they in close contact with CDC and the ACIP working groups as they work on vaccine development. They also work with NVAC and share information about their plans for vaccine development to target infectious diseases in the US and around the world. Information is shared at this working-group level. Dr. Santoli added that when there is an issue or a challenge, the Vaccine Supply Stakeholders Group shares proprietary information as part of their discussions. They use this information to make decisions and recommendations. The involved organizations share a great deal of information that is not always made public. For example, the information used to make the decision about pediatric hepatitis B was based on month-by-month supply projections from each of the manufacturers, plus stockpile data. Dr. Stan Grogg (AOA) expressed concern about Merck’s decision to produce monovalents, and his concern about delays in immunizations. Dr. Schuchat reminded the group that pediatric vaccine shortages are addressed with a pediatric vaccine stockpile, which is part of the VFC program. There is a six-month supply of pediatric vaccines. With all of the new vaccines and combination vaccines, and with some formulations going out of production, the stockpile is undergoing re-evaluation and assessment. It has helped in some shortage situations and fallen short in others. Dr. Christine Hahn (CSTE) recalled a discussion about combination vaccines in which it was concluded that MMR is not a combination vaccine because the individual antigens are not available. The vaccine recommendations were used to support combination vaccines, but the newly-approved statement is softer and includes patient preference as a prominent consideration. She felt that this statement could be interpreted as support for moving to monovalents for MMR. This interpretation seems to be in conflict with the committee’s sentiments. Ms. Stinchfield (NAPNAP) echoed concern for single-antigen vaccines for measles, mumps, and rubella. Science should drive ACIP’s decisions, and it seems that producing these vaccines is not a good use of resources or efforts when the call for them comes from a small minority of parents and providers who will give in to the “too many, too soon” or “too young” arguments. Science disproves those assertions. To make single-antigen vaccines available goes against science and toward public opinion, which is sometimes erroneous. Dr. McGlynn (President, Merck) indicated that there is a two-year time period between now and a point at which Merck would be able to reintroduce these vaccines. She welcomed and encouraged clear and specific ACIP recommendations. The physician community places orders for vaccines, and these calls influence Merck’s decision. Clearly, the physician community is most influenced not by Merck’s statements as a manufacturer, but by clear and strong recommendations from ACIP and other stakeholder groups. She expressed hope that they could work together to assure that the right outcome takes place. Dr. Schuchat suggested that since an upcoming session of the meeting would focus on MMRV, they should delay their discussions about formulations until that session. Dr. Birkhead said that ACIP has issued clear guidance on the MMR and monovalent issue. He pointed out that ACIP “holds the strings” to the VFC program, and he was not sure that monovalents would automatically be included in the program when they became available, or whether it would require an ACIP vote to include them. Dr. Lance Rodewald noted that monovalents were previously available from Merck, but were never in the VFC program. Dr. Temte said that before the measles vaccine, the rate of febrile seizure with measles was 70 per 10,000 people. The rate with the monovalent measles vaccine is about 9 seizures per 10,000. The rate with MMR is 3 to 4 per 10,000. The perception that the measles vaccine by itself is safer than measles mixed with mumps and rubella is not supported by data. He suggested that they take a proactive approach to keep this information in front of physicians and the public. Ms. Hannon (AIM) was grateful that manufacturers share information with CDC and the Stakeholders Group, which includes an AIM representative. This information cannot be shared further than those groups, however. Some grantees were informed about the hepatitis B vaccine situation either by providers or by McKesson’s announcement that the product was on back order. Even given the numerous legal issues, it is possible to make significant improvements in planning if more information about supply is available. Grantees are sometimes the last to find out even though they are engaged with CDC, and CDC makes decisions with information from manufacturers. In light of the request from Dr. McGlynn, Dr. Ehresmann suggested that ACIP make a strong statement in opposition of Merck’s approach to producing monovalents, based on the current status of the science and ACIP statements. She suggested that a future meeting could generate a formal resolution to express the committee’s concern. Dr. Keyseling (SHE) pointed out a limited use of monovalent vaccines during epidemic situations of mumps or measles for healthcare personnel and community coverage. If a limited supply of monovalent vaccine were controlled by the government and available for release, then it could be a cost-effective method for handling epidemics. Dr. Schuchat said that one of the uses of the stockpile is for outbreak response, but CDC’s recommendation for outbreak response in the US is MMR. Mr. Hosbach (sanofi pasteur) recalled discussions from the previous day regarding policy decisions and their influence and impact on manufacturers. Many manufacturers were surprised at the direction of the committee regarding combination vaccines, as the manufacturers were not involved with the Combination Working Group. Knowing that the committee no longer prefers a type of vaccine will change manufacturers’ plans. Manufacturers try to share their development plans. A policy change has a significant impact on what they have done previously and their future directions. Manufacturers should not drive policy, but should be part of the process. If manufacturers participate, then they can help committees make well-informed decisions and understand complete impacts. Further, the public is also included in decision-making processes. ACIP is concerned about maintaining public involvement, and the manufacturers are also seeking guidance and information from providers and the public. He asked that manufacturers stay involved as much as possible. Jane Quinn (GSK) supported Mr. Hosbach’s comments and elaborated on the collaborative efforts and willingness of manufacturers to work closely with CDC and all stakeholders. Issues of global planning capacity and supply constraints on particular antigens, as well as combination vaccine planning versus monovalent use, are important for all to consider. GSK has produced monovalent vaccines on a number of occasions, but they realize the breadth and interconnectedness of vaccine supply planning, especially around infant immunization schedules and combination vaccines. The process is difficult, and they take as many inputs into account as possible. They wish to remain open with CDC and all stakeholders in this effort. Vaccines must be brought forward in appropriate volumes and are readily available to all who need them. GSK is supportive of continued collaboration and supports Merck’s comments regarding transparency, especially in public health crises. Dr. Katz (IDSA) said that the Measles Partnership, which administers the measles vaccine throughout resource-poor nations, uses monovalent measles vaccine. Some countries have now been able to switch to measles-rubella. MMR is not necessarily the international product. The Serum Institute in India, which makes most of the vaccine used for the Measles Partnership, makes monovalent measles vaccine. International use of monovalent vaccine does not mean that the US should change its preferences, but serves to point out that from the manufacturers’ point of view, different markets demand different products. Introduction Jonathan Temte, MD, PhD University of Wisconsin ACIP, Working Group Chair Dr. Temte opened the MMRV Vaccine Safety Working Group session, first offering background information pertaining to the group’s process. They have worked on MMRV vaccine safety issues for approximately 16 months. In February 2008, preliminary data were presented to ACIP suggesting an increased risk for febrile seizures following the first dose of MMRV vaccine among children aged 12 through 23 months in the first to second week after vaccination. Therefore, ACIP recommended removing the preference for the combination MMRV vaccine over separate administration of MMR and varicella vaccines and forming and ACIP MMRV Vaccine Safety Working Group [Morbidity and Mortality Weekly Report (MMWR), March 2008]. The group’s first term of reference was risk assessment being lead by the CDC Immunization Safety Office (ISO). The group was charged with a careful review of post-licensure studies and suggesting any additional analyses that might be needed to fill data gaps. Further, the group was to review encephalitis cases following the MMRV vaccine, and to communicate vaccine safety findings in a clear and transparent manner. The second term of reference concerned risk management and the formulation of policy options for ACIP’s consideration, taking into account both the benefit of vaccination and risks of vaccine adverse events. Additionally, the group was charged to identify and reconcile potential inconsistencies in previous ACIP statements related to measles, mumps, rubella, varicella vaccination, and febrile seizure prevention. In June 2008, the work group presented the terms of reference and other process information to ACIP. In October 2008, they presented results from the Vaccine Safety Datalink MMRV Febrile Seizure Study and heard final results from the Merck-sponsored febrile seizure study. October’s report also included work group’s interim synthesis of risk for febrile seizures after MMRV. In February 2009, ACIP heard preliminary results from a physician survey regarding opinions for MMRV vaccine use and was presented the elements of the policy framework that would be assessed to formulate options for MMRV vaccine use. Dr. Temte stressed that the group’s overall procedure had been intensive. They have had the benefit of great expertise of the work group members, as well as input from various other federal, state and local organizations and programs. They have also benefited from two unpublished studies providing detailed information on MMRV vaccine safety. Physician and mother opinion surveys and studies and the ethics consultation had an important impact on their work. An abundance of data has filtered through the work group in over 50 hours of teleconference meetings. He reminded everyone of the social context in which they are dealing with discussing febrile seizure as a vaccine adverse event. Over the last few years, there has been a substantial increase in the number of vaccines recommended for usual use. Because of the effectiveness of vaccines, we are now in a situation in which many parents express more concern and fear of a vaccine and its potential adverse events than of the disease the vaccine has been so successful in preventing. Public trust in the safety and efficacy of vaccines is key at this point to the on-going success of immunization programs. Also, communication and influence from multiple media sources is rapid (e.g., internet). These sources of information may or may not be factual. In conclusion, Dr. Temte reminded everyone that the recommended schedule in the US in 2009 is for the first dose of measles, mumps, and rubella for persons aged 12 through 15 months of age followed by a second dose at 4 to 6 years of age. The same schedule applies for varicella vaccine. MMRV vaccine is approved for use among healthy children aged 12 months through 12 years [http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm]. Parental Perceptions of MMRV Vaccine Alan P. Janssen, MSPH Health Communication Specialist National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Mr. Janssen provided preliminary results of a qualitative study conducted with mothers and pediatricians regarding the MMRV vaccine. The objective of the study was to explore perceptions regarding the risks and benefits of the MMRV vaccine with pediatricians and with mothers. In addition, the study tested draft communication materials regarding the MMRV vaccine with mothers. Regarding the methodology of the pediatrician survey, data collection included in-depth, thirty-minute interviews conducted one-on-one with 21 pediatricians. The interviews addressed dose one and dose two of the MMRV vaccination. The pediatricians were provided with an MMRV product profile. Studies were conducted in a commercial market-research facility in New York City and Kirkland, a suburb of Seattle, Washington, from May 9 - 15, 2009. They encouraged a diverse panel of respondents from the pediatric community, all of whom were board-certified. Of the panelists, 6 were male and 15 were female; 14 were White, 4 were African-American, and 3 were Asian. The pediatricians surveyed spend 70% of practice time in direct patient care and self-reported giving at least 5 MMR vaccines per month. Pediatrician perceptions of MMRV vaccine were generally favorable. Common comments included the following: “We loved having it.” “I have no reservations about ProQuad.” “I miss it. I wish it would come back.” “I’m definitely in the ProQuad pack.” A few pediatricians expressed reservations, such as the following: “I’m not that comfortable with it, really.” “I don’t like it that much.” Pediatricians were asked to rank the significance of the MMRV vaccine to their armamentarium on a scale of 1 to 7, with 1 representing no significant contribution to the practice and 7 representing a highly significant addition to the practice. Most of the 17 pediatricians interviewed were very favorable toward the MMRV vaccine, with 9 respondents rating the vaccine’s significance at a 7, and 5 at a 6. When provided with data regarding the rates of fever and febrile seizures following MMRV vaccine, several pediatricians remarked on the data, but were not alarmed by them. Some of their remarks were as follows: “I don’t think [fevers, febrile seizures] are numerous or serious enough to not use [ProQuad].” “It makes sense. If you have more fevers, you’ll have more seizures.” “…of significance to the patient, not clinically…I’d still use it.” Pediatricians considered that for parents fever and febrile seizures are important and distressful events. Some of the comments were as follows: Fever “Fever is worrisome [for parents] and it’s across the board.” Febrile Seizure “The kids are fine and it takes the parents years to recover.”  “It’s really not a big deal. I talk the parents down.” “Really scary for the parents; really harmless for the child.” “It’s a very, very scary thing for parents to observe.” “That’s what freaks them out. Then they get fever phobia.” “[Parental trauma] – that’s the big one.” Regarding acceptance of the MMRV vaccine, most pediatricians reported that they would stock the MMRV vaccine as well as MMR and varicella vaccines. The top four factors rated as “very important” in influencing the decision to use MMRV vaccine were: 1) ACIP and AAP recommendations; 2) the potential for the MMRV vaccine to improve coverage for varicella vaccine; 3) parental preference for fewer injections at a visit; and 4) parental concerns for risk of febrile seizure. Another factor considered for decision-making was pediatricians’ support for flexibility to be able to meet the needs of their patients. The interview included this question: “What do you think ACIP should recommend for dose 1 MMRV at ages 12 to 15 months?” Of the 21 responding pediatricians, 11 said that they wanted provider choice between the MMRV vaccine and separate MMR and varicella vaccines, 5 stated a preference for separate MMR and varicella vaccines with an option to permit the use of MMRV, and 5 stated a preference for the MMRV vaccine. Some of their comments were “We want families to have choices.” “There are families that want to unbundle vaccines and some who want to bundle. It would be nice to have a choice.” “It makes our lives a little bit easier.” “I just want to keep it simple. MMRV for both would simplify our conversation.” The interview also asked pediatricians’ opinions regarding ACIP recommendations for dose 2 of MMRV vaccine at ages 4 to 6 years. Again, 11 pediatricians recommended provider choice between the MMRV vaccine and separate MMR and varicella vaccines, 10 had a preference for the MMRV vaccine for the second dose, and none supported separate MMR and varicella vaccines for dose two. Some of their comments were: “It’s a much bigger deal with 5-year olds.” “I think it’s more distressing with older kids.” “Four-to-six year olds really, really, really don’t like shots” In summary, among the 21 pediatricians interviewed in two cities, approximately 50% stated a preference for provider choice between the MMRV vaccine and the separate MMR and varicella vaccines for both doses. Consistent with other studies, pediatricians reported less concern for fever and febrile seizures, but they also perceived that parents were likely to have greater fever and seizure concerns. With respect to the methodology utilized in the Mother study, data were collected by means of a series of “mini focus groups” in Kirkland, Washington and New York City. The sessions included up to six participants per group, lasted about one hour and were moderated by a professional moderator who provided the mothers with background material about the MMRV vaccine and febrile seizures. The study assessed the mothers’ views about combination vaccines in general and about dose one of the MMRV vaccine for children aged 12 through 15 months. The participants all had children aged 7 months to 3 years of age. Their children had neither experienced seizures nor had a condition which compromised the child’s immune system and thus their ability to receive certain vaccinations. The participants also expected their child to receive all or most of the recommended childhood vaccinations. A total of 16 focus groups were conducted with 82 respondents. The median age was 31 years, with a range of 20 through 46 years. Of the 82 participants, 63 had at least one college degree. Respondents were White (n=58), African-American (n=10), Hispanic (n=6), Asian (n=5), and mixed race (n=3). When asked about combination vaccines in general, the mothers produced a modest list of advantages, a longer list of disadvantages, and an even longer list of questions. The list of advantages included the chance for fewer shots and less pain and trauma; protection against several diseases at once; fewer doctor trips; and potentially lower costs for vaccination. The list of disadvantages associated with combination vaccines included an inability to pinpoint a source of allergic reaction; the potential for increased side effects; the concern that the combination shot may be too great a challenge for the child’s immune system; and less parental choice regarding how children receive vaccines. The mothers’ questions focused on the side effects of the combination vaccines, whether the combination is as effective as separate vaccines, and how combination vaccines fit into the immunization schedule, including the catch-up schedule. The degree of acceptance of the MMRV vaccine varied substantially among the mothers. After reviewing information about the MMRV vaccine, mothers were asked if their physician recommended MMRV for dose 1 for their child aged 12 to 15 months, to rank their acceptance of that recommendation on a scale of 1 to 7. Of the respondents, 18 gave a rank of 1, or “no way / no how” and 18 gave a rank of 7, or acceptance without reservations. Comments of mothers who were acceptors of the MMRV vaccine centered on their trust of their pediatrician. They also liked the idea of giving one less shot. The non-acceptors of the MMRV vaccine determined that the risks were not worth the benefit of the combination vaccine, and there was a great deal of concern regarding seizures among this group. Mothers were generally less concerned about fever than they were about seizures, although some respondents did express strong concern about fever. Their assessment of the importance of the difference between the separate and combination vaccines varied. Some mothers spontaneously reported that fever and seizures could be prevented by using Tylenol™. The mothers’ perception of post-vaccination fever in general appeared to be affected by their experience. One mother commented, “That just comes with the territory, but you still worry.” Regarding seizures, there was general agreement among the mothers that seeing their child have a febrile seizure would be a harrowing experience. For some, information on the rates of febrile seizure was of significant concern; for others it was not. A number of the mothers responded that they did not know what a febrile seizure was. After receiving information on the rates of seizure and the MMRV vaccine, some mothers responded that the numbers were not alarming. In summary, the Mothers study was conducted with a small sample of mothers who reported that they have their children vaccinated. They generally expressed a high degree of trust in their pediatricians. Mothers can differ in their conclusions regarding the data about MMRV vaccine and the rates of fever and febrile seizures and, thus, in their acceptance of MMRV vaccine. After reviewing and discussing risks and benefits of MMRV and separate MMR and varicella vaccines, almost one-third of the mothers reported that they would be resistant to having their child receive the MMRV vaccine; about one-quarter of the mothers were neutral, and about 40% of them would accept it. Discussion Dr. Neuzil thought that it might be helpful to put these surveys into perspective with the perception survey reviewed at the February 2009 meeting. That survey included 300 pediatricians and family practitioners. The physician interviews and mothers’ focus groups have very small numbers, and there could be different types of biases. Dr. Temte answered that two different methodologies were used. The first survey was a randomized sampling of family physicians and pediatricians to have a general overview. Focus groups and interviews are not intended to be representative, but rather to determine common themes that occur across clinicians. In this case, they involved a multi-modal approach. Some themes were fairly consistent. They were not necessarily looking for percentages, but at themes that could be followed up with questions. Taken as a whole, the comments were consistent. Mr. Janssen said that an advantage of a qualitative study is the ability to explore in more depth and to learn what is behind decisions. The combination of both methods is helpful in the decision-making process. Dr. Dixie Snyder noted that the group of mothers had no major concerns about vaccines, as they planned to have their children vaccinated. A large proportion of the mothers were concerned when they received information about fever and febrile seizures after the MMRV vaccine. All studies have limitations or biases, but it is striking that this group of respondents were vaccine-friendly, yet expressed these concerns. Dr. Baker echoed Dr. Snyder’s comment, adding that the “vaccine acceptable” group is not concerned about safety and is generally “pro-vaccination.” She asked about the methodology behind the selection of cities for the study. Mr. Janssen replied that the Seattle area population has numerous questions about the safety and use of vaccines. Mothers in this area were recruited via their play groups and asked a series of questions about vaccines. The New York City area has more concerns with disease because of the crowded nature of the city, so mothers there are likely to have opinions regarding vaccines. In contrast, focus groups in the center of the country showed that parents tend to follow physician recommendations. They chose areas in which they were likely to receive a range of responses. He has conducted studies like these for 10 years and was struck by the number of questions and concerns raised, even among groups of vaccine acceptors. They trust their physicians, but many are going to other sources for information about vaccines that they then discuss with their physicians. Dr. Baker commented on the finding that many parents do not know what a febrile seizure is, or that there is a risk for one with any vaccines. When counseling their patients, practitioners need to be aware of these gaps in knowledge and of reluctance on the part of parents. Dr. Temte observed the New York City focus groups and noted the following: 1) fevers were of concern to parents; 2) in general, parents were not aware of febrile seizures until they heard a description of them, and the description alarmed them; and 3) almost all of the focus groups mentioned a risk of thimerosal exposure with MMR, even though that does not exist. The amount of misinformation is immense, making it even more important to ensure that patients receive clear information. Dr. Sumaya agreed with the utility of the methodology that assesses perceptions. At the same time, these studies need to be supplemented by studies with multiple providers and populations with broader demographic characteristics. Evaluation of MMRV and Febrile Seizures: Updated VSD Analyses with Chart Review Results Nicola Klein, MD, PhD Northern California Kaiser Permanente and the Vaccine Safety Datalink MMRV Team Dr. Klein reported on the updated VSD analyses with chart review results from the Vaccine Safety Datalink (VSD) / MMRV Rapid Cycle Analysis (RCA) study evaluating MMRV and febrile seizures. The VSD is comprised of 8 HMOs: Group Health Cooperative, Kaiser Permanente Colorado, Kaiser Permanente Northwest, Harvard Pilgrim Health Care, Health Partners, Northern California Kaiser Permanente, Marshfield Clinic and Southern California Kaiser Permanente. Data are available on more than 8 million members. Over the last few years, following the licensure of new vaccines, the VSD has undertaken RCA studies for each new vaccine. RCA utilizes data which are updated weekly on all vaccines and all outcomes. Analyses on outcomes specific for each vaccine are conducted every week. Each RCA study has a lead principal investigator from one of the VSD sites. Dr. Klein is the principal investigator at Northern California Kaiser Permanente, which is the lead site for the MMRV RCA Study. Dr. Klein reviewed the MMRV seizure results, which were presented at the February 2008 ACIP meeting. The study monitored for seizures, among other outcomes, after the first dose of MMRV for patients presented in the emergency room and inpatient settings during post-vaccine days 0 to 42 among 12 through 23 month olds. A signal for seizures was detected in the 42-day period following MMRV compared with historical rates in MMR recipients. Upon further evaluation, the study found significant clustering of seizures on days 7 through 10 after both MMRV (N= 43,353) and MMR + varicella (V; N= 314,599) vaccines using temporal scan statistics. VSD reviewed charts to confirm febrile seizures during the seven to ten days after vaccination for both MMRV (N=45) and MMR + V (N=132) through 2007. Based on those reviews, the study calculated an odds ratio of 2.3 (95% CI 1.6, 3.2), which translates to one additional febrile seizure for every 1,923 MMRV doses administered instead of MMR + V. Following this presentation, ACIP voted to change the recommendations from a preference for MMRV to no preference for MMRV or MMR + V. In addition, an MMRV Work Group was formed. One of the terms of reference of the Work Group was to evaluate additional data that would be helpful. A few questions remained after the preliminary work: 1) chart confirmation of febrile seizures outside the 7- to 10-day risk period; 2) the risk for seizures after MMRV versus MMR + V in different time windows: 0 to 42 days, 0 to 30 days, 5 to 12 days, and 13 to 30 days to directly compare with the Merck-sponsored Phase 4 study in a post-hoc analysis; and 3) to conduct further investigations of risk for seizures in 4- to 6-year-olds, particularly evaluating for excess risk. To address these questions, the investigators took advantage of the fact that the VSD had a supply of MMRV through most of 2008, so they utilized those data to conduct additional studies. The investigators considered seizures among 12 through 23 month olds after the first dose of vaccine administered during 2000 – 2008. There was a strong peak and clustering between days 7 and 10 for MMRV, MMR + V, and MMR alone. Further, there are no obvious clustering or peaks outside this window. Temporal scan statistics show that for MMRV, MMR + V, and MMR, there is significant clustering between 8 and 10 days, 7 and 10 days, and 7 and 11 days, respectively, depending on the vaccine. No clustering was identified for varicella alone. The investigators also considered the question of detecting outpatient visits for fever. They collected data on outpatient fever visits among 12 through 23 month olds after the first dose of vaccine from 2000 – 2008. The results were similar to the seizure conclusions in that there was a peak in days 7 through 10. Temporal scan statistics of fever showed remarkable clustering between days 7 and 10 for all three measles-containing vaccines. Again, no significant clustering was identified for varicella alone. Using these data, the investigators evaluated chart confirmation of febrile seizures outside the 7- through 10-day risk period. In consultation with the VSD investigators and the ACIP MMRV Working Group, a chart review plan was devised to include all seizures 0 to 42 days after MMRV, all seizures 7 to 10 days after MMR + V, and a sample of seizures at 0 to 6 and 11 to 42 days after MMR + V. That sample was equivalent to the number of MMRV seizures during days 0 to 6 and 11 to 42. A total of 491 charts were sampled, and 451 were reviewed. The review confirmed that an acute seizure of any type had occurred in 94% of the charts (n=424). One of the study questions concerned whether there is a differential confirmation between MMRV versus MMR + V. There was no difference in confirmation rate between MMRV and MMR + V, with 94% of the charts being confirmed as an acute seizure of any type for both vaccines (n=424). Further, 87% of the total charts reviewed were febrile seizures (n=392), and there was no difference between the MMRV and MMR + V groups. Another question concerned whether there was a differential confirmation rate between cases that occurred within the 7- to 10-day risk period or outside it. Of the cases, 90% were confirmed in the 7- to 10-day window as febrile seizures, versus 83% outside the 7-10 day risk window and these two confirmation rates are significantly different from each other. More importantly, there is no differential in terms of the confirmation rate in the MMRV versus MMR + V groups either during the 7-10 day window or outside this risk period. However, because there was a difference between the confirmation rates of the two windows, when the sampling scheme was applied to a regression analysis, 90% was applied to any case in the window (7-10 days), and 83% to cases outside the window. In the chart review findings among febrile seizure cases in 12 through 23 month olds, no difference was detected between whether it was a first seizure event between MMRV versus MMR + V, or whether there was a positive family history for seizures between recipients of MMRV versus MMR + V. Given that data pertaining to family history were missing from nearly half the charts, the results should be interpreted with caution. The study next sought to evaluate the risk for seizures after MMRV versus MMR + V in the time windows of 0 - 42 days, 0 - 30 days, 5 - 12 days, and 13 - 30 days to directly compare with the Merck-sponsored Phase 4 study. When the study compared the risk of seizures 7 to 10 days after MMRV compared to MMR + V, the automated data showed a relative risk of 1.98 with confidence intervals of 1.43 and 2.73. These results were similar to Dr. Klein’s presentation to ACIP in February 2008. Chart-confirmed febrile seizures are similar, with approximately a two-fold increase in relative risk (RR=2.04). These data translate to risk difference of 4.3 per 10,000 doses; that is, for every 2,300 MMRV doses given rather than MMR + V, one more febrile seizure will occur 7 to 10 days after vaccination. A similar analysis for seizures 0 – 42 days after MMRV showed an increased relative risk of 1.42 in the automated data, with confidence intervals of 1.11 and 1.81. The chart-confirmed febrile seizure case data were very similar, with a relative risk of 1.46 and confidence intervals of 1.11 and 1.92. The risk difference for this window was 6.2 per 10,000 doses. The data from 2000 – 2008 include mostly historical data for controls. While the investigators controlled for confounders as best they could, there are issues associated with using historical controls. Therefore, a case-centered logistic regression analysis was conducted. This analysis is a variation of the self-controlled case series method. Given that a seizure occurred, this analysis compares MMRV to MMR + V and determines whether the patient was more likely to have received the vaccine 7 to 10 days before the seizure, or during the control window of 43 – 180 days before the seizure. This analysis showed an increased odds ratio for febrile seizures of 1.92 and significant confidence intervals of 1.39 and 2.66 for the MMRV compared with MMR + V for the 7-10 day postvaccination period. When the analysis was conducted for the window of 0 – 42 days, there was an increased odds ratio of 1.3 and confidence intervals of 1.03 and 1.65. Thus, the previous analyses were confirmed, and there is increased risk for febrile seizures in these windows. Using regular regressions, post-vaccination risk was considered for days 5 through 12; 13 – 30; and 0 – 30 days. Using chart-confirmed cases only, increased relative risk was found for having a febrile seizure during the 5 – 12 and 0 – 30 day periods. However, no difference in risk of febrile seizures in the MMRV versus MMR + V group was detected in the 13 – 30 day window. The automated data results were very similar to the chart-confirmed data. Further investigations were also conducted on risk for seizures in 4 - 6 year olds, particularly evaluating for excess risk. In this group, there were 4 seizures during days 7 – 10 after the MMRV vaccine. Zero occurred during that time for MMR + V. There is no significant difference between the 4 versus zero split. Further, only 1 of the 4 cases was diagnosed as a febrile seizure. In evaluating risk for 4 – 6 year olds, the investigators adopted a conservative approach. Instead of evaluating excess risk as before, in this case they evaluated for absolute risk. When evaluating absolute risk for MMRV for one case out of approximately 85,000 doses given, the upper limit of the confidence interval was one per 15,194. At most, therefore, for every 15,000 MMRV doses given, 1 febrile seizure will occur 7 to 10 days after vaccination, even if all of the risk is due to the MMRV vaccine. Similar calculations for MMR + V show one febrile seizure per approximately 17,000 doses. In summary, among 12 - 23 month olds after the first vaccine dose, fever and seizure are elevated 7 - 10 days after all measles-containing vaccines. MMRV increases fever and seizure about twice as much as does MMR + V. Analyses of chart-reviewed febrile seizures confirmed a two-fold increase risk of febrile seizures on days 7 - 10 following MMRV as compared to MMR + V. The increased risk for seizures observed during other time windows is due to the risk during the 7 - 10 day window. Among 12 - 23 month olds after the first vaccine dose, for every 2,300 MMRV doses given instead of MMR + V, one additional febrile seizure will occur 7 - 10 days after vaccination. Among 4 - 6 year olds, no evidence of elevated seizure risk was found during the six weeks after MMRV. For the 7 - 10 days after vaccination, an absolute risk greater than 1 febrile seizure per 15,000 doses of MMRV can be ruled out. Among 12 – 23 month olds after vaccination, there is a sharp peak for seizures between days 7 and 10 for MMRV. The graph demonstrates that the increased risk for seizures detected during the longer windows is due solely to the increased risk in the 7- to 10-day window. Synthesis of Evidence for Febrile Seizure Risk after MMRV Vaccination Karen Broder, MD CDC / CCID /NCPDCID / DHQP / ISO Dr. Broder presented the final synthesis of the evidence for febrile seizure risk after MMRV vaccination on behalf of the MMRV Vaccine Safety Work Group. She reminded everyone that an interim synthesis was presented in October 2008. The framework for her presentation included a review of the evidence framework used to assess risk for febrile seizures after MMRV vaccine; risk assessment for Doses 1 and 2 of MMRV; the clinical importance of febrile seizures assessment; and a discussion of other terms of reference, including an encephalitis case review, additional analyses, and communication of findings. In October, the work group presented an evidence framework that they developed to assess the risk for febrile seizures after MMRV. The framework was based on frameworks used by IOM, WHO, and the draft ACIP evidence-based work group guidance. The framework contains three lines of evidence, and all lines were evaluated for Doses 1 and 2. The first line is population-based risk, or epidemiologic risk. The second is biologic plausibility, which in this case is the plausibility of having a febrile seizure after MMRV vaccination. The last line is clinical importance of the adverse event, which the group divided into two assessments: 1) the medical importance of febrile seizures, and 2) the psychosocial importance of febrile seizures as an adverse event. The analysis used quality of evidence grading definitions from the draft evidence-based work group guidance. One modification has been made since the October 2008 presentation in that evidence ratings no longer include the impact of further research. They are specific to the nature of the evidence. Four levels were used: high, moderate, low, and very low. The approach to evaluating the evidence across all lines included a thorough review of two unpublished post-licensure studies of febrile seizure risk after MMRV: VSD (principal investigator: N. Klein), and a Merck-sponsored study (principal investigator: S. Jacobsen). In addition to these studies, the group reviewed literature and other data sources, including unpublished data. They consulted with numerous experts and held multiple discussions. Two work group surveys assessed and graded the quality of evidence for MMRV and febrile seizure risk. As noted, the group presented its first assessment in October 2008. With respect to the synthesis of the Dose 1 MMRV risk assessment, Dr. Broder summarized the data available in October 2008 from the VSD and Merck-sponsored studies. Both studies considered rates of confirmed febrile seizures after MMRV and compared them with rates after MMR and varicella vaccines administered in separate injections at the same visit (MMR + V) in children aged 12 through 23 months. Both studies found an increased risk for febrile seizures in the 1 to 2 weeks after vaccination with MMRV compared to MMR + V. No chart review data were available in the VSD study outside the 7- to 10-day period at the time. The results in the Merck-sponsored study were final. In the Merck-sponsored study, no difference in risk was noted in the 0 – 30 days after MMRV compared to MMR + V. A non-statistically significant decrease in febrile seizure risk was observed after MMRV compared to MMR + V in the 13 – 30 day window after vaccination, with a relative risk of 0.6. Since October 2008, the VSD has provided data from the expanded chart review study of children aged 12 through 23 months receiving Dose 1 of MMRV compared with MMR + V. They enrolled more children, employed additional methods, and reviewed charts in time periods outside the 7- to 10-day window. The work group assessed the evidence for the early and late risk windows after MMRV compared with MMR+V to determine whether there is a decreased risk for febrile seizures after MMRV compared with MMR+V in the 13 to 30 days after vaccination that might compensate for the increased risk observed after MMRV in the 5 to 12 day period. Both studies compared rates of confirmed febrile seizures after dose 1 MMRV with rates after separate injections of dose 1 MMR + V in children aged 12 to 23 months. Both studies used a largely historical comparison cohort for the MMR + V cases. The VSD study included about 83,000 MMRV and about 376,000 MMR + V subjects. The Merck-sponsored study included about 31,000 subjects in each vaccination group. The primary interval of interest in the VSD study was 7 to 10 days after vaccination on the basis of the temporal scan analysis. The primary interval of interest in the Merck-sponsored study was 5 to 12 days after vaccination, on the basis of pre-licensure data for fever. With the exception of one additional analysis in the 7 to 10 day period, which was not statistically significant, the Merck-sponsored data have remained unchanged since October 2008. Similar to the October 2008 data, the updated VSD study continues to show about a two-fold increase in risk for febrile seizures in the 7 to 10 days after MMRV vaccination compared with MMR + V. The VSD results in the later window showed a significant increased risk for febrile seizures during the 6 weeks after vaccination and observed no decreased risk in 13 to 30 days after vaccination for MMRV compared with MMR + V. In terms of the previous experience regarding biological plausibility, the increased risk for febrile seizures in the 1 to 2 weeks after MMRV vaccination compared with MMR + V vaccination is biologically plausible. A study in the VSD of approximately 137,000 children under age 7 years showed that vaccination with MMR is associated with an increased risk for febrile seizure during the 8 to 14 days after vaccination. About one additional febrile seizure occurs per 3000 to 4000 children vaccinated [Barlow, Davis et al. NEJM, 2001]. A population-based study of about 35,000 children aged 12 through 23 months who were vaccinated with varicella vaccine identified no increased risk for febrile seizures during the month after vaccination, after controlling for co-administration of MMR vaccine. Pre-licensure trial rates of vaccine-related fever and measles-like rash were higher in children aged 12 through 23 months receiving Dose 1 MMRV than those receiving Dose 1 MMR + V, in the 6 weeks after vaccination [Black S et al. NEJM, Pediatric Infectious Diseases Journal, 1999]. In the trials, 22% of MMRV recipients had fever, compared with 15% of MMR + V recipients. The fever was clustered in the 5 to 12 days after vaccination. Among subjects who had fever after vaccination, the proportion who had fever during the 5 to 12 days was 45% for MMRV and 36% for MMR + V. Among subjects who had measles-like rash after vaccination, the proportion who had this rash during the 5–12 days was 82% for MMRV and 81% for MMR + V [Source: Package insert 2-2008 and unpublished data from Merck on 10-20-08]. Rates of outpatient fever visits after different patterns of MMR and varicella vaccine administration show that the medically-diagnosed fevers in all of the MMR-containing groups are clustered in the 7 to 10 days after vaccination, and MMRV rates are higher than MMR + V rates [N. Klein, ACIP presentation, June 25, 2009; excludes KPSC site]. The work group used the evidence scores to grade population-based risk and biological plausibility. The survey of the work group addressed two questions: 1) the quality of evidence supporting an increased risk for febrile seizures after MMRV versus MMR + V in the 1 to 2 weeks after vaccination; and 2) the quality of evidence supporting whether there is a decreased risk for seizures after MMRV compared with MMR + V in the 13 to 30 days after vaccination. The work group felt that the quality of evidence was high for the increased risk after MMRV in the early window, and that the quality of evidence was low to support the notion of a compensatory risk of MMRV compared with MMR + V. In summary, two post-licensure studies assessed rates of febrile seizures in children aged 12 through 23 months who received Dose 1 MMRV vaccine and compared these rates with children who received separate Dose 1 injections of MMR and varicella vaccines at the same visit. The studies used different methods and populations of children. Despite using different methods and populations, the two studies showed remarkable consistency during the 1 to 2 weeks after vaccination. On the basis of this review, the work group made two conclusions regarding the evidence for febrile seizure risk after Dose 1. First, among children aged 12 through 23 months, during the 1 to 2 weeks after vaccination (5 to 12 or 7 to 10 days, depending on the study) compared with separate Dose 1 injections of MMR and varicella vaccines administered at the same visit (MMR + V), the evidence supports a causal relationship between receipt of Dose 1 MMRV vaccine and an increased risk for febrile seizures; the magnitude of the risk is about two-fold. After vaccination, 7 to 9 febrile seizures occur per 10,000 children vaccinated with MMRV and 3 to 4 febrile seizures occur per 10,000 children vaccinated with MMR + V. After Dose 1 MMRV vaccine, 1 additional febrile seizure is expected to occur per approximately 2,300 to 2,600 children vaccinated, compared with MMR + V. Additionally, among children aged 12 through 23 months, after considering multiple lines of evidence, the MMRV Work Group concluded that the body of evidence suggests that during the 6 weeks after vaccination (0 to 30 or 0 to 42 days, depending on the study), an increased risk for febrile seizures after Dose 1 MMRV compared with MMR + V is only present during the 1 to 2 weeks after vaccination (7 to 10 or 5 to 12 days, depending on study). The risk of febrile seizures occurring during other periods after vaccination is similar between Dose 1 MMRV and MMR + V. Therefore, the risk of febrile seizures occurring during the 1 to 2 weeks after Dose 1 MMRV compared with MMR + V is not offset by a decline in risk after MMRV in the later period after vaccination. Regarding Dose 2 MMRV vaccine, the pre-licensure safety experience during Days 0 to 42 after vaccination, showed lower fever rates in children aged 15–26 months receiving dose 2 MMRV compared with dose 1 MMRV (N=1035) [ProQuad® Package Insert, February 2008]. There were similar fever rates in children aged 4–6 years receiving dose 2 MMRV (N=397) compared with MMR and varicella vaccines (N=193) (children received dose 1 MMR and varicella at least once month earlier) [Reisinger et al. Pediatrics, 2006]. Fever >102º F or warm to touch was 10% in the MMRV group versus 9% in the MMR+V group. No febrile seizures were reported in pre-licensure study subjects receiving Dose 2 MMRV vaccine [Personal communication with Dr. Kuter, Merck on 10-20-08]. In terms of the summary of evidence for febrile seizure risk after Dose 2 MMRV vaccination, among children aged 4 to 6 years, epidemiologic and clinical data suggest adverse event experiences, including fever, are similar after vaccination with MMRV or separate injections of MMR and varicella vaccine administered at the same visit. Febrile seizures are much less common in the age range when Dose 2 MMRV is recommended (age 4 to 6 years) than when Dose 1 MMRV is recommended (age 12 to 15 months). Post-licensure studies were not designed to assess risk for febrile seizures after Dose 2 MMRV; however, in light of findings from the Dose 1 studies regarding febrile seizure risk in the early window, the MMRV Work Group assessed the evidence for febrile seizure risk in children aged 4 to 6 years. Information about Dose 2 MMRV febrile seizure risk was inferred from data on febrile seizure rates in 4 to 6 year olds. Regarding the summary results from VSD and Merck-sponsored studies for confirmed febrile seizures in children aged 4 to 6 years after MMRV versus MMR + V vaccines, in the VSD study, there was one febrile seizure in the MMRV group of almost 85,000 subjects, and no febrile seizures in the MMR + V group of about 65,000. The VSD study did a calculation showing that given these observations, at most, one febrile seizure will occur after vaccination per approximately 15,000 doses of MMRV and 17,000 doses of MMR + V in children aged 4 to 6 years. The Merck-sponsored study identified no febrile seizures in the 5 to 12 days after MMRV or MMR + V in approximately 50,000 subjects [Sources: 2008-09 ACIP presentations; personal communication N. Klein 6/22/09; Personal communication with Merck-sponsored study investigators on 12-16-08]. In conclusion, regarding the risk of febrile seizure after Dose 2 vaccination, among children aged 4 to 6 years, the available data do not suggest that children who receive Dose 2 MMRV have an increased risk for febrile seizures after vaccination compared with those who receive separate MMR and varicella vaccine injections at the same visit; however, less information is available regarding the risk for febrile seizures after Dose 2 MMRV at ages 4 to 6 years than Dose 1 MMRV at ages 12 to 23 months. Clinical importance of febrile seizures. Febrile seizures are defined in the medical literature as seizures that occur in febrile children who do not have an intracranial infection, metabolic disturbance, or history of afebrile seizures [AAP. Pediatrics. 2008; Johnston M. Nelson Textbook of Pediatrics. 2007]. They can occur in any setting of fever. They usually occur at ages 6 to 60 months, with a peak age of 14 to 18 months. This peak overlaps with the age of recommendation for the first dose of MMRV. Febrile seizures affect about 2% to 5% of young children in the US [AAP. Pediatrics. 2008; Baulac. The Lancet Neurology. 2004]. Other countries provide similar estimates. Febrile seizures generally have an excellent prognosis. More than 90% of children who have a febrile seizure will not develop epilepsy; however, certain factors and genetic predisposition can increase the risk for future development of epilepsy after a febrile seizure. One third of children with a first febrile seizure will have recurrent febrile seizures [Baulac. The Lancet Neurology. 2004]. The first conclusion of the Work group regarding the medical importance of febrile seizures is that children who have a first febrile seizure for any reason are likely to seek medical attention, which commonly includes a visit to the emergency department. The evidence from two population-based studies suggests that children who have a febrile seizure shortly after MMR vaccination are not more likely than children who have febrile seizures for other reasons to have future epilepsy or neurodevelopmental disorders [Barlow, NEJM 2001 and Vestergaard, JAMA 2004]. The evidence from one study in Denmark suggests that children who have a febrile seizure after Dose 1 MMR vaccination may have a higher risk for having another febrile seizure than children who had a febrile seizure for other reasons. The magnitude of this risk is likely small, estimated by this study at about a 19% increased risk. Although data on sequelae of febrile seizures after MMRV vaccine are not available, experts believe it is likely that the findings described above for MMR vaccine would be applicable to MMRV. The medical assessment is the same for Doses 1 and 2 of MMRV, except that febrile seizures in the 4 to 6 year age group occur less frequently than in the 12 to 15 month age group. Experts believe that the risk for recurrent febrile seizures would be lower for a child aged 4 to 6 years who has a febrile seizure after Dose 2 MMRV than a child aged 12 to 23 months who had a febrile seizure after Dose 1 MMRV [Vestergaard, JAMA 2004]. The second conclusion, pertaining to the psychosocial importance of febrile seizure, a national survey of physicians, which was presented to ACIP in February 2008, as well as interviews and focus groups of physicians and mothers, suggest consistently that parents and caregivers generally consider febrile seizures to be a more severe adverse event than is perceived by physicians [ACIP Presentations, Kempe 2/09 and Janssen 6/09]. Multiple studies across various cultures show that when a child experiences a febrile seizure, it may have a negative effect on the family, including adverse mental and physical health consequences in the parents and caregivers [Literature review presented to the WG by Dr. Skillen on 2/11/09]. One of the work group’s terms of reference was a clinical review of the encephalitis cases identified in the VSD study and the Merck-sponsored general safety study. The VSD study assessed for outcomes other than seizures, and encephalitis and meningitis were among those outcomes. The VSD study detected 2 cases of possible encephalitis after MMRV using ICD-9 codes. These cases were presented by Dr. Klein in February 2008. Both cases were in children who also had febrile seizures 7 to 10 days after vaccination. When the cases were presented to ACIP, some clinicians raised questions about whether they were true encephalitis cases. The Merck-sponsored study detected 1 possible case of encephalitis after MMRV vaccine. This child did not have a febrile seizure. The work group then coordinated an expert review by two independent pediatric neurologists. They applied the Brighton Collaboration case definition [Sejvar, Vaccine 2007]for encephalitis to these three cases. Remarkably, both neurologists had the same assessment: 1 of the VSD cases met the criteria for encephalitis, and the other 2 cases were ruled out. The work group was also charged to consider additional analyses that should be conducted regarding MMRV and febrile seizure risk. Over the last year, many of these analyses were completed, either by the VSD Study, focus groups, or special data requests. The work group believes that routine adverse event monitoring, which is done for all recommended vaccines, should continue when MMRV returns to the market. Further, an area of potential research might include studies regarding health outcomes in MMRV recipients who have febrile seizures shortly after vaccination. The work group also worked under the terms of reference to communicate its findings regarding risk assessment in a clear and transparent manner. To this end, materials are under development by CDC communication experts to communicate the risk of febrile seizures after MMRV vaccine, as well as the benefits of MMRV vaccine in a clear and transparent manner. Additionally, the Vaccine Information Statement (VIS) will be updated to reflect updated data. Discussion after Drs. Klein and Broder’s presentations Dr. Judson congratulated all those involved in the exhaustive investigation, complimenting their thorough approach to a large problem. He felt that the work made causal relationships clear, and he was glad that they were in a position to achieve closure on the subject. Dr. Marcy concurred and added a perspective from the point of view of a pediatrician. The average pediatrician has approximately 1500 patients in his or her cohort. If 10% of them are changing every year, if there is 1 seizure per 2300 injections, then it will be 15 years before one additional seizure is observed. During this time, if 4% of patients have febrile seizures due to viral infections, the pediatrician will have seen 92 first febrile seizures, and a total of 120 if a third of those patients have a second seizure. Therefore, they are comparing 120 seizures over 15 years in a pediatric practice with 1 in 15 years. To him, that was a “small price to pay” when considering the probable increase in compliance. Parents frequently do not return for a varicella shot for many months, creating an increased period of risk. The minority opinion in the MMRV Work Group regarded the risks and benefits of vaccine and raised the point, “First, do no harm.” If one seizure every 15 years is used in that principle, then no vaccines would be administered, as every vaccine has adverse events. While the MMRV vaccine may result in additional office and / or emergency room visits due to febrile seizures, most emergency rooms can handle that volume. Public trust in vaccines is only a problem when there is a lack of transparency. If parents are not informed of the possibilities, then public trust will be lost. But if parents know the risks up front, and if they have the option to decline, the approach is reasonable, and the public trust will not be an issue. He believed that vaccine coverage would suffer and children would be put at risk for periods of time if MMRV was not used and if parents were not given the option to use it as much as possible. Dr. Amy Middleman wondered about the existence of data regarding the difference in fever rates in those older than 6 years of age, since the vaccine is indicated for use up to age 12. Dr. Broder answered that there are no safety data available beyond ages 4 to 6, but in the area of biological plausibility, similar adverse events were seen in 4- to 6-year-olds receiving the second dose as MMRV or as separate MMR and varicella vaccines. From a biological standpoint, it is fair to extrapolate that this would apply to older children. They do not have data to support this idea, however. Dr. Klein said that they did consider fever in 4- to 6-year-olds, and those seem to be background seizure visits. There are 20-fold fewer overall visits than for children aged 12 to 23 months. Dr. Harry Keyserling inquired about data on injection site risk. By giving a second injection, are there local site reactions, such as a localized infection at the injection site. Data were presented on thousands of doses, and he wondered whether infection is an issue. Dr. Klein replied that they did not specifically look at injection sites, as they were monitoring for 6 outcomes following the RCA study. Injection site is not typically used in RCA studies for a variety of reasons. They tend to focus on outcomes that would not be evaluated in pre-licensure studies, but rather on outcomes that are more serious or rare. Using the model by which the pathogenesis of varicella was developed, Dr. Mercy said after the injection is given there is a local, minor infection and a primary viremia. Then, the virus is disseminated throughout the body, and there is a secondary viremia, when the fever occurs. For this reason, he did not feel that the injection site was important. Rather, the secondary viremia is important, if the model for attenuated virus immunization is the same as natural varicella. Dr. Judson asked whether the question concerned bacterial infection. Dr. Harry Keyserling clarified that if there is an infection in 1 out of 10,000 injections, or one out of 100,000 injections, then the risk of a local infection is compared to the risk of excess febrile seizures. But if data support that giving 100,000 injections does not cause an increased local problem, then the information would be useful. Dr. Dixie Snider responded that bacterial infections after vaccinations are relatively uncommon. Clearly, injection safety is an important issue, particularly in developing countries. He wondered about data on frequency of injection site infections, although Chesley Richards indicated that they did not have those data. Barbara Kuter (Merck) addressed some of the conclusions based on the pre-licensure safety data that was collected in Merck’s clinical trials. Regarding fever in the pre-licensure studies, she noted that in a study in which children were vaccinated with 2 doses of MMRV (first at 12 months and second at 15 months), the rates of fever were considerably lower with the second dose at a rate of 23% with the first dose, versus 8% with the second dose. In addition, Merck conducted studies in 4- to 6-year-olds. In these studies, children were either given MMR + V or MMRV. The fever rates were identical between the two groups. Further, there were no serious injection site reactions related to the MMRV vaccine. In fact, overall rates of injection site complaints were lower with MMRV than they were with MMR + V, with the exception of the rate of injection site rash, which was 1% higher for MMRV than for MMR + V. Dr. Ehresmann commented that while she agreed with Dr. Mercy’s comments, in Minnesota, with a birth cohort of 67,000 children, 30 febrile seizures would be expected per year. Even though the increase might not be significant to an individual practice, it may have a bigger impact on a population basis. Dr. Joe Bocchini (APA) asked Dr. Klein whether the chart review, which indicated that 16% and 22% of two groups had a first febrile seizure, implied that this was the only group for which data were available, or whether a significant percentage had a prior febrile seizure. Dr. Klein said that of all the reviewed charts, 16% for MMRV had a prior febrile seizure, and 22% for MMR + V had one. Data were available in 85% of the charts. The children were aged 12 through 23 months. The study did not exclude someone who had a febrile seizure from the study unless the second seizure did not occur within 42 days of the event. In that case, they were excluded when they were identified from automated data. Dr. Bocchini followed up, asking if the patients had a febrile seizure prior to that period, what percentage included in the study may have had a febrile seizure that was their second or third. Dr. Klein clarified that they were excluded if their seizure occurred within 42 days. Dr. Patricia Whitley-Williams asked for verification that the population studies reflected the heterogeneity of the US population. Dr. Klein replied that VSD covers a large geographical area. This study included patients from Kaiser Permanente’s Center in northern California. This population is representative of the underlying population of California, which is quite diverse. However, it is slightly under-representative of the very poor and of the very rich. Policy Options for Use of MMRV Vaccine Mona Marin, MD CDC / CCID / NCIRD / DVD Dr. Marin described the MMRV Vaccine Safety Work Group assessment of the elements of the policy framework and presented the work group’s proposed policy options for MMRV vaccine use. The elements of the policy framework were presented to ACIP in February 2009 and include vaccine safety; efficacy / effectiveness and immunogenicity; burden of disease to prevent (i.e., measles, mumps, rubella, and varicella); program implementation; equity in access to vaccines and use of public funds; and social context. The work group offered the following assessment of these elements for Dose 1 at ages 12 to 15 months, which is the age at which Dose 1 vaccine is routinely recommended. Regarding vaccine safety, Dr. Marin reiterated Dr. Broder’s summary and emphasized that the safety summary describes an increased risk for febrile seizures during the first to second weeks (5 to 12 or 7 to 10 days, depending on the study) after Dose 1 MMRV vaccine compared with Dose 1 MMR and varicella vaccines administered at the same visit (MMR + V); one additional febrile seizure is expected to occur per approximately 2,300 to 2,600 children vaccinated with Dose 1 MMRV, compared with MMR + V. During the 4 to 6 weeks after vaccination, an increased risk for febrile seizures after Dose 1 MMRV compared with MMR+V is only present during the 1 to 2 weeks after vaccination [Adapted from presentation by Dr. Karen Broder, CDC. ACIP meeting, June 25, 2009]. Regarding the efficacy / effectiveness and immunogenicity, MMRV was licensed on the basis of non-inferior immunogenicity of the antigenic components compared with simultaneous administration of MMR and varicella vaccines, based on the results of four randomized, controlled clinical trials [FDA, ProQuad clinical review, available at http://www.fda.gov/cber/review/proquadR.pdf]. Efficacy was inferred on the basis of non-inferior immunogenicity. Effectiveness of MMRV was not evaluated in clinical studies. Based on this evidence, the work group assessment was that the quality of evidence for non-inferiority was high and that MMRV and MMR + V had equal immunogenicity. Equal effectiveness was assumed. Dr. Marin reminded the committee that the burden of disease prevented is a function of vaccine effectiveness and vaccine coverage. The current burden of disease in the US for measles, rubella, and mumps is eliminated or very low 1-3. The burden of varicella is low, with the 10-year vaccination program having had an important impact of approximately 90% reduction in disease incidence during 1995-20053. There are still an estimated 400,000 varicella cases per year. These disease levels were achieved in the absence of MMRV. The current low levels of disease are due to high population immunity achieved through high vaccine coverage. The coverage of MMR vaccine among 19 to 35-month-olds has been between 90% and 93% since 19965. All states had second dose measles-containing vaccine school entry requirements in 2005 – 2006. These requirements are an important tool for ensuring high vaccination rates. Coverage of varicella vaccine among 19 to 35 month-olds reached 90% in 2007. Forty-six states had one dose school entry requirements in 20087 [1. Katz SL and Hinman AR. J Infect Dis, 2004; 2. Reef SE and Cochi SL. J Infect Dis, 2006; 3. Barsky A et al. IDSA abstract, 2008; 4. Guris D et al. J Infect Dis, 2008; 5. NIS, www.cdc.gov/vaccines/stats-surv/default.htm#nis; 6. http://www.cdc.gov/vaccines/vac-gen/laws/downloads/izlaws05-06.pdf; 7. CDC, unpublished data (courtesy of Jessica Leung, MPH)]. For burden of disease to prevent, the work group concluded that MMRV as a first dose likely has a similar impact to that of MMR + V for prevention of measles, mumps, rubella, and varicella. MMRV may lead to more children vaccinated against varicella at age 12 months rather than 15 to 18 months. An important burden of disease for varicella is not seen among children aged 12 to 18 months. The quality of evidence for this conclusion was expert opinion and the benefit of MMRV and MMR + V for preventing measles, mumps, rubella, and varicella for the first dose was assessed as equal. Regarding program implementation, the work group discussed differences in storage conditions. MMR is stored in the refrigerator, where varicella and MMRV must be stored frozen. Further, many discussions focused on the impact of the number of injections, given that 9 or 10 vaccinations are recommended either routinely at age 12 to 15 months or for ages that overlap ages 12 to 15 months1. The work group also discussed the known parent and provider preference for fewer injections per visit 2-4. The group examined the current experience with vaccine administration using data from two immunization information systems5. These data showed that the majority of children receive Dose 1 MMR and varicella vaccines at age 12 months. A minority receive them at 15 – 18 months. Among children who receive varicella vaccine, about 84% receive the first dose at 12 months, and the percentage increases to 97% by 18 months. The Immunization Information Systems also showed that one-third to one-half of children received four or more injections at one visit at ages 12 to 14 months [1.http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm; 2. Meyerhoff A. Clinical Pediatrics, 2004; 3. Lieu TA et al. Vaccine, 2000; 4. Freed GL et at. Pediatrics, 2006; 5. Source: Immunization information Systems, MI and OR sentinel sites]. Information was available from the 2006 – 2007 National Immunization Survey1. Regarding timeliness of vaccination among 24 to 35 month-olds, 20% of children fell behind in their vaccinations during the interval from the 6-month to the 15-month vaccines schedule, 67% of children were not fully vaccinated by age 16 months, including about 28% who did not receive MMR. The work group discussed multiple factors that could lead to delayed vaccination or under-vaccination. The group also discussed the potential impact of combination vaccines. There was expert opinion agreement that combination vaccines may offer benefit in terms of overall coverage or timeliness, but the literature is limited to quantitate the benefit2-4 [1. Luman ET et al. Am J Prev Med, 2009; 2. Marshall GS et al. Pediatr Infect Dis J, 2007; 3. Happe LE et al. Pediatr Infect Dis J, 2009; 4. Allred NJ et al. PAS abstract, 2009]. In their consideration of program implementation, the work group discussed additional information from focus groups with mothers which indicated that mothers had questions and concerns related to safety of vaccines1. If MMRV were recommended by their physician, 41% of mothers would accept and 31% would refuse. Several different studies on physician use and opinions of MMRV vaccine were considered as well. These studies found good uptake when MMRV was available. Physicians interviewed reported no differences in experience using MMRV compared with MMR1. Regarding intended use of MMRV given post-licensure safety data, one study found that 9% of family physicians and 21% of pediatricians would give MMRV to a healthy 12- to 15-month-old, where 20% to 24% would let parents decide2. Another study indicated that about half of prior users and about 20% of non-prior users expect their patients aged 12 to 15 months to receive Dose 1 MMRV3 [1. A. Janssen, CDC. ACIP meeting June 25, 2009; 2. Dr. A. Kempe, Univ of Colorado. ACIP meeting February 26, 2009; 3. J. Kramer, Merck & Co. Presentation to the WG, May, 2009]. Examining all of this evidence, the work group considered the general preference among parents and providers for fewer injections at one visit and that it is likely that vaccination against measles, mumps, rubella, and varicella at ages 12 to 15 months would be preferred as one injection instead of two, assuming that the safety profile is similar. MMRV potentially can have a favorable impact on the on-time administration of other vaccines recommended for ages 12 to 15 months. However, for some parents and providers, the benefit of the reduced number of injections is outweighed by the increase in febrile seizure rate after MMRV. Based on expert opinion, the work group concluded that there was insufficient evidence to assess the difference in benefit between MMRV and MMR+V in terms of program implementation. Available data from the National Immunization Survey suggest that in terms of coverage for Dose 1, there was no difference for measles, mumps rubella and varicella vaccines coverage by age 19 months with the use of MMRV. This is likely due to the already-high coverage rates prior to MMRV introduction [Zhen Z, CDC, communication to the WG, May, 2009. Source: NIS Q307-Q208]. A minority of work group members expressed concerns that use of MMR + V could adversely affect the overall vaccine coverage rates and incidence for other vaccine-preventable diseases. Also, the impact of the recommendation on acceptance by parents is unknown. Regarding access to vaccines and the use of public funds, ACIP has issued recommendations for MMR, MMRV, and varicella vaccine use. These vaccines should be covered similarly by insurance companies. There are VFC resolutions, and the price of the vaccines per dose is similar [Available at http://www.cdc.gov/vaccines/programs /vfc/cdc-vac-price-list.htm. However, MMR + V includes two administration dose fees as opposed to one. MMRV and varicella are stored frozen, so there is no difference in availability due to storage requirements. The work group concluded that there is high quality of evidence for no difference in access and use of public funds between MMRV and MMR + V. Besides the social context in general presented by Dr. Temte in the introduction, the work group consulted with CDC and academic ethicists regarding possible ethical aspects associated with the MMRV vaccine recommendations. The key question explored was whether the increased protection for the population offsets any increased risk for the individual. Considering the ethical principles of risk / benefit analysis, parental and provider preferences, and justice and fairness considerations, the ethics group recommended an approach that makes safety the default, therefore favoring a preference for separate MMR and varicella vaccines for Dose 1. The choice to use MMRV vaccine should be made available if the physician and parents decide it is the best option. Additionally, if future data show that a preference for separate vaccines has a larger-than-expected impact on coverage, then the option should be reconsidered. In terms of the policy options for Dose 1, of the four options discussed by the work group and presented to ACIP in February 2009, three policy options received support from at least one group member. The work group proposes for a vote two of those options: 1) preference for separate MMR and varicella vaccines over MMRV vaccine; and 2) no preference for MMRV vaccine over separate MMR and varicella vaccines (current interim recommendation) [CDC. Update: Recommendations from the Advisory Committee on Immunization Practices (ACIP) Regarding Administration of Combination MMRV Vaccine. MMWR. 57(10);258-260]. The third option was: MMRV not recommended for ages one to two years; always use separate MMR and varicella vaccines, and was supported by one work group member. With respect to the work group’s assessment of the elements of the policy framework for Dose 2 at ages 4 to 6 years, regarding vaccine safety the conclusion presented by Dr. Karen Broder indicated that there was no increased risk after Dose 2 MMRV vaccine for children 4 to 6 years. For efficacy / effectiveness and immunogenicity, as mentioned, MMRV was licensed on the basis of non-inferior immunogenicity of the antigenic components. The geometric mean titer (GMT) was the primary end point to demonstrate similar antibody responses. For measles, mumps and rubella the GMT fold rises were comparable between MMRV and MMR + V groups [Reisinger KS et al. Pediatr Infect Dis J, 2006]. However, for varicella, the GMT fold rise was higher after MMRV than MMR + V (difference statistically significant) but there were no tests done to show superiority. Therefore, the work group concluded that the evidence supports that MMRV and MMR + V are at least equal in terms of immunogenicity and effectiveness. Some experts felt that because GMT is higher after Dose 2 MMRV compared with Dose 2 MMR + V or varicella vaccine, the effectiveness may be higher after MMRV, but there are no data on possible superior protection against varicella provided by MMRV. The quality of evidence for non-inferiority was high, and the benefit of MMRV and MMR + V was equal in terms of immunogenicity. Equal effectiveness was assumed. The burden of disease prevented was considered similar to that for Dose 1 at ages 12 to 15 months, with several differences in coverage for varicella. The second dose for varicella was recently recommended in 2006, compared with 1989 for MMR. In 2008, only 12 states had school entry requirements for two doses of varicella vaccine, compared with all states for measles-containing vaccine [CDC, unpublished data (courtesy of Jessica Leung, MPH)]. There are currently no good ways of measuring coverage for the second dose of varicella, so estimates are relied upon based on the number of states that have school-entry requirements. The work group concluded that MMRV as a second dose has the potential to have a greater impact on the control of varicella disease than MMR + V through increasing second-dose varicella coverage until states implement school entry requirements. There will likely be similar impact to that of MMR + V for prevention of measles, mumps, and rubella. The quality of evidence for this conclusion is expert opinion. For the difference in benefit between MMRV and MMR + V, the Working Group concluded that MMRV is potentially more beneficial for varicella than MMR + V. Regarding program implementation, storage conditions for Dose 2 are similar to those discussed for Dose 1. In terms of the number of injections, 5 vaccines are routinely recommended at ages 4 to 6 years1. Anecdotal reports indicate that it is more difficult to administer multiple injections at one visit to children aged four to six years. Data from two immunization information systems indicates that the routine age for Dose 2 MMR vaccine is four years, and 37% to 48% of children aged 4 to 6 years received 4 to 5 injections at one visit2. One physician opinion study on the use of MMRV showed that 20 percent of family physicians and 38% of pediatricians would give MMRV to a healthy 4- to 6-year-old, and 21% to 25% would let parents decide3. Another study found that two-thirds of prior users and one-third of non-prior users expect their patients aged 4 to 6 years to receive Dose 2 as MMRV4 [1. http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm; 2. Source: Immunization information Systems, MI and OR sentinel sites; 3. Dr. A. Kempe, Univ of Colorado. ACIP meeting February 26, 2009; 4. J. Kramer, Merck & Co. Presentation to the WG, May, 2009]. The work group reached a conclusion regarding program implementation that it is likely that vaccination against measles, mumps, rubella, and varicella at ages 4 to 6 years is preferred as one injection (MMRV) instead of two (MMR + V) by both parents and providers, provided that the safety profile is similar. A potential benefit for MMRV is a more rapid increase of coverage for Dose 2 varicella vaccine and improved coverage for other vaccines recommended at this age. The quality of evidence for this conclusion is expert opinion, and in terms of difference in benefit, it was concluded that MMRV is more beneficial than MMR + V. Regarding equity in access to vaccines, use of public funds, and social context, the evidence and assessment for Dose 2 are similar to those for Dose 1 at age 12 to 15 months. The ethics consult did not address recommendations for Dose 2. In terms of the policy options for Dose 2, after the previous day ACIP meeting when a vote occurred on the general recommendations for combination vaccines, the MMRV Work Group held a conference call. The group proposes to defer the recommendation for Dose 2 MMRV at ages 4 to 6 years to the ACIP General Recommendations for combination vaccines with the same language adopted by the committee. In terms of evidence for Dose 1 and Dose 2 of MMRV vaccine at ages other than routinely recommended, no safety data are available for Dose 1 MMRV among children aged older than 23 months1. It should be noted that febrile seizures usually occur at ages 6 to 60 months, with the peak age being 14 to 18 months. Some data are available regarding the MMR experience: a study in Denmark showed a decreased risk for febrile seizures with increasing age at vaccination within the age group 15 to 23 months1. For Dose 2 MMRV at ages less than 4 years, data are available for ages 15 to 26 months. There is a lower incidence of fever and measles- and varicella-like rash than post-Dose 12,3. In clinical trials, among approximately 2,700 subjects, two febrile seizures occurred (of which one in a setting of roseola) after Dose 2 when Dose 2 was administered 3 months and 6 – 9 months after Dose 14. The immune response after dose 2 is primarily anamnestic response, of measles-containing vaccine recipients 95% have antibodies after Dose 1 administered at age 12 months. Immunogenicity was not inferior when the second dose was administered at ages younger than 4 years2,3. No safety or immunogenicity data are available for Dose 1 or Dose 2 MMRV at ages 7 to 12 years. However, febrile seizures occur almost exclusively among children aged 6 to 60 months [1. Vestergaard M et al. JAMA, 2004; 2. Shinefield H et al. Pediatr Infect Dis J, 2005; 3. Shinefield H et al. Pediatr Infect Dis J, 2005; 4. Merck & Co. Presentation to the WG, December, 2008]. With this evidence and in light of the recent ACIP General Recommendations on combination vaccines, the work group proposes that the Dose 1 recommendation apply to children aged 12 to 47 months. Supporting evidence for using 47 months, or 3 years, as the cutoff age: 1) the two post-licensure studies found an increased risk for febrile seizures 5 to 12 days after Dose 1 MMRV compared with MMR + V among children aged 12 - 23 months, 2) In the absence of safety data, the group recommended adopting an approach that favored safety during the period of risk for febrile seizures, and 3) The first febrile seizure is uncommon after age four, with 94% of seizures occurring in children aged younger than 4 years in a population-based study in Finland [Sillanpaa M et al. Population based study of febrile seizures in Finland. J Pediatr Neurology, 2008]. Further, the work group proposes that for Dose 1 at other ages besides 12 - 47 months and Dose 2 at any age up to MMRV’s license of 12 years, the recommendation should be that from the ACIP General Recommendations on combination vaccines. Regarding other MMRV vaccine-related guidance from the work group, studies suggest that children who have a personal or family history of febrile seizures or family history of epilepsy are at increased risk for febrile seizures compared with children who do not have such histories (see table in the slide presentation). The MMRV (ProQuad®) package insert lists individual or family history of convulsions as a warning. The work group therefore proposes that ACIP includes a personal or family history of seizures as a precaution for MMRV vaccine use. “Family” is defined as a first-degree relative. The ACIP General Recommendation document’s definition of “precaution” was presented in the footnote [“A precaution is a condition in a recipient that might increase the risk for a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity (e.g., administering measles vaccine to a person with passive immunity to measles from a blood transfusion). A person might experience a more severe reaction to the vaccine than would have otherwise been expected; however, the risk for this happening is less than expected with a contraindication. In general, vaccinations should be deferred when a precaution is present. However, a vaccination might be indicated in the presence of a precaution because the benefit of protection from the vaccine outweighs the risk for an adverse reaction.” ACIP General Recommendations on Immunization. MMWR 2006;55(No. RR-15)]. One of the work group’s terms of reference was to reconcile the guidance for use of antipyretics for prevention of febrile seizures. In its 2008 guidance for long-term management of the child with simple febrile seizure, the American Academy of Pediatrics (AAP) states that no studies have demonstrated that antipyretics, in the absence of anticonvulsants, reduce the risk of simple febrile seizures [American Academy of Pediatrics. Clinical practice guideline for the long-term management of the child with simple febrile seizure. Pediatrics, 2008]. Although antipyretics may improve the comfort of the child, they will not prevent febrile seizures. Based on a literature review presented to the work group, there is insufficient evidence to recommend either ibuprofen or acetaminophen prophylaxis to prevent simple febrile seizures [Dr. R. Baumann, Univ of Kentucky. Literature review, presentation to the WG, December, 2008]. The work group therefore proposes to adopt the AAP guidance regarding use of antipyretics to prevent febrile seizures to the MMR and MMRV situations. The proposed wording is as follows: “MMR or MMRV vaccines may cause fever after vaccination. Most fevers after a measles-containing vaccine occur during the five to 12 days after vaccination. Parents and caregivers should be counseled about the possibility of fever after a measles-containing vaccine and educated on timing and measures to control it. Studies have not demonstrated that antipyretics (e.g., acetaminophen or ibuprofen) prevent febrile seizures. Guidance on diagnosis and management of febrile seizures has been published elsewhere.” The new language is proposed because the language regarding the use of antipyretics to prevent febrile seizure in the 1998 MMR statement is vague. It says that antipyretics may prevent febrile seizures, but notes that preventing febrile seizure is difficult due to the sudden onset of fever. Dr. Marin then presented options for ACIP to consider for a vote. She began with a summary for Dose 1 at routine ages 12 to 15 months. To protect against measles, mumps, rubella, and varicella, two vaccine options are available: MMRV vaccine or MMR and varicella vaccines. The two options are considered equivalent in terms of disease protection. Use of MMRV vaccine results in one fewer injection compared with use of separate MMR and varicella vaccines and may improve the on-time coverage for the vaccines recommended at ages 12 to 15 months. Use of MMRV vaccine results in a higher risk for fever and febrile seizures 5 to 12 days after the first dose when administered during the second year of life compared with use of separate MMR and varicella vaccines at the same visit. There is about one extra febrile seizure for every 2,300 - 2,600 MMRV doses. The risk for febrile seizures after MMRV can be reduced, but not eliminated, by administering separate injections of MMR and varicella vaccines. Children who have febrile seizures generally have an excellent prognosis; however, febrile seizures often require a medical visit to the emergency room for the child and are distressing to parents and caregivers. Therefore, the work group’s first option proposed to the ACIP for a vote, which was supported by the large majority of the group, was as follows: “For the first dose of measles, mumps, rubella, and varicella vaccines at ages 12 to 15 months, separate MMR and varicella vaccines are preferred to MMRV vaccine. However, providers may choose to administer MMRV vaccine after discussing the benefits and risks of each option with the parents or caregivers.” The pros of this option include: 1) it considers evidence-based criteria for decision-making, including vaccine safety; 2) in the setting of language barriers, sets the default for the alternative with the lower risk for febrile seizure; and 3) leaves open the possibility of administering MMRV in situations in which its use provides a benefit. The cons of this option include: 1) it might negatively affect the on-time coverage for other vaccines recommended for ages 12 to 15 months and the control of the respective diseases; and 2) it might lead to more complex recommendations. Dr. Marin then presented the work group’s second policy option, which was supported by a sizeable minority of the group: “For the first dose of measles, mumps, rubella, and varicella vaccines at ages 12 to 15 months either MMRV vaccine or separate MMR and varicella vaccines can be used. The benefits and risks of both vaccination options should be discussed with the parents or caregivers.” The pros of this option are: 1) it allows physicians and parents to make a decision that best suits the child’s individual situation; 2) it could result in simpler, more streamlined recommendations for all age groups, depending on the option chosen for Dose 2; and 3) it might be perceived favorably by the category of providers who prefer to be given the facts and let them make the decision. The cons of this option are: 1) it might mean more time for providers to counsel the parents about the options, weigh the evidence, and make a decision; 2) in practice, the choice could stop at the provider level, and not all children or parents would have access to the two options; and 3) it could potentially be perceived as a less pro-active role taken by the public health community for a vaccine safety issue. Discussion Dr. Chilton offered his comments as a practicing pediatrician in private practice in a state where there is universal purchase. He was in favor of recommending separate MMR and varicella vaccines for 5 reasons: The cost of inventory was one of his reasons. If he had to maintain an inventory of both MMRV and MMR + V, without knowing which one would be picked by patients, then he would prefer to have only one available. Second, if both vaccine options were available, then extra time would be needed to counsel parents about the available vaccines and the relative risks and benefits of both. Third, if he were to give the MMRV vaccine, his office would receive one fewer administration fee. He would be giving more counseling for less money. Fourth, he felt that there is an over-emphasis on the number of vaccines given. He did not feel that babies cried more when given four vaccines as opposed to three vaccines, and he hoped that they would downplay this aspect, given that they administer three or more vaccines at each visit at two, four, and six months. Fifth, taking his personal experience into account, he said that with each child that has a febrile seizure in his practice, he spends a fair amount of time counseling the family about the fact that febrile seizures are not important. He then schedules another visit for a week later, knowing that the family is worried at their initial conversation and the family will have more questions in the week following the seizure. Finally, he commented that his daughter has a child who has had three febrile seizures. Each time, his daughter calls him from the emergency room. Even when parents have a pediatrician in the family, febrile seizures are important. He recognized that the additional risk of febrile seizure may not add excessively to his overall “quotient,” but he hoped to avoid any febrile seizures that he could. He added that the work group had done a great deal of epidemiological work on this problem, and he hoped that they would consider doing similar work on another problem, that of whether the availability of measles, mumps, and rubella as monovalent vaccines actually increases or will decrease the amount of vaccine uptake. They have time to consider this question before they issue a statement opposing the reappearance of these monovalent vaccines. Dr. Temte thanked Dr. Marin and Dr. Broder for their work, as well as CDC, VSD, and Merck. There is a great deal of very good evidence, which was carefully reviewed by the work group. Their votes came out of this careful consideration. In essence, there is one clear signal that the MMRV first dose at young ages has a higher rate of febrile seizures. The evidence does not inform regarding differences in coverage rates depending on the two options. Until February 2008, ACIP expressed a clear preference for MMRV. Yet in actual practice, physicians still had the ability to choose between two options. They chose the separate vaccines at a high rate of 30% to 40% despite ACIP’s preference. Therefore, expressing a preference did not close off other options. Dr. Ehresmann expressed her personal preference for Option 1, based on the epidemiological data. For MN that would mean 30 extra febrile seizures per year. She also pointed out the “con” for Option 2, a potential perception as a less proactive role taken by the public health community. With all of the parental concern about vaccine safety, she felt that they should take a strong stance. Dr. Marcy responded to Dr. Chilton’s observation about febrile seizures. Parents perceive vulnerability. He estimated that, based on the patient population of a pediatrician and the rate of febrile seizures after MMRV and MMR + V, a pediatrician would see one more seizure every 15 years and reiterated that that is not many. Further, 30 extra seizures in a state is not many for an entire state. He would have liked more data to make a decision, but they have to consider the frequency of seizures, not only the fact that they occur. He did not know what the VIS would say, but presumed that it would be modified to include the finding of the increased risk for febrile seizures after MMRV. This will make it easier to present the situation to patients. He favored Option 2. Dr. Marin replied that the VIS is going to present the increased risk information and include the rates of febrile seizure after MMR and MMRV. Dr. Sawyer identified himself as a member of the work group and one of the “significant minority” who favored Option 2. His concern stemmed from data from the physician and parent interviews and focus groups. A significant minority of physicians and parents feel that the combined MMRV vaccine is a valuable option. Option 1 may effectively take that choice away, even though the language said that the choice was still there. If the ACIP statement clearly preferred separate vaccines, only a small number of pediatricians would choose the combination vaccine due to concerns regarding liability issues. They should weigh that possibility carefully. Further, there is a lack of clear evidence that a separate vaccination recommendation will lead to decreased coverage or decreased disease prevention; however, these decreases would be certain. There is a potential for 8 or 9 injections at a 12- to 15-month-old visit. Data from the Immunization Information Systems show that less than half of children will receive more than 4 doses at a single visit. It is inevitable that multiple visits and therefore failed visits and failed immunizations will occur. He feared that a separate recommendation would ultimately lead to decreased coverage. Regarding storage issues, he noted that the physician focus group participants did not indicate concern about stocking both vaccines. Dr. Judson agreed with Drs. Sawyer and Marcy, clarifying that his focus was on the absolute risk of an adverse event, which is not terribly consequential in the overall perspective of febrile seizures. He recognized the effects of seizures, but he supported the minority opinion. Dr. Meissner was a member of the work group who favored Option 2. He commented that there is an increased risk of 3 to 4 per 10,000 for febrile seizures for MMR + V. The conversation regarding seizure possibility will take place with parents if MMRV is administered, when the rate increases to 7 to 9 per 10,000, but it still needs to take place for MMR + V. Secondly, regarding storage, the recommendation for Dose 2 is unknown. If there is a preference for MMRV for Dose 2, then there will be a need for 3 different vaccines. Regarding the idea of ensuring that the recommendation is perceived as proactive, he did not feel that an ACIP recommendation should be based on concern of what the anti-vaccine group might say. The decision should be based on what is best for the child. He then offered a theoretical advantage for administering MMRV. MMRV may lead to more children vaccinated against varicella at age 12 months, rather than waiting until 15 to 18 months. The varicella vaccine has been available for approximately 15 years, and females who were vaccinated are entering their childbearing years and will likely have lower titers, and the antibodies that they will pass to their babies will be lower. If there is a later administration of the varicella vaccine, then there may be a longer window of vulnerability to varicella among children of these women. While the consideration is theoretical, it may become an issue as the years go by. Dr. Marin responded that they do not see an important burden of varicella among young children or varicella outbreaks in preschool children. The virus tends to circulate among school-age children, so they do not see a burden of disease now in the younger children. Dr. Meissner agreed, reiterating that this situation may change as these women begin to have children. Dr. Englund agreed with her fellow pediatricians, who in her experience do a good job of explaining the risks and benefits of the vaccines. The explanation process is part of the standard of care, and she felt that Option 1 took away choice; whereas, Option 2 preserved choice. Further, she was concerned about clinical significance versus statistical significance. Dr. Morse recognized compelling arguments existed on both sides. ACIP’s charge is to make science-based decisions, and the science shows an increased risk. Science alone is not the determining factor, though, and there are a number of other benefits to combination vaccines, as mentioned in the session that discussed the general recommendations on combination vaccines voted that morning. Other considerations, such as safety, are paramount. With regard to storage, Dr. Judson indicated that for several decades, he was responsible for the Denver Public Health Immunization Program and Clinic. They found problems within clinics and other administration areas in the area of storage. For live virus vaccines, there is a greater chance that something will go wrong with a refrigerator door or in a general refrigerator where the temperatures get too warm or too cold than there is for a vaccine that is stored in the freezer. A number of early reports of measles and rubella vaccine failures were associated with potential failures with vaccine holding temperatures in refrigerators. Dr. Joseph Bocchini reported on discussions at AAP concerning this issue. They addressed the issue most recently in April 2009 to keep up-to-date with ACIP and to provide input. AAP had a similar debate with strong opinions on both sides. Overall, there was favor for what would be considered Option 1. Dr. David Kimberlin was the AAP liaison to the work group. Throughout their yearlong deliberations, the work group heard from numerous public health physicians regarding provider choice of either MMRV or MMR + V, Option 2, versus a recommended preference for separate MMR and varicella vaccines, phrased as Option 1. In addition, he had spoken with practicing pediatricians about the issue of provider choice versus a recommended preference. Overwhelmingly, the physicians strongly requested that provider choice be allowed for Dose 1. They want to make the decisions that they and the parents think are best for each child. This is consistent with the majority of the 21 pediatricians, and Mr. Alan Janssen’s presentation, which requested that choice be allowed. Speaking for himself, Dr. Kimberlin added that the main issue for ACIP is whether a concern over a 0.05% increased chance of febrile seizures, which have no lasting medical consequence, is great enough to justify ACIP inserting itself into the physician-parent communication process in a way that limits the physician’s options as a Dose 1 preference for MMR + V, as Option 1 would do. An option with provider choice for MMRV or MMR + V would allow physicians the flexibility that they request. Additionally, stating a preference for MMR + V for Option 1 put them on a slippery slope, especially when they heard of plans to make available monovalent measles, mumps and rubella vaccines. Dr. Temte said that physicians and care providers see febrile seizures retrospectively; that is, they see them after the fact and after the child has recovered. Parents see the seizures prospectively and perceive the seizures as their children are perhaps dying. This common theme emerged from numerous cross-cultural studies. The parents see the children “doing something very