Updated July 2020
The United States’ long-standing vaccine safety program closely and constantly monitors the safety of vaccines. This chapter describes how vaccines licensed for use in the United States are monitored for safety and presents general information about the provider’s role in immunization safety.
Like any medical product, no vaccine is completely without risk. While most vaccine adverse reactions are minor and self-limited, some vaccines have been associated with extremely rare but serious health effects. The following key considerations underscore the need for an active and ongoing vaccine safety program.
Decreases in Disease Risks
Most vaccine-preventable diseases are at or near record lows. Many people no longer see reminders of the severity and potential life-threatening complications of these diseases. Parents and providers in the United States may be more likely to know someone who has experienced an adverse event (an event that may or may not be related to vaccination) following vaccination than they are to know someone who has experienced a vaccine-preventable disease. The success of vaccination has led to increased public attention on potential health risks associated with vaccines.
Maintaining public confidence in vaccines is critical to prevent a decline in vaccination coverage that can result in outbreaks of disease. While most parents understand the benefits of vaccination and have their children vaccinated, some parents have concerns about the safety of vaccines. Despite high national vaccination coverage, there are local areas of low coverage that allow outbreaks of vaccine-preventable diseases to occur —often the result of parents refusing or delaying their children’s vaccinations because of concerns about vaccine safety.
A higher standard of safety is generally expected of vaccines than of other medical interventions because, in contrast to most pharmaceutical products that are administered to ill persons for treatment purposes, vaccines are generally administered to healthy persons to prevent disease. Public tolerance for adverse reactions related to products given to healthy persons—especially healthy infants and children—is substantially less than for reactions to products administered to persons who are already sick. Less tolerance of risk associated with vaccines requires close monitoring and timely assessment of vaccine adverse events to help distinguish true vaccine adverse reactions from coincidental unrelated events and to help maintain public confidence in vaccination.
Balancing Immunization Recommendations with Risk of Disease
Public health recommendations for immunization programs and practices represent a dynamic balance of risks and benefits. Vaccine safety monitoring is necessary to accurately weigh this balance and adjust immunization policy. For example, monitoring of smallpox and oral polio vaccines being used in the United States as these diseases neared global eradication found complications associated with each vaccine that exceeded the risks of the diseases. This observation led to discontinuation of routine smallpox vaccination in the United States (prior to global eradication) and a shift from the oral poliovirus vaccine to a safer, inactivated poliovirus vaccine.
Adverse Events Following Immunization and Assessment of Causality
Adverse events following immunization can be classified by frequency (common, rare), extent (local, systemic), severity (requiring hospitalization or causing disability or death), causality, and preventability (intrinsic to vaccine, production challenge, administration error). Adverse events following vaccinations may be coincidental, or the vaccine may have increased the risk of the adverse event. However, many adverse events following vaccination are coincidental; they are temporally related to vaccination but occur by chance without a causal relationship.
To assess causality of an adverse event following vaccination, a great deal of information is generally needed. An adverse health event can be causally attributed to a vaccine more readily if:
- The health problem occurs during a plausible time period following vaccination.
- The adverse event corresponds to adverse events previously associated with the vaccine.
- The event is consistent with a specific clinical syndrome where association with vaccination has strong biologic plausibility (e.g., anaphylaxis) or where the syndrome is known to occur following the natural disease.
- A laboratory result confirms the association (e.g., isolation of vaccine-strain varicella virus from skin lesions of a patient with rash).
- The event recurs with readministration of the vaccine in the same patient.
- A controlled clinical trial or epidemiologic study shows greater risk of a specific adverse event among vaccinated vs. unvaccinated groups.
- A finding linking an adverse event to a vaccine has been confirmed by other studies.
Vaccines, like other pharmaceutical products, undergo extensive safety and efficacy evaluations in the laboratory, in animals, and in sequentially phased human clinical trials prior to licensure. Phase I human clinical trials usually involve anywhere from 20 to 100 volunteers and focus on detecting serious adverse reactions. Phase II trials generally enroll hundreds of volunteers. Phase II trials determine the best dose and number of doses for effectiveness and safety. Phase I and II trials might take a few months or last up to three years. Next, the vaccine moves into Phase III trials, which may last several years and involve a few hundred to several thousand volunteers. Some volunteers receive another vaccine that has already been licensed, allowing researchers to compare one vaccine with another for adverse health effects—anything from a sore arm to a serious reaction. If the vaccine is shown to be safe and effective in Phase III, the manufacturer applies for a license from the Food and Drug Administration (FDA). During the application process, the FDA reviews the clinical trial results, product labeling, and manufacturing plant and protocols. If approved, the FDA licenses the vaccine itself (product license) and licenses the manufacturing plant where the vaccine will be made (establishment license).
Postlicensure Vaccine Safety Monitoring
Monitoring for vaccine-associated adverse events is essential even after vaccine licensure because rare reactions, delayed reactions, or reactions among subpopulations may not be detected before vaccines are licensed. While Phase III trials include enough persons to identify certain potential adverse reactions, such as injection-site reactions and fever, the comparatively small number of patients enrolled in these trials generally limits detection of rare adverse reactions, including those occurring many months after the vaccine is administered. For example, in the pentavalent rotavirus vaccine trials, 70,000 infants received either vaccine or placebo, permitting evaluation of safety with respect to intussusception, which occurs so rarely that large trials would be needed to detect even a single occurrence.
The objectives of postlicensure surveillance are to:
- Identify rare adverse reactions not detected during prelicensure studies.
- Monitor increases in known adverse health events after vaccination.
- Identify risk factors or preexisting conditions that may be associated with a higher incidence of adverse reactions.
- Identify whether there are particular vaccine lots with unusually high rates or certain types of events.
- Identify possible adverse reactions that might warrant further study to establish the association of an adverse event with vaccination or affect current immunization recommendations.
To achieve these objectives, as part of FDA approval, some drugs enter Phase IV clinical trials (postmarketing studies) to obtain information beyond what Phases I through III provided. Also, fundamental to preventing safety problems is the assurance that all vaccines are made using good manufacturing practices and undergo lot testing for purity and potency. Manufacturers must submit samples of each vaccine lot and results of their own tests for potency and purity to the FDA before releasing them for public use. Several monitoring systems are used in the United States to detect and study adverse events that occur after vaccinations. CDC and the FDA use four main systems to monitor the safety of vaccines in use: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), the Clinical Immunization Safety Assessment (CISA) project, and the Postlicensure Rapid Immunization Safety Monitoring System (PRISM).
Vaccine Adverse Event Reporting System (VAERS)
The National Childhood Vaccine Injury Act of 1986 mandates that vaccine providers and vaccine manufacturers report adverse health events following vaccinations. This led to the creation of the Vaccine Adverse Event Reporting System (VAERS) in 1990. VAERS is a national, spontaneous surveillance system, jointly administered by CDC and the FDA. VAERS receives about 30,000 reports per year, a seemingly large number, but relatively small considering that millions of doses of vaccines are administered yearly to adults and children in the United States.
Vaccine providers are required by law to report:
- Any adverse event listed by the vaccine manufacturer as a contraindication to further doses of the vaccine (see vaccine package inserts)
- Any adverse event listed in the VAERS Table of Reportable Events Following Vaccination pdf icon[5 pages]external icon
Vaccine providers are encouraged to report:
- Any adverse event that occurs after the administration of a U.S. licensed vaccine, whether it is clear a vaccine caused the adverse event
- Vaccine administration errors
Vaccine manufacturers are required to report all adverse health events that come to their attention.
VAERS collects information about the patient, the vaccination(s) administered, the adverse event, and the person reporting the event. All reports are coded using Medical Dictionary for Regulatory Activities (MedDRA) terms and entered into the VAERS database. Attempts are made to obtain additional medical information for all reports classified as a serious adverse event, including hospitalization or prolongation of hospitalization (if a vaccine was administered in the hospital), life-threatening illness, permanent disability, congenital deformity, or death. For these reports, letters to obtain information about recovery status are also sent to the persons reporting the events. All patient-identifying information submitted to VAERS, directly or as part of follow-up activities, is protected by strict confidentiality requirements.
VAERS has limitations inherent to spontaneous reporting systems. Also, VAERS is not designed to determine if a vaccine caused an adverse event, and additional studies are required to confirm possible safety signals detected by VAERS. Despite these limitations, VAERS has been able to fulfill its primary purpose of detecting new or rare vaccine adverse events, increases in rates of known adverse reactions, and patient risk factors for types of adverse events. In addition, VAERS often provides early safety data after a vaccine is licensed or during a public health emergency. Visit the VAERS web page to report an adverse eventexternal icon and view data with personal identifiers removedexternal icon.
Vaccine Safety Datalink (VSD)
CDC established the Vaccine Safety Datalink (VSD) to address gaps in the scientific knowledge of rare and serious adverse events following vaccination. This project involves partnerships with large, integrated health plans to monitor vaccine safety. Each participating plan uses its electronic health records and immunization information systems to contribute to a large, linked database. These participating health plans serve more than 10 million people annually, representing nearly 3% of the U.S. population, and contain records for more than 180 million vaccinations, enabling the VSD to study possible rare adverse events. Available information includes vaccination data (vaccine type, vaccination date, concurrent vaccinations), health conditions, medical encounter types (outpatient, inpatient, urgent care), birth data, and census data. A complete list of VSD partners can be found on the VSD web page.
The VSD allows for planned immunization safety studies, as well as timely investigations of hypotheses arising from review of medical literature, reports to VAERS, changes in immunization schedules, or the introduction of new vaccines. A rapid cycle analysis conducted by the VSD enables CDC and its co-investigators to monitor adverse events following vaccination for a specific disease in near real time, so the public can be informed quickly of possible risks.
Clinical Immunization Safety Assessment (CISA) Project
CDC’s Clinical Immunization Safety Assessment (CISA) Project‘s mission is to improve the understanding of adverse events following vaccination at the individual patient level. The CISA Project provides consultation to public health partners in the United States and conducts high-quality clinical research, including clinical trials across life stages, on the safety of influenza vaccines and the safety of vaccines in special populations. All clinical research studies conducted by the CISA Project are registered on clinicaltrials.govexternal icon.
The goals of the CISA Project are to:
- Assist with immunization decision-making by serving as a vaccine safety resource for U.S. health care providers with complex vaccine safety questions about a specific patient that are not readily answered by published sources such as guidelines from the Advisory Committee on Immunization Practices (ACIP).
- Conduct clinical research studies to better understand vaccine safety and identify strategies for preventing adverse events following vaccination.
- Assist CDC, the Department of Health and Human Services (DHHS), and other partners in evaluating emerging vaccine safety issues.
The CISA Project is part of the CISA Network, which addresses unmet vaccine safety clinical research needs in the United States. Additional information can be found on the CISA Project web page.
Postlicensure Rapid Immunization Safety Monitoring System (PRISM)
FDA’s Postlicensure Rapid Immunization Safety Monitoring System (PRISM) uses a computer algorithm to conduct active vaccine safety surveillance. A cooperative effort between FDA’s Center for Biologics Evaluation and Research and four health care and medical insurance organizations, PRISM analyzes health insurance claims data for potential vaccine safety signals. PRISM is also used to evaluate safety issues in targeted groups and to evaluate specific health conditions or outcomes.
Vaccine Injury Compensation
A main impact of the National Childhood Vaccine Injury Act (NCVIA) was the creation of the National Vaccine Injury Compensation Program (VICP). This program, administered by the Health Resources and Services Administration (HRSA), compensates persons injured by rare, vaccine-related adverse events and provides liability protection for vaccine manufacturers and administrators. Compensation is provided to persons who experience certain health events on a no-fault basis. No fault means persons filing claims are not required to prove negligence on the part of either the health care provider or manufacturer to receive compensation. The program covers all routinely recommended childhood vaccines, and adults who receive a covered vaccine may also file a claim.
During the 2009 H1N1 influenza pandemic, the federal government implemented another compensation program, the Countermeasures Injury Compensation Program (CICP). This program provides compensation for certain persons who are seriously injured by countermeasures as specified in a declaration by the Secretary of DHHS. Both bioterrorism and pandemic countermeasures are covered. Covered countermeasures within the CICP are not limited to vaccines and may include certain medications or devices used to diagnose, prevent, or treat the covered condition. People have one year from receipt of the countermeasure to file a claim with the CICP. Additional information is available on the CICP web pageexternal icon.
Even though the testing phases to approve a vaccine can take years before the vaccine can be licensed and vaccines are monitored continually for safety and effectiveness, vaccination providers also play a key role in helping to ensure the safety and efficacy of vaccines. Vaccine providers are responsible for proper vaccine storage, handling, and administration; timing and spacing of vaccine doses; observation of contraindications and precautions; management of vaccine adverse reactions; reporting of adverse events following vaccination to VAERS; and communicating with patients and parents about vaccine benefits and risks. Each of these steps is described only briefly here. Further information is available elsewhere in this book or in resource materials from CDC and other organizations.
Vaccine Storage, Handling, and Administration
To achieve the best possible results from vaccines, vaccine providers should carefully follow the recommendations found in each vaccine’s package insert for storage, handling, and administration. Specific actions to help ensure vaccine safety include:
- Inspecting vaccines upon delivery and monitoring refrigerator and freezer temperatures to ensure maintenance of the cold chain
- Rotating vaccine stock so the oldest vaccines are used first
- Never administering a vaccine after the expiration date
- Administering vaccines within the prescribed time periods following reconstitution
- Waiting to draw vaccines into syringes until immediately prior to administration
- Never mixing vaccines in the same syringe unless they are specifically approved for mixing by the FDA
- Recording vaccine and administration information, including lot number and injection site, in the patient’s medical record
Timing and Spacing
Timing and spacing of vaccine doses are two of the most important issues in the appropriate use of vaccines. To ensure optimal results from each vaccination, providers should follow the recommended immunization schedules for children, adolescents, and adults. Decreasing the timing intervals between doses of the same vaccine may interfere with the immune response elicited by the vaccine. Therefore, under most circumstances, a vaccine that is administered too soon will have to be readministered. For more specific information on timing and spacing of vaccines, see the “General Best Practice Guidelines for Immunization” chapter. A table showing recommended minimum ages and intervals between vaccine doses is contained in Appendix A.
Providers should also remember:
- Administer all needed vaccines during the same visit because, which increases the likelihood that patients will be fully immunized. Studies have shown the simultaneous administration of vaccines is safe and effective.
- Some vaccines, such as pediatric DTaP and DT, may cause local reactions when administered too frequently. Keeping good records and accurate patient histories and following recommended schedules can decrease the chance of patients receiving extra doses, thus reducing the possibility of such reactions.
Contraindications and Precautions
A contraindication is a condition in a recipient that increases the likelihood of a serious adverse reaction to a vaccine. A vaccine should not be administered when a contraindication is present. More information about contraindications can be found in the individual disease chapters and in the ACIP recommendations for individual vaccines.
A precaution is a condition in a recipient that might increase the chance or severity of a serious adverse reaction, might compromise the ability of the vaccine to produce immunity (such as administering measles vaccine to a person with passive immunity to measles from a blood transfusion), or might cause diagnostic confusion. Vaccination should generally be deferred when a precaution is present. However, situations may arise when the benefits of vaccination outweigh the risk of an adverse reaction, and the provider may decide to administer the vaccine.
Screening for contraindications and precautions is important for preventing serious adverse events after vaccination. Every provider who administers vaccines should screen every patient before giving a vaccine dose. Sample screening questionnaires can be found in the “General Best Practice Guidelines for Immunization” chapter.
Many contraindications and precautions are temporary, and the vaccine may be administered at a later time.
Many conditions are often inappropriately seen as contraindications to vaccination. In most cases, the following are not generally considered contraindications or precautions:
- Minor acute illness (e.g., diarrhea and minor upper respiratory tract illnesses, including otitis media, with or without low-grade fever)
- Current antimicrobial therapy
- Convalescent phase of illness
- A person in the household who is pregnant or immunosuppressed
- Preterm birth
- Allergies to products not in the vaccine
Recommendations for vaccinating persons who are immunocompromised can be found in Appendix A. Information on allergic reactions to vaccines can be found in the “General Best Practice Guidelines for Immunization” chapter as well as in the American Academy of Pediatrics Red Book.
Managing Adverse Reactions after Vaccination
Health care personnel should be familiar with identifying immediate-type allergic reactions, including anaphylaxis, and be competent in treating these events at the time of vaccine administration. While severe allergic reactions to vaccines are rare, occurring at an approximate rate of 1 to 2 for every million doses of vaccine administered, all immunization personnel should have emergency procedures in place and be prepared to provide emergency care for a person who experiences an anaphylactic reaction. All vaccine providers should be certified in cardiopulmonary resuscitation (CPR) and epinephrine administration, and equipment for maintaining an airway should be available for immediate use. All immunization personnel should be familiar with the office emergency plan.
Reporting Adverse Events Following Vaccination to VAERS
Health care providers are required by the NCVIA to report certain adverse events to VAERS and are encouraged to report any adverse event, even if they are not sure a vaccine was the cause. Instructions for reporting to VAERS are available on the VAERS web pageexternal icon. More information on VAERS is found in the “Vaccine Adverse Event Reporting System (VAERS)” section in this chapter.
Benefit and Risk Communication
Patients and parents should be informed of the benefits and risks of vaccines in understandable language. An opportunity for questions should be provided before each vaccination. Discussion of the benefits and risks of vaccination is sound medical practice and is required by law.
Immunization personnel should anticipate questions parents or patients may have regarding the need for or safety of vaccination. Some people may refuse certain vaccines or even reject all vaccinations. Some people might have religious or personal objections to vaccination. It is essential that health care personnel have a basic understanding of how patients view vaccine risk and develop effective approaches to deal with vaccine safety concerns when they arise. When a parent or patient initiates discussion of a vaccine concern, the provider should discuss the specific concern and use appropriate language to provide facts. Effective, empathic vaccine risk communication is essential in responding to misinformation and concerns. It’s important to remind parents that state laws for school or child care entry might require unvaccinated children to stay home from school during outbreaks. For patients who question or refuse vaccination, identifying common ground and discussing measures for deferring vaccination are more effective public health strategies than excluding these patients from a practice.
VISs provide an outline for discussing vaccine benefits and risks. CDC’s Vaccine Safety web page contains extensive and up-to-date information on vaccines and tools for discussing vaccines with patients.
While documentation of VIS distribution is required, additional information about these discussions should be documented in the patient’s record, including the refusal to receive certain vaccines (i.e., informed refusal). Such documentation might reduce any potential liability if a vaccine-preventable disease occurs in the unvaccinated patient.
The editors thank Dr. John R. Su, Dr. Michael M. McNeil, Mr. Eric S. Weintraub, Dr. Akpobome P. Wodi, and the Division of Healthcare Quality Promotion, CDC, for their update and critical review of this chapter.
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