Clinical Immunization Safety Assessment (CISA) Clinical Research Studies
CISA clinical research studies use the most current methods and technology to investigate questions of key importance to vaccine safety. Below are brief summaries of CISA clinical research studies. Complete details of these studies are available through the provided links to ClinicalTrials.gov.
Simultaneous mRNA COVID-19 and IIV4 Vaccination Study
Coronavirus disease 2019 (COVID-19) has caused significant illness and death in the United States. The majority of individuals with COVID-19 will recover but some individuals will have severe complications such as pneumonia, respiratory failure, multiorgan failure, clots, and death. Severe clinical outcomes are more common among older adults and those with underlying health conditions. CDC’s Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States recommends that everyone 5 years and older receive a COVID-19 vaccine. The Advisory Committee on Immunization Practices (ACIP) also recommends that people aged 6 months and older receive influenza (flu) vaccine each influenza season. Giving COVID-19 vaccine and influenza vaccines on the same day may make it easier for individuals to get these recommended vaccines. However, there is limited information on the health effects of giving both vaccines on the same day versus on different days.
The purpose of this CISA study is to examine the safety of an mRNA COVID-19 vaccine and influenza vaccines given on the same day compared with giving the COVID-19 and influenza vaccines on different days. Persons aged >12 are being assigned by chance to receive the vaccines on the same day (simultaneous group) or approximately 2 weeks apart (sequential group). The simultaneous group will receive COVID-19 vaccine and influenza vaccine at the first vaccination visit and return about 2 weeks later for a second vaccination visit, where they will receive a placebo vaccine. The sequential group will receive COVID-19 vaccine and a placebo vaccine at the first vaccination visit and return about 2 weeks later for an influenza vaccine at visit 2. Participants and study staff conducting follow-up assessments will be blinded and will not know at which visit they received the placebo or influenza vaccine. Safety outcomes, such as local and systemic reactions to the vaccine, as well as the occurrence of other health conditions during the study period will be assessed. The primary objective is to compare the proportion of participants with moderate or more severe reactions (fever, chills, muscle aches or joint pain) during the week after vaccination visits 1 and visit 2 in each group. The rates of other reactions and health outcomes will also be compared between the participants who get the vaccines on the same day and the participants who get the vaccines on different days. In addition, blood samples from the participants are being collected and will be used to look at levels of COVID-19 and influenza antibodies and explore reactions after vaccination in persons with and without pre-existing immunity to COVID-19.
Information from this study may lead to a better understanding of the safety of simultaneous vaccination of mRNA COVID-19 vaccine and influenza vaccines in adolescents and adults. The results could also assist healthcare providers and their patients with making decisions about vaccination.
Lead CISA Site: Duke University
Contributing CISA sites: Cincinnati Children’s Hospital Medical Center and Johns Hopkins University
Collaborator: Centers for Disease Control and Prevention (CDC)
Study start year: 2021
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT05028361
Study status: Recruiting
ClinicalTrials.gov results posted: No
Publications: None
Pregnant People
Observational Maternal COVID-19 Vaccination Study
Pregnant people may experience severe complications from Coronavirus disease 2019 (COVID-19), including hospitalization, ICU admission, and need for mechanical ventilation. Babies born to mothers who have COVID-19 may be born premature. CDC’s Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States recommends that any of the currently authorized COVID-19 vaccines can be administered to pregnant or lactating people. The Advisory Committee on Immunization Practices (ACIP) does not state a product preference. However, there is limited information on the safety of COVID-19 vaccines in pregnant people.
The purpose of this CISA study is to learn more about the safety of COVID-19 vaccines in pregnant people and their babies. This study is looking at outcomes among mothers and babies after the mothers receive a COVID-19 vaccine. The study objectives are to examine local and systemic reactions to the vaccine, adverse events, birth outcomes and infant outcomes.
In addition, blood samples from the pregnant people and from infant cord blood are being collected in this study. They may be used to study COVID-19 antibody levels.
Lead CISA Site: Duke University
Contributing CISA Sites: Cincinnati Children’s Hospital Medical Center and Boston Medical Center
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2021
ClinicalTrials.gov Identifier: NCT04826640
Study status: Recruiting
ClinicalTrials.gov results posted: No
Publications: None
The CDC Advisory Committee on Immunization Practices (ACIP) and American College of Obstetricians and Gynecologists (ACOG) recommend that women who are pregnant during the influenza (flu) season receive an influenza vaccine to protect both themselves and their babies from influenza. In 2017, ACIP included Recombinant Inactivated Influenza vaccine (RIV4) (Flublok® Quadrivalent) as one of the influenza vaccines that can be given to pregnant women. RIV4 is a type of influenza vaccine that is made using an egg-free process.
The purpose of this CISA study is to learn more about the safety of RIV4 in pregnant women and their babies. This study is comparing the safety of RIV4 with an influenza vaccine that is made using an egg-based process (IIV4). Egg-based influenza vaccines have been in use for decades. Pregnant women enrolled in this study are assigned by chance to receive either RIV4 or IIV4. The study participants and investigators will not know which vaccine the women received during the study. Health and pregnancy outcomes are assessed in the mothers and their infants. The primary study objective is to compare the proportion of adverse birth outcomes in pregnant women vaccinated with RIV4 versus IIV4.
In addition, blood samples from the pregnant women are being collected in this study. They may be used to compare influenza antibody levels in pregnant after RIV4 versus IIV4.
Lead CISA Site: Duke University
Contributing CISA Sites: Cincinnati Children’s Hospital Medical Center and Boston Medical Center
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2018
ClinicalTrials.gov Identifier: NCT03969641
Study status: Enrollment completed
ClinicalTrials.gov results posted: Yes
Publications: None
The Advisory Committee on Immunization Practices (ACIP) and American College of Obstetricians and Gynecologists (ACOG) recommend that pregnant women receive an influenza (flu) vaccine if they are pregnant during influenza season, and a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) during each pregnancy. Influenza vaccine given during pregnancy protects both mothers and their babies from influenza. When a woman receives Tdap during pregnancy, her baby receives some protection from pertussis (whooping cough) until they are old enough to be vaccinated themselves. Giving influenza vaccine and Tdap on the same day may make it easier for more pregnant women to be fully immunized. However, there is limited medical information on the health effects of giving both vaccines on the same day versus on different days.
CISA conducted this study to look at differences between giving pregnant women inactivated influenza vaccine (IIV) and Tdap on the same day versus on different days. During the 2016-2017 and 2017-2018 influenza seasons, pregnant women were assigned by chance to receive both Tdap and IIV vaccines on the same day, or on different days (Tdap first, and IIV about 3 weeks later). The study looked at the proportions of pregnant women with reactions at the site of injection and systemic reactions after vaccination, such as fever. The study also collected information on the outcomes of the pregnancy including information on the infants. The reactions and pregnancy outcomes in women who get both Tdap and IIV vaccines on the same day are compared with those who get the vaccines on different days.
Blood samples were also taken from the pregnant women and their babies. These samples were analyzed to assess if giving both Tdap and IIV vaccines on the same day versus different days affects levels of antibodies to the vaccine components in pregnant women and the transfer of these antibodies to their infants.
Information from this pilot study may be used to design larger studies to better understand the safety and immune responses of giving both IIV and Tdap vaccines on the same day in pregnant women.
Lead CISA Site: Duke University
Contributing CISA Site: Cincinnati Children’s Hospital Medical Center
Collaborators: Centers for Diseases Control and Prevention (CDC) and National Vaccine Program Office
Study start year: 2015
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02783170
ClinicalTrials.gov results posted: Yes
Publications: None.
The Advisory Committee on Immunization Practices (ACIP) and American College of Obstetricians and Gynecologists (ACOG) recommend that pregnant women receive a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) during each pregnancy. When a woman receives Tdap during pregnancy, her baby receives some protection from pertussis (whooping cough) until they are old enough to be vaccinated themselves.
CISA conducted this study to compare health outcomes after Tdap vaccination in pregnant women versus non-pregnant women. Pregnant women enrolled in the study participated in the study through delivery. The women were monitored for reactions at the site of injection and systemic reactions after vaccination, such as fever. Their infants were also evaluated for health outcomes and growth parameters through age 6 months. Non-pregnant women participated for one month after vaccination.
Blood samples were also taken to assess levels of antibodies to components of the Tdap vaccine after vaccination in pregnant women and non-pregnant women.
This study provided additional information about the safety and immune responses after Tdap in pregnant women, including repeated Tdap doses. Tdap was well tolerated in pregnant and non-pregnant women. Pregnant women were more likely to report moderate/severe pain at the Tdap injection-site compared with non-pregnant women, but did not need medical visits. Prior Tdap receipt did not increase occurrence of moderate/severe injection-site or systemic reactions in pregnant women. Robust immune responses to all vaccine components were seen in both pregnant and non-pregnant women after Tdap.
Lead CISA Site: Vanderbilt University
Contributing CISA Site: Duke University
Collaborators: Centers for Diseases Control and Prevention (CDC) and National Vaccine Program Office
Study start year: 2013
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02209623
ClinicalTrials.gov results posted: No
Publications: Fortner KB, Swamy GK, Broder KR, Jimenez-Truque N, Zhu Y, Moro PL, et al. Reactogenicity and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant and nonpregnant women. Vaccine 2018 Oct 8; 36(42): 6354-6360.
PregText: Feasibility of Monitoring Influenza Vaccine Safety in Pregnant Women Using Text Messaging
Text messaging may be a convenient and cost-efficient way to monitor vaccine safety in pregnant women, but it had not been studied for this purpose. CISA conducted a study to assess the feasibility of using text messaging to monitor the safety of inactivated influenza (flu) vaccine (IIV) in pregnant women.
The study included pregnant women who were less than 20 weeks gestational age at the time they received an inactivated influenza vaccine (IIV) as part of their usual care during the 2013-2014 influenza season. After getting IIV, these women received periodic text messages throughout their pregnancy to 1) monitor for the occurrence of fever shortly after getting the influenza vaccine, and 2) assess pregnancy outcomes.
This study demonstrated the feasibility of text messaging for influenza vaccine safety surveillance sustained throughout pregnancy. In these women receiving IIV during pregnancy, fever after vaccination was infrequent and a typical pattern of maternal and infant health outcomes was observed.
Lead CISA Site: Columbia University
Contributing Site: None
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2013
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT01974050
ClinicalTrials.gov results posted: Yes
Publications: Stockwell MS, Cano M, Jakob K et al. Feasibility of Text Message Influenza Vaccine Safety Monitoring During Pregnancy. Am J Prev Med. 2017 May 2. pii: S0749-3797(17)30204-0.
Infants and Young Children
Safety of Simultaneous mRNA COVID-19 Vaccine With Other Childhood Vaccines in Young Children
CDC recommends that all people ages 6 months and older stay up to date with COVID-19 vaccination to protect against COVID-19. This includes infants and young children. Studies continue to show that COVID-19 vaccines protect against the virus that causes COVID-19, with the benefits outweighing any known risks. COVID-19 vaccine is a routinely recommended vaccine for children and can be given during the same visit as other routine childhood vaccines.
CISA is conducting this study in young children to improve understanding of fever occurrence and other health outcomes, such as feeling tired or irritable, after receiving mRNA COVID-19 vaccine on the same day as other routine childhood vaccines, compared with receiving mRNA COVID-19 vaccine and other childhood vaccinations on separate days.
In this CISA study, up to 600 healthy children aged 6 months to <5 years will have two study visits about one to two weeks apart. Participants will be assigned by chance to receive study vaccines on the same visit (simultaneous group) or at two separate visits (sequential group). Children in the simultaneous group will receive mRNA COVID-19 vaccine and other recommended routine childhood vaccines at Visit 1, and health education without vaccines at Visit 2. Children in the sequential group will receive recommended routine childhood vaccines at Visit 1 except for COVID-19 vaccine, and then mRNA COVID-19 vaccine and health education at Visit 2. After each visit, children will be monitored for fever, other health outcomes, and unscheduled medical visit. The primary objective of the study is to compare the proportions of children with fever in the first 2 days following Visit 1 and Visit 2 combined. Parental perceptions about their children’s vaccination experience in this study will also be assessed.
Fever is a common event after childhood vaccination. Also, some young children have febrile seizures when they develop a fever for any reason. Information from this study may lead to a better understanding of the risk of fever and possible risk of febrile seizure when mRNA COVID-19 vaccine is given on the same day as other routine childhood vaccines. The results would provide anticipatory guidance to parents about fever after simultaneous vaccination with mRNA COVID-19 vaccine. The results of this study could also assist healthcare providers and parents of infants and young children with making decisions about vaccination.
Lead CISA Site: Duke University
Contributing Sites: Cincinnati Children’s Hospital Medical Center, Columbia University, Kaiser Permanente Northern California
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2023
Study status: Enrolling
ClinicalTrials.gov Identifier: NCT06038617
ClinicalTrials.gov results posted: No
Publications: N/A
Apnea in Hospitalized Preterm Infants Following the Administration of Routine Childhood Vaccines
Except for the birth dose of hepatitis B vaccine, the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that preterm infants should be vaccinated at the same age and according to the same schedule as full-term infants. This includes preterm infants who remain hospitalized after birth. Apnea (i.e. brief stopping of breathing) is common in babies born prematurely. Some preterm babies may have episodes of apnea shortly after they receive vaccines, but it is not known if the vaccines contribute to the apnea or if this occurs by chance. Concern about apnea after vaccination contributes to the underimmunization of preterm infants.
CISA is conducting this study to assess if apnea is more likely to occur in preterm infants after receipt of routine childhood vaccines. The study also looks at the severity of apnea events shortly after preterm infants are vaccinated. Preterm infants born at or earlier than 32 weeks gestational age who have remained hospitalized since birth, and are eligible to receive 2-month recommended vaccines are assigned by chance to a “vaccinated” or “unvaccinated” group. Both groups are monitored for apnea for at least 48 hours after they are assigned to the group. The study compares the proportion of infants who have apnea during the 48 hours after vaccination in the “vaccinated” group versus during 48 hours after group assignment in the “unvaccinated” group. Healthcare providers for the infants assigned to the “unvaccinated” group will make the decision on when to vaccinate the infants after their participation in the study.
Information from this study may lead to a better understanding of apnea after vaccination and help healthcare providers and parents make decisions about vaccinating preterm infants.
Lead CISA Site: Duke University (Sub-contracting site: University of North Carolina)
Contributing Site: Cincinnati Children’s Hospital Medical Center
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2017
Study status: In progress
ClinicalTrials.gov Identifier: NCT03530124
ClinicalTrials.gov results posted: No
Publications: None
Fever after Simultaneous versus Sequential Vaccination in Young Children
In recent years, some studies have suggested that giving the inactivated influenza (flu) vaccine (IIV) with 13-valent pneumococcal conjugate vaccine (PCV13) and/or diphtheria, tetanus toxoids, and acellular pertussis adsorbed (DTaP) on the same day is associated with an increased risk of febrile seizure in young children. However, some other studies have not shown this increased risk for febrile seizures. CDC’s Vaccine Information Statement for IIV (https://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.pdf [PDF – 2 pages]) notes this possible increased risk of febrile seizure in young children who get IIV with PCV 13 and/or DTaP vaccine on the same day.
CISA conducted this study in young children to improve understanding of fever after vaccination on the same day compared with vaccination on separate days. Fever is a common event after vaccination and it is reasonable to study fever after vaccination to learn more about febrile seizure risk after vaccination. In this CISA study, healthy children aged 12-16 months had two study visits about two weeks apart during the 2017-2018 influenza season. The children were assigned by chance to receive study vaccines on the same visit (simultaneous group) or at two separate visits (sequential group). Children in the simultaneous group received IIV, PCV13 and DTaP at Visit 1 and health education without vaccines at Visit 2. Children in the sequential group received PCV13 and DTaP together at Visit 1 and then IIV at Visit 2. Children may have received other recommended vaccines at Visit 1, but not Visit 2. After each visit, children were monitored for fever, other health outcomes, and having an unscheduled medical visit. The primary objective of the study is to compare the proportions of children with fever in the first 2 days following Visit 1 and Visit 2 combined.
Information from this study may lead to a better understanding of the risk of fever when IIV is given on the same day as PCV13 and DTaP vaccines. This information could also provide anticipatory guidance to parents about fever after receipt of multiple vaccines on the same day.
Lead CISA Site: Duke University
Contributing Site: Kaiser Permanente Northern California
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2016
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT03165981
ClinicalTrials.gov results posted: Yes
Publications: Walter EB, Klein NP, Wodi AP, Roundtree W, Todd CA, Wiesner A, Duffy J, Marquez PL, Broder K. Fever after Influenza, Diphtheria-Tetanus-Acellular Pertussis, and Pneumococcal Vaccinations. Pediatrics. 2020 Mar;145(3):e20191909.
Potential Mechanisms for Intussusception after Rotavirus Vaccine-Pilot Study
The Advisory Committee on Immunization Practices (ACIP) recommends rotavirus vaccination for infants. Rotavirus vaccination is associated with an increased risk for intussusception (i.e. the telescoping of one portion of the intestine into another). CDC’s Vaccine Information Statement for rotavirus vaccine notes this increased risk. The reason for this increased risk of intussusception is unknown.
CISA conducted this study to improve understanding of the occurrence of rotavirus vaccine-associated intussusception. The study looked at the effects of the first dose of rotavirus vaccination on the structure and movement of the intestines, and on cytokines in the blood and stool. Cytokines are substances that are secreted by immune cells and act on other cells to coordinate appropriate immune responses. The association between these outcomes and the pattern of the shedding of vaccine strain rotavirus in the stool is also being evaluated.
Healthy infants aged 6-13 weeks were assigned by chance to be vaccinated in one of the following ways listed below. The parents and study investigators did not know which group the infants were assigned to during the study.
- Monovalent rotavirus vaccine (Rotarix®) alone
- Rotarix® with other vaccines routinely recommended at 2-months of age
- Pentavalent rotavirus vaccine (RotaTeq®) alone
- RotaTeq® with other vaccines routinely recommended at 2-months of age
The infants in this study had an MRI and ultrasound of their gastrointestinal tract before, and about 5 days after vaccination. The study also collected information about vaccine reactions, such as fever, and collected samples of blood and stool from the infants before and after vaccination.
Information from this pilot study may be used to assess the feasibility of conducting a larger scale study. Information may also help understand possible reasons why rotavirus vaccine is associated with an increased risk for intussusception.
Lead CISA Site: Cincinnati Children Hospital Medical Center
Contributing Site: None
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2014
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02542462
ClinicalTrials.gov results posted: Yes
Publications: None
Antipyretics [such as acetaminophen (e.g. Tylenol®) or ibuprofen (e.g. Motrin®] are fever-reducing medicines. Using fever-reducing medications immediately after vaccination and during the next 24 hours can prevent the occurrence of fever after vaccination. However, giving these medicines to prevent fever after vaccination may also decrease immune responses to vaccine in children.
CISA conducted this study to assess the effect of fever-reducing medications on the immune responses and rates of fever after inactivated influenza (flu) vaccine (IIV). This study enrolled healthy children 6-47 months of age during the 2014-2015 and 2015-2016 influenza seasons. This study used lessons learned from a pilot study conducted by CISA during the 2013-2014 influenza season (learn more information about the Pilot Study to Assess the Effect of Prophylactic Antipyretics on Immune Response and Fever After IIV – NCT01946594).
In this study, children were assigned by chance to be in one of three groups: the first group of children received acetaminophen, the second group received a placebo – a substance containing no medicine, and the third group of children received ibuprofen. In groups one and two the child, parent and study investigator were blinded and did not know the study group assignment. Group three was not blinded. Children in all groups received IIV and then received doses on the study medicine immediately after vaccination and for the next 24 hours. Children were followed for the occurrence of vaccine reactions, such as fever, and having an unscheduled medical visit on the day of, and for two days following IIV vaccination. Blood samples were also taken to check antibody levels to the 2014-2015 and 2015-2016 influenza vaccines before, and about four weeks after IIV was given.
There were no significant differences in antibody levels to influenza vaccine in the children who received fever-reducing medicine vs. placebo. Our results do not suggest any blunting of the immune response to IIV when fever-reducing medicines are given to children shortly after IIV vaccination. Studies with larger sample sizes are needed to definitively establish the effect of antipyretics on immune responses after IIV.
Lead CISA Site: Duke University
Contributing site: None
Collaborator: Centers for Diseases Control and Prevention
Study start year: 2014
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02212990
ClinicalTrials.gov results posted: No
Publications: Walter EB, Hornik CP, Grohskopf L, McGee CE, Todd CA, Museru OI, Harrington L, Broder KR. The effect of antipyretics on immune response and fever following receipt of inactivated influenza vaccine in young children. Vaccine. 2017 Dec 4; 35(48 Pt B): 6664–6671.
Some children have fevers after receiving vaccines, including influenza (flu) vaccines. In recent years there have been four types of flu vaccines for children: trivalent inactivated influenza vaccine (3 strain, flu shot) (IIV3), trivalent live attenuated influenza vaccine (3 strain, nasal spray) (LAIV3), quadrivalent inactivated influenza vaccine (4 strain, flu shot) (IIV4), and quadrivalent live attenuated influenza vaccine (4 strain, nasal spray) (LAIV4).
CISA conducted this study to assess rates of fever in healthy children aged 24-59 months after they received pediatric influenza vaccines. The main study objective is to compare rates of fever after LAIV3/LAIV4 versus IIV3/IIV4 on the day of vaccination through two days after vaccination. After vaccination, parents took their children’s temperature beginning on the day of vaccination (day 0) through 10 days after vaccination. The parents sent the temperature readings to study staff using text messaging each day.
Fever frequencies after influenza vaccination were low overall and did not differ according to influenza vaccine type during the 2013–2014 influenza season. The results of this study further support the use of text messaging for monitoring vaccine adverse events, because response rates to text messages were high compared to response rates to other sources, such as a paper diary, and results were similar when analyses were limited to text message data.
In a companion study, dried blood spot samples were collected in some children to learn more about the feasibility of collecting dried blood spot samples after vaccination in children with fever. It may be useful in future studies to analyze dried blood spots to look for biomarkers associated with febrile reactions in children who receive influenza vaccines.
Lead CISA Site: Columbia University
Contributing site: None
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2012
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT01764269
ClinicalTrials.gov results posted: No
Publication: Stockwell MS, Broder KR, Lewis P et al. Assessing Fever Frequency After Pediatric Live Attenuated Versus Inactivated Influenza Vaccination. J Pediatric Infect Dis Soc. 2017 Sep 1; 6(3):e7-e14.
Children and Adolescents
Safety of Pediatric COVID-19 Vaccination
CDC recommends that all people ages 6 months and older stay up to date with COVID-19 vaccination to protect against COVID-19. This includes school-aged children and adolescents. Studies continue to show that COVID-19 vaccines protect against the virus that causes COVID-19, with the benefits outweighing any known risks.
COVID-19 vaccine is a routinely recommended vaccine for children and adolescents and can be given during the same visit as other routine childhood vaccines. In clinical trials including school-aged children and adolescents, injection-site reactions, such as pain or swelling, and systemic reactions, such as fatigue and headache, after COVID-19 vaccination occurred more frequently in this age group than in the same age group as those who received a placebo injection. These reactions were usually not severe and resolved quickly.
The study will complement other studies and describe the safety of COVID-19 vaccination in school-aged children and adolescents from four study sites.
In this study, approximately 320 participants ages 5-15 years will be enrolled. The study will take place in the clinics where children and adolescents are getting routine care, including other routine vaccinations. Information will be collected about reactions that occur during the week after COVID-19 vaccination and other health outcomes that occur during the 6 months after COVID-19 vaccination. The study will also assess adolescent and parent perceptions about COVID-19 vaccines. In addition, optional blood samples from the participants will be collected to study COVID-19 antibody levels.
This study addresses areas that were not studied in clinical trials before authorization or approval of COVID-19 vaccines, including safety of simultaneous COVID-19 vaccination with other routine vaccines and the safety of COVID-19 vaccination in children who previously had COVID-19 infection. The immune response to COVID-19 vaccines will also be assessed.
Lead CISA Site: Duke University
Contributing CISA Sites: Cincinnati Children’s Hospital Medical Center, Columbia University, and Kaiser Permanente Northern California
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2022
ClinicalTrials.gov Identifier: NCT05157191
Study status: Enrollment completed
ClinicalTrials.gov results posted: No
Publications: None
Syncope (fainting or passing out) after vaccination is uncommon but may lead to severe injuries when it occurs. Some people may experience symptoms of presyncope, such as feeling faint or lightheaded, after vaccination before they faint. A previous studyDrinking Water to Prevent Postvaccination Presyncope in Adolescents: A Randomized Trial,” identified anxiety and pain as risk factors for presyncope after vaccination. Presyncope is more common than syncope and studies about people donating blood have looked at ways to prevent both presyncope and syncope.
Drug-free pain prevention intervention (Buzzy®) and distraction/anxiety-reducing intervention (playing an electronic game) are two possible interventions to prevent fainting or feeling faint/lightheaded after vaccination. An earlier study, “Preventing Post-Vaccination Presyncope and Syncope in Adolescents Using Simple, Clinic-based Interventions: A Pilot Study,” suggested adolescents would find these interventions acceptable and that it would be feasible to conduct a larger study.
This CISA study builds on the findings from the pilot study to assess whether the combined intervention (Buzzy® and electronic game) would reduce the occurrence of presyncope after vaccination. The study also assessed whether the intervention is acceptable to adolescents and the effect of the intervention on injection-site pain and anxiety around the time of vaccination.
Adolescents ages 10-14 years receiving one or more intramuscular (IM) vaccinations were assigned by chance to one of two groups before vaccination: 1) A combination of Buzzy® and electronic game (intervention) and 2) standard of care (no intervention). The intervention was applied before and during vaccination, and adolescents were assessed for symptoms of presyncope and syncope during the 20 minutes after vaccination. This study is anticipated to provide information about approaches to reduce the occurrence of fainting feeling faint/lightheaded after vaccination in adolescents.
Lead CISA Site: Duke University
Contributing Sites: None
Collaborator: Centers for Diseases Control (CDC)
Study start year: 2021
Study status: Enrollment completed.
ClinicalTrials.gov Identifier: NCT04772755
ClinicalTrials.gov results posted: No
Publications: None
Preventing Post-Vaccination Presyncope in Adolescents Using Simple, Clinic-based Interventions
Syncope (fainting) after vaccination is uncommon but may lead to severe injuries when it occurs. Some people may experience symptoms of presyncope, such as feeling faint or lightheaded, after vaccination before they faint. This study built on the findings from an earlier study conducted by CISA that suggested possible simple, low-cost interventions might be useful to prevent fainting or feeling faint after vaccination. Learn more information about the earlier study, Oral Water Hydration to Prevent Post-Vaccination Presyncope – NCT02353390.
Two possible interventions to prevent fainting or feeling faint/lightheaded after vaccination are: 1) drug-free pain prevention intervention (Buzzy®) and 2) distraction/anxiety-reducing intervention (listening to music). CISA conducted this pilot study to assess if it was feasible and acceptable to adolescents to implement these simple interventions in a clinic setting.
Adolescents aged 10-17 years were assigned by chance to one of three groups before vaccination: 1) Buzzy® alone, 2) music alone, or 3) Buzzy® and music together. These interventions were applied before and during vaccination, and adolescents were assessed for symptoms of presyncope and syncope. Feasibility of using the interventions was assessed by the ability of study staff to successfully administer the interventions, and by both study staff and healthcare provider responses to written feasibility assessments. Acceptability was assessed by self-report of the adolescent participants.
The pilot study suggested that adolescents found the Buzzy® and music interventions to be acceptable, and that it would be feasible to study these simple interventions further to prevent presyncope and syncope and associated injuries after vaccination.
Lead CISA Site: Duke University
Contributing Sites: None
Collaborator: Centers for Diseases Control (CDC)
Study start year: 2017
Study status: Enrollment completed.
ClinicalTrials.gov Identifier: NCT03533829
ClinicalTrials.gov results posted: Yes
Publications: None
Oral Water Hydration to Prevent Post-Vaccination Presyncope
Syncope (fainting) after vaccination is uncommon but may lead to severe injuries when it occurs. Some people may experience symptoms of presyncope, such as feeling faint or lightheaded, after vaccination before they faint. The Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) recommend that all adolescents be sitting or lying down during vaccination to help prevent fainting. Providers should also consider observing patients for at least 15 minutes after vaccination to prevent potential injuries related to fainting after vaccination.
Studies suggest drinking 500 ml of water within fifteen minutes before venipuncture (i.e. puncturing a vein) can help prevent feeling faint or lightheaded among blood donors. It was not known if drinking water would also prevent presyncope or syncope after vaccination.
CISA conducted this study in adolescents and young adults (aged 11-21 years) receiving at least one vaccine that is injected into a muscle. Study participants were assigned by chance to drink a 500mL bottle of water shortly before vaccination or to receive routine care before vaccination. This study determined whether drinking water shortly before vaccination decreases the rate of feeling faint in adolescents and young adults. The study also evaluated whether drinking water before vaccination is acceptable to adolescents and young adults.
The study did not find that drinking water before vaccination was effective in reducing presyncope symptoms after vaccination in adolescents and young adults. However, the study did identify factors associated with presyncope after vaccination that could be targeted in future research to develop prevention strategies.
Lead CISA Site: Duke University
Contributing CISA Site: Boston Medical Center
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2014
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02353390
ClinicalTrials.gov results posted: No
Publications: Kemper AR, Barnett ED, Walter EB, et al. Drinking Water to Prevent Postvaccination Presyncope in Adolescents: A Randomized Trial. Pediatrics. 2017 Nov; 140(5): e20170508.
The Advisory Committee on Immunization Practices (ACIP) recommends people aged 6 months and older receive influenza (flu) vaccine each influenza season. People can receive either the inactivated influenza vaccine (IIV) (flu shot) or live-attenuated influenza vaccine (LAIV) (nasal spray). This influenza vaccine recommendation is particularly important for persons at elevated risk from complications of influenza, including children with asthma. Asthma is a condition that inflames and narrows the airways in the lungs and can lead to symptoms such as coughing and wheezing. ACIP considers use of LAIV in persons with asthma aged 5 years and older to be a precaution due to the potential increased risk for wheezing after LAIV.
CISA is conducting this study to evaluate whether LAIV is as safe as IIV in children with asthma. These vaccines are approved for use in the United States. This study applies lessons learned from an earlier feasibility conducted by the CISA Project during the 2016-2017 influenza season. Learn more information about the pilot study Influenza Vaccine Feasibility Study in Children with Persistent Asthma – NCT02967393.
Children aged 5-17 years are assigned by chance to receive either the quadrivalent nasal spray flu (LAIV4) or quadrivalent flu shot (IIV4). The children are monitored for symptoms of asthma and other health outcomes for 6 weeks after vaccination. The primary objective of this study is to compare the proportion of children with an asthma exacerbation (flare-up) after LAIV4 versus IIV4. The study also compares asthma symptoms and vaccine reaction symptoms such as fever, between children in the two groups.
Information from this study could help healthcare providers and parents make decisions about influenza vaccination in children with asthma.
Lead CISA Site: Vanderbilt University
Contributing Sites: Cincinnati Children’s Hospital Medical Center and Duke University
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study Start year: 2015
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT03600428
ClinicalTrials.gov results posted: Yes
Publications: Sokolow AG, Stallings AP, Kercsmar C, Harrington T, Jimenez-Truque N, Zhu Y, Sokolow K, Moody MA, Schlaudecker EP, Walter EB, Staat MA, Broder KR, Creech CB. Safety of Live Attenuated Influenza Vaccine in Children with Asthma Pediatric. 2022 April 1;149(4):e2021055432. Epub 2022 Mar 28.
Fever and Wheezing Events in Children after Influenza Vaccines Using Text Messaging
Text messaging may be a useful way to monitor vaccine adverse events because it is inexpensive and can gather information rapidly from many people located in different geographical areas at the same time. It also allows for monitoring health issues that often do not result in a visit to a healthcare provider such as fever or wheezing. Demonstrating the feasibility of using text messaging to assess wheezing episodes could provide important new information since previous studies using text message monitoring after vaccination have been for fever only. Expanding use of text messaging to monitor vaccine adverse events can also provide additional information that may be useful in preparing for a public health response during an influenza pandemic.
CISA conducted this study to assess the feasibility of using text messaging to monitor the occurrence of fever and wheezing in healthy children aged 2 through 11 years who received influenza (flu) vaccine; either the inactivated influenza vaccine (IIV) (flu shot) or live-attenuated vaccine (LAIV) (nasal spray). Fever was assessed on vaccination day through the following 7 days after vaccination. Wheezing was assessed from vaccination day through the next 6 weeks after vaccination.
This study demonstrates the feasibility and acceptability of using text messaging to assess pediatric respiratory symptom after influenza vaccination through 6 weeks post-vaccination.
The results also illustrate the capacity to monitor fever and wheezing after vaccination across multiple study sites, which could be helpful during an influenza pandemic or other emergency vaccination program.
Lead CISA Site: Columbia University
Contributing CISA Site: Boston Medical Center
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2014
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02295007
ClinicalTrials.gov results posted: No
Publications: Stockwell MS, Marchant CD, Wodi AP, Barnett ED, Broder KR, Jakob K, Lewis P, Kattan M, Rezendes AM, Barrett A, Sharma D, Fernandez N, LaRussa P. A multi-site feasibility study to assess fever and wheezing in children after influenza vaccines using text messaging. Vaccine 2017 Dec 15; 35(50):6941-6948.
The Advisory Committee on Immunization Practices (ACIP) recommends people aged 6 months and older receive influenza (flu) vaccine each influenza season. This influenza vaccine recommendation is particularly important for persons at elevated risk from complications of influenza, including individuals with systemic lupus erythematosus (lupus or SLE). Lupus is an autoimmune disease that leads to inflammation in different parts of the body, including joints, skin, and kidneys. Persons with lupus are recommended to receive an inactivated influenza vaccine (IIV) every influenza season. Vaccines stimulate the immune system to make antibodies to protect against diseases. There is limited medical information on the effect of IIV on possibly stimulating flares of lupus.
CISA conducted this pilot study to assess whether children and adolescents with lupus have worsening of lupus symptoms after receipt of IIV. Persons aged 8-18 years who were being treated with immunosuppressive medication for lupus were enrolled in this study. This study assesses clinical symptoms before and after IIV, and the feasibility of conducting a larger study. Blood samples from subjects were collected before vaccination and at fixed time points after administration of IIV to examine various aspects of the immune response.
This study may provide more information about the safety and immune responses of IIV in persons with lupus, and information could be used to design a larger study.
Lead CISA Site: Vanderbilt University (Sub-contracting site: Baylor Institute for Immunology Research)
Contributing CISA Site: None
Collaborator: Centers for Diseases Control and Prevention (CDC)
Study start year: 2012
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT02006784
ClinicalTrials.gov results posted: No
Publications: None
Non-Pregnant Adults
Simultaneous RZV and allV4 Vaccination
This CISA study will compare the safety of administering the two adjuvanted vaccines for herpes zoster and influenza (RZV and aIIV4) versus the adjuvanted herpes zoster and the unadjuvanted high-dose influenza vaccine (RZV and HD-IIV4) in older adults during the same visit (“simultaneous”).
- Herpes zoster, also known as shingles, is a painful disease that affects the nervous system and the skin. It is caused by the reactivation of latent varicella zoster virus from nerves. Latency is a phase during which viruses remain dormant in the body and do not replicate. Latent viruses can be reactivated by a number of internal or external factors and cause a new infection. The risk of developing herpes zoster,and the chronic pain it causes, increases with The Advisory Committee on Immunization Practices (ACIP) recommends an adjuvanted recombinant zoster vaccine (RZV; Shingrix®) for the prevention of herpes zoster in adults ages ≥50 years. An adjuvant is an ingredient used in some vaccines that helps create a stronger immune response.
- To protect against influenza (flu) and its complications, ACIP recommends people ages 6 months and older receive an influenza vaccine each influenza season. Two of the three influenza vaccines recommended by ACIP for persons ages 65 years and older are an adjuvanted quadrivalent inactivated influenza vaccine (aIIV4) (Fluad® Quadrivalent) and an unadjuvanted vaccine that has a higher than regular dose of hemagglutinin antigen (high-dose quadrivalent inactivated influenza vaccine (HD-IIV4) (Fluzone®High-Dose Quadrivalent).
In this study, approximately 400 adults ages 65 years and older will be enrolled during the 2021-2022 and 2022-2023 influenza seasons. The participants will be randomly assigned to receive either simultaneous RZV and aIIV4 vaccines or RZV and HD-IIV4 vaccines; the RZV will be dose 1 of the 2-dose series. Participants and study investigators will not know which vaccine group the participants are in until the study ends. The study’s primary and secondary safety objectives are to compare the proportions of severe reactions, serious adverse events, and adverse events of clinical interest after RZV dose 1 in the RZV and aIIV4 group versus RZV and HD-IIV4 group. The study will also look at whether reactions to the vaccines will affect quality of life.
Blood will be collected from participants before vaccination and one month after vaccination. The study will compare antibody levels to the components of the influenza vaccine between the two groups.
Information from this study may lead to a better understanding of the safety of simultaneous administration of two adjuvanted vaccines, RZV and influenza vaccine, in older adults. The results may also assist healthcare providers and their patients with making decisions about RZV and influenza vaccination in older adults. Additionally, the study will provide information about immune responses to influenza vaccine.
Lead CISA Site: Duke University
Contributing site: Johns Hopkins University
Collaborator: Centers for Disease Control and Prevention (CDC)
Study start year: 2021
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT05007041
ClinicalTrials.gov results posted: No
Publications: none
The Advisory Committee on Immunization Practices (ACIP) recommends people aged 6 months and older receive influenza (flu) vaccine each influenza season. Compared with younger adults, older adults generally have decreased immune responses to influenza vaccines due to the gradual weakening of the immune response from natural aging. This may result in influenza vaccine being less effective in older adults. Two types of influenza vaccines are approved for use in older adults: 1) high-dose trivalent inactivated influenza vaccine (IIV3-HD) (Fluzone® High-Dose), which has an increased amount of the hemagglutinin antigen compared with standard inactivated influenza vaccines; and 2) adjuvanted inactivated influenza vaccine (aIIV3) (FLUAD®), which has an adjuvant added to the vaccine to enhance its immune response. An adjuvant is ingredient used in some vaccines that helps create a stronger immune response. The ACIP does not express a preference for any licensed influenza vaccine products indicated for persons aged 65 years and older, leaving the decision to healthcare providers and their patients.
CISA is conducting this study to compare the safety of aIIV3 versus IIV3-HD in older adults. Adults aged 65 years or older were enrolled during the 2017-2018 and 2018-2019 influenza seasons, with a goal of at least 20 percent of participants being aged 80 years and older. The participants were assigned by chance to receive either IIV3-HD or aIIV3. The participants and study investigators did not know which vaccine participants received during the study. The primary safety objectives of this study are to compare the proportions of moderate/severe reactions, serious adverse events, and adverse events of clinical interest after aIIV3 versus IIV3-HD. The study is also assessing whether the influenza vaccination affects the participants’ quality of life.
Blood was collected from participants before vaccination and about one month after vaccination. In a subgroup of participants, blood was also collected 6 months after vaccination. The study compares antibody levels to the components of the influenza vaccine between the two groups.
Information from this study may lead to a better understanding of the safety and immune responses to influenza vaccines in older adults. The results could also assist healthcare providers and their patients with making decisions about influenza vaccination in older adults.
Lead CISA Site: Duke University
Contributing site: Boston Medical Center (Sub-contracting site: Cincinnati Children’s Hospital Medical Center)
Collaborator: Centers for Disease Control and Prevention (CDC)
Study start year: 2016
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT03183908
ClinicalTrials.gov results posted: Yes
Publications: Schmader KE, Liu CK, Harrington T, Rountree W, Auebach H, Walter EB, Barnett ED, Schlaudecker EP, Todd CA, Poniewierski M, Staat M A, Wodi P, Broder KR. Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted versus Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults. A Randomized Clinical Trial JAMA Network Open. 2021 Jan 4;4(1):e2031266.
A Pilot Study of the Immune Response to Influenza Vaccination and Effect on Reproductive Hormones
The Advisory Committee on Immunization Practices (ACIP) recommends people aged 6 months and older receive influenza (flu) vaccine each influenza season. This includes women of reproductive age. Giving inactivated influenza (flu) vaccine (IIV) induces an early immune, or germ-fighting, response and changes the body’s level of cytokines. Cytokines are substances that are released by immune cells and act on other cells to coordinate appropriate immune responses. It is not known whether this cytokine response might affect female reproductive hormone levels.
CISA conducted this study to examine the effect of IIV on inflammatory cytokines and hormonal responses in healthy women of reproductive age (18-39 years). Non-pregnant women with normal menstrual cycles were enrolled during the 2013-2014, 2015-2016, and 2016-2017 influenza seasons. Study procedures were timed around the menstrual cycle. Study participants received IIV during the week before ovulation during one menstrual cycle, and in a second menstrual cycle (control cycle) they did not receive any vaccines. The level of reproductive hormones and cytokines were measured during both menstrual cycles at several time points. The levels of hormones and cytokines were compared for each woman during the vaccinated menstrual cycle and the unvaccinated cycle.
This study is also assessing the feasibility of conducting further research in this new area of women’s health. Information from this study may be used to design a larger study to better understand the effects of influenza vaccination on women’s reproductive hormones.
Lead CISA Site: Johns Hopkins University
Contributing site: None
Collaborator: Centers for Disease Control and Prevention (CDC)
Study start year: 2013
Study status: Enrollment completed
ClinicalTrials.gov Identifier: NCT01978262
ClinicalTrials.gov results posted: Yes
Publications: None
Projects/Studies initiated under the CISA Network (2001-2012)
The CISA Network has published numerous studies and technical reports on vaccine safety.