Vaccine Risk Monitoring and Evaluation at the Centers for Disease Control and Prevention (2025)
Chapter: Appendix D: Case Studies
Appendix D
Case Studies
INTRODUCTION
The goal of these case studies is to illustrate how the Centers for Disease Control and Prevention (CDC) identified, assessed, and communicated adverse events (AEs) associated with COVID vaccines. They highlight both prespecified AEs and those that emerged during the vaccination campaign, offering insight into the Immunization Safety Office (ISO) approach to vaccine safety monitoring and response. The case studies focus on three specific AEs linked to vaccination: myocarditis, tinnitus, and menstrual irregularities. Myocarditis was identified early as an adverse event of special interest (AESI); the latter two emerged as concerns through postmarketing surveillance and public reports. Additionally, a brief case study on the chikungunya vaccine is included as a real-time example of how vaccine safety monitoring continues to evolve beyond the COVID response.
The case studies were developed using publicly available information from the COVID-19 Vaccine Safety Technical (VaST) Work Group and Advisory Committee on Immunization Practices (ACIP), primarily sourced through the CDC Stacks archive website during the time of the U.S. public health emergency (PHE). Publications and public presentations to this committee from ISO were also used. While these sources provide valuable insights into ISO’s and CDC’s safety monitoring and communication strategies, there are inherent limitations. These case studies rely exclusively on publicly available data, which means they may not fully capture all internal deliberations, emerging evidence, or evolving risk assessments conducted within CDC and its partner agencies. Despite this limitation, these case
studies offer a useful perspective on ISO’s vaccine safety efforts and highlight key lessons for future vaccine monitoring, regulatory decision making, and public health communication strategies.
MYOCARDITIS CASE STUDY
Myocarditis is an inflammatory condition that affects the myocardium or heart muscle (Ammirati et al., 2020). It can result from an infection, immune system response, or drug exposure, prompting immune activation, inflammation in the heart muscle, and heart cell damage (Ammirati et al., 2020; Nagai et al., 2023). Acute myocarditis frequently presents with nonspecific signs and symptoms, such as chest pain, dyspnea, or palpitations. It most often affects people aged 30–45, with men making up 60–80 percent of cases (Ammirati and Moslehi, 2023; Basso, 2022). Globally, myocarditis occurs in about 4–14 people per 100,000 each year, though the actual rate is likely higher due to many mild or undiagnosed cases (Ammirati and Moslehi, 2023; Nagai et al., 2023). Outcomes vary depending on the disease cause and form, with reported death rates for acute myocarditis of 1–7 percent (Ammirati and Moslehi, 2023; Nagai et al., 2023).
Myocarditis was not reported as a postvaccination event in the clinical trial data for BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen) vaccines that were granted initial emergency use authorization, according to Baden et al. (2021), Polack et al. (2020), and Sadoff et al. (2021). However, myocarditis was designated as an AESI for the COVID vaccine in the United States (VAERS, n.d.) due to its association with the COVID disease pathology and potential to signal vaccine-associated enhanced disease (VAED).
The case definition of myocarditis developed by the ACIP Joint Smallpox Vaccine Safety Working Group and Armed Forced Epidemiology Board (AFEB) during the 2002–2003 vaccination campaign for military personnel and civilian health care and public health professionals in response to a bioterrorism threat (CDC, 2003; Poland et al., 2005) was adopted for monitoring during the COVID vaccination effort (CDC, 2003; VAERS, n.d.). Myopericarditis was an unexpected AE from the live smallpox vaccine used in the campaign (Poland et al., 2005). An incidence of 16.11 per 100,000 vaccine recipients was observed among military personnel (Arness et al., 2004; Poland et al., 2005). It was concluded that the smallpox vaccination appeared to increase the risk in recipients, particularly among men (Poland et al., 2005). Aside from these cases, myocarditis is rarely reported to the Vaccine Adverse Event Reporting System (VAERS) or in the literature as a vaccine-related AE (Mei et al., 2018; Montgomery et al., 2021).
Event Timeline
As it was an AESI, multiple vaccine safety systems were used to proactively monitor for myocarditis once U.S. COVID vaccinations commenced, including several ISO systems, specifically VAERS and the Vaccine Safety Datalink (VSD) (Gee et al., 2024; Markowitz et al., 2024). VaST routinely reviewed data on AESIs, including myocarditis, to make a benefit–risk assessment. The Vaccine Safety Team (VST) reported safety monitoring data, and VaST reported its risk assessments to the ACIP COVID-19 Vaccines Work Group and ACIP. VST reported that no safety signals had been detected related to myocarditis at the ACIP meetings on January 27, 2021 and March 1, 2021 based on interim analyses of VSD rapid-cycle analysis (RCA) (Shimabukuro, 2021c). The VSD RCA used data on AESIs reported weekly by nine participating integrated health care organizations to monitor for potential safety signals. Table D-1 presents a timeline summarizing the events related to the initial safety signal detection through ACIP determination and communication.
Initial Signal Detection
The first signs of a potential safety concern related to myocarditis emerged in spring 2021 (Gee et al., 2024). In February 2021, the Ministry of Health in Israel began active monitoring for myocarditis after receipt of the Pfizer-BioNTech vaccine based on reports from HCPs (Mevorach et al., 2021). All hospitals were asked to report myocarditis cases; 142 were reported following COVID vaccination from December 2020 through May 2021. The incidence was greatest among boys and men after the second dose.
In the United States, the first signal was detected within the military population based on referrals to the Defense Health Agency clinical specialists and VAERS reports (Gee et al., 2024; Montgomery et al., 2021). Between January and April 2021, the military administered 2.8 million vaccine doses, and 23 men were evaluated and diagnosed with myocarditis following mRNA COVID vaccination (Montgomery et al., 2021). Twenty of these cases occurred following the second vaccine dose. The Pfizer-BioNTech vaccine was authorized for individuals aged ≥16 and adolescents aged 12–15, while the Moderna and Janssen vaccines were authorized for persons aged ≥18 (CDC, 2024).
TABLE D-1 Timeline of Events Related to Signal Detection of Myocarditis Following U.S. mRNA COVID Vaccination
| Date | Vaccine Authorization/Approval and Recommendation | Myocarditis Signal Detection |
|---|---|---|
| December 11, 2020 | FDA issues EUA for Pfizer-BioNTech vaccine; ACIP recommends for people aged ≥16 (CDC, 2024) | |
| December 14, 2020 | First COVID vaccine administered (Guarino et al., 2020) | |
| December 18–19, 2020 | FDA issues EUA for Moderna vaccine; ACIP recommends for people aged ≥18 (CDC, 2024) | |
| January 27, 2021 | VST reports no safety signal detected for myocarditis in VAERS or VSD at ACIP meeting (Shimabukuro, 2021c) | |
| February 27–28, 2021 | FDA issues EUA for Janssen vaccine; ACIP recommends for people aged ≥18 (CDC, 2024) | |
| February 2021 | Israeli Ministry of Health begins active monitoring for myocarditis after the Pfizer-BioNTech vaccine (Mevorach et al., 2021) | |
| March 1, 2021 | VST reports no safety signal detected for myocarditis in VAERS or VSD at ACIP meeting (Shimabukuro, 2021c) | |
| April 2021 | VaST first discusses myocarditis as a safety concern following mRNA vaccination (Markowitz et al., 2024) | |
| May 10–12, 2021 | FDA expands Pfizer-BioNTech vaccine EUA; ACIP recommends for adolescents aged 12–15 (CDC, 2024) | |
| May 17, 2021 | VaST issues report on myocarditis following mRNA vaccinationa,b (NCIRD, 2021a) |
| Date | Vaccine Authorization/Approval and Recommendation | Myocarditis Signal Detection |
|---|---|---|
| May 24, 2021 | VaST issues report on myocarditis following mRNA vaccinationc,d (NCIRD, 2021c) | |
| May 2021 | VaST issues clinical guidance to HCPs on the assessment and treatment of myocarditis (ACIP, 2021a; Shimabukuro, 2021d) | |
| June 23, 2021 | ACIP issues determination on myocarditis following mRNA vaccination and initiates a study to evaluate the long-term outcomese (Gargano, 2021) | |
| June 25, 2021 | FDA revises the EUAs and fact sheets for the Pfizer-BioNTech and Moderna vaccines with information about myocarditis (ACIP, 2021a) | |
| July 9, 2021 | MMWR publishes ACIP determination on myocarditis risk from June 23, 2021 meeting (Gargano, 2021) | |
| August 13, 2021 | ACIP recommends an additional dose of vaccine after the two-dose primary series for moderately to severely compromised individuals (CDC, 2024) | |
| August 23–30, 2021 | FDA fully approves the Pfizer-BioNTech vaccine for people 18+; ACIP recommends for people 16+ (CDC, 2024) | |
| August 2021 | CDC launches follow-up study on long-term outcomes of myocarditis after mRNA vaccine (Kracalik et al., 2022) |
a Concluded that the rate of myocarditis reports following mRNA COVID vaccination was consistent with expected baseline rates; however, cases seemed to occur more frequently in adolescents and young adults, boys and men, following the second dose, and within 4 days following vaccination.
b Recommended ongoing monitoring of reported myocarditis cases, education for HCPs to support timely identification and proper management, and the development of clinical guidance on diagnosis and treatment.
c Continued to support ongoing monitoring of reported cases, particularly in younger age groups, HCP education, and the development of clinical guidance.
d Advocated for follow-up of individuals with myocarditis following COVID vaccination to understand long-term outcomes.
e Determination: “... the benefits of using mRNA COVID-19 vaccines under the FDA’s EUA clearly outweigh the risks in all populations, including adolescents and young adults.”
NOTE: ACIP = Advisory Committee on Immunization Practices; EUA = emergency use authorization; FDA = Food and Drug Administration; HCP = health care provider; VAERS = Vaccine Adverse Event Reporting System; VaST = Vaccine Safety Technical (a work group); VSD = Vaccine Safety Datalink; VST = Vaccine Safety Team.
VaST Review
VaST first discussed the myocarditis as a safety concern after mRNA COVID vaccination in April 2021 (Markowitz et al., 2024). On May 17, 2021, its meeting included updates on myocarditis reports following mRNA vaccination from VAERS and VSD, among other vaccine safety monitoring systems (NCIRD, 2021a). VaST concluded that the rate of reports was consistent with expected baseline rates. Among the limited number of cases, myocarditis seemed to occur more frequently in adolescents and young adults, boys and men, following the second dose, and within 4 days of vaccination. VaST recommended ongoing monitoring of reported cases, education for HCPs to support timely identification and proper management, and the development of clinical guidance on diagnosis and treatment.
On May 24, 2021, the VaST meeting included updates on myocarditis following mRNA vaccination (NCIRD, 2021c). VAERS data indicated that reports were higher than expected among 16–24-year-old individuals within 30 days of the second dose. VSD data showed no difference in the rates of myocarditis following mRNA vaccination compared to expected rates. VaST continued to support ongoing monitoring of reported cases, particularly in younger age groups, HCP education, and the development of clinical guidance and advocated for ongoing monitoring of individuals who were affected to understand long-term outcomes.
ACIP Determination
The ACIP meeting on June 23, 2021 focused on myocarditis after mRNA vaccination (ACIP, 2021b). Speakers presented an overview of myocarditis, updates from the COVID-19 VST, and VaST’s assessment (Lee and
Hopkins, 2021; Oster, 2021b; Shimabukuro, 2021d; Wallace and Oliver, 2021). As of June 11, 2021, VAERS had received 791 reports following administration of the Pfizer-BioNTech vaccine (150 after the first dose and 563 after the second) and 435 reports following the Moderna vaccine (117 after the first dose and 264 after the second), when approximately 300 million mRNA vaccine doses had been administered (ACIP, 2021b; Shimabukuro, 2021d). The highest number of reports occurred after the second dose, predominantly among individuals in their late teens to mid-20s, and typically within 7 days of vaccination.
As of June 12, 2021, the VSD rapid cycle analysis (RCA) detected no statistical signal for myocarditis or pericarditis within 21 days after either dose of an mRNA vaccine, with an adjusted rate ratio slightly above 1 (ACIP, 2021b; Shimabukuro, 2021d). An age-stratified analysis of individuals aged 12–39 identified a statistically significant increase in myocarditis cases within 21 days of receiving an mRNA vaccine, with a combined adjusted rate ratio of 3.5. The increased risk was significant after the second dose but not the first. Estimates for the Pfizer-BioNTech vaccine did not reach significance. Thus, the overall findings were likely influenced by cases associated with the Moderna vaccine, despite limited data for control comparisons. A similar analysis using a 7-day risk window yielded comparable findings. VaST concluded that current evidence supported a likely link between mRNA COVID vaccination and myocarditis in adolescents and young adults, particularly among boys and men and after the second dose (ACIP, 2021b; Lee and Hopkins, 2021). These cases typically presented within 1 week postvaccination and were consistent across both VAERS and VSD data, strengthening confidence in the observed patterns.
The ACIP COVID-19 Work Group presented a benefit–risk framework that included consideration of the following benefits: COVID-19 cases prevented, COVID-19 hospitalizations prevented, and COVID-19 intensive care unit (ICU) admissions and deaths prevented (Gargano, 2021). Risks included the number of myocarditis reports to VAERs within 7 days after a second dose of an mRNA vaccine. The benefits and risks were assessed across various age cohorts and sex. At the population level, the absence of alternative vaccines for adolescents was considered. ACIP concluded that the benefits of mRNA vaccination still outweighed the risks for adolescents and young adults based on available data related to myocarditis (ACIP, 2021b; Gargano, 2021). The ACIP conclusion also affirmed the importance of continuing to monitor myocarditis outcomes and providing education to HCPs and the public. To monitor, CDC initiated a study with follow-up on myocarditis reports to VAERS (Kracalik, 2022).
Public and Provider Communication
CDC used multiple strategies to communicate information regarding myocarditis after mRNA COVID vaccination to the public and HCPs. In May 2021, VaST issued clinical guidance to HCPs on assessing and treating myocarditis via the “Clinical Considerations: Myocarditis and Pericarditis after Receipt of mRNA COVID-19 Vaccines Among Adolescents and Young Adults” webpage (CDC, 2023b) and a webpage with clinical guidance regarding administration of a second dose in people who developed myocarditis after the first dose (ACIP, 2021a; Gargano, 2021; Shimabukuro, 2021d).
Furthermore, a summary of ACIP’s determination from the June 23rd meeting and rationale were published in MMWR on July 9, 2021 (Gargano, 2021). Beyond CDC’s communication efforts, the Food and Drug Administration (FDA) revised the Pfizer-BioNTech and Moderna COVID vaccine EUAs and fact sheets with information about myocarditis on June 25, 2021 (Gargano, 2021; Lee and Hopkins, 2021; Markowitz et al., 2024).
The webpage “Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination,” summarized key information for the public, including CDC’s ongoing recommendation that all individuals 12+ years be vaccinated and what symptoms to monitor for afterward (NCIRD, 2021f). Information about the risk of myocarditis after mRNA vaccination was added to CDC’s webpages about the Pfizer-BioNTech and Moderna vaccines (Gargano, 2021; NCIRD, 2021e,h). Several additional webpages were updated to educate the public about myocarditis after mRNA vaccination, including “Selected adverse events reported after COVID-19 vaccination,” “COVID-19 Vaccines That Require 2 Shots,” and “COVID-19 Vaccines for Children and Teens” (NCIRD, 2021b,i).
Ongoing Monitoring
While ACIP’s determination that the benefits of mRNA COVID vaccination outweighed the risk of myocarditis remained unchanged and vaccination continued to be recommended, cases of myocarditis after mRNA vaccination were continuously monitored through vaccine safety systems and regularly presented at ACIP meetings throughout the PHE (see Table D-2).
Myocarditis Long-Term Outcomes Study
In August 2021, CDC launched a follow-up study to examine clinical recovery and quality-of-life outcomes following an mRNA COVID vaccine (Kracalik et al., 2022). The study focused on patients aged 12–29 years
TABLE D-2 ACIP Meetings Addressing Myocarditis Following mRNA COVID Vaccination During the Public Health Emergency
| Meeting Date | Summary |
|---|---|
| June 23, 2021 | This was the first ACIP meeting focused on myocarditis after mRNA COVID vaccination (ACIP, 2021b). As of June 11, 2021, VAERS had received 791 reports following administration of the Pfizer-BioNTech vaccine and 435 reports following the Moderna vaccine out of approximately 300 million mRNA doses administered. As of June 12, 2021, a VSD age-stratified analysis of individuals aged 12–39 identified a statistically significant increase in cases within 21 days of receiving an mRNA vaccine, with a combined adjusted rate ratio of 3.5, likely influenced by cases associated with the Moderna vaccine. ACIP concluded that the benefits of mRNA vaccination still outweighed the risks for adolescents and young adults based on available data related to myocarditis. To monitor outcomes, CDC initiated a study with follow-up on myocarditis reports to VAERS. |
| August 30, 2021 | Updated VAERS and VSD data were presented after FDA’s approval of the Pfizer-BioNTech vaccine for individuals 18+ (ACIP, 2021a). As of August 18, VAERS had 1,903 reports of myocarditis, with patterns remaining consistent with previously reported data—most in younger male recipients shortly after the second dose of an mRNA vaccine. No safety signals were detected in the overall VSD population (≥12 years), but in individuals aged 12–39, both mRNA vaccines were linked to higher rates of myocarditis, particularly within the first week following vaccination. VaST presented its evaluation, indicating that the data suggest a link between myocarditis and mRNA vaccination in adolescents and young adults. ACIP voted to recommend the Pfizer-BioNTech vaccine, now fully approved, for individuals aged 16+, as a 30-microgram dose. |
| Meeting Date | Summary |
|---|---|
| September 22–23, 2021 | VaST presented on a potential third dose of the Pfizer-BioNTech vaccine (ACIP, 2021c). Data from Israel as of September 13, 2021, reported only a single case of myocarditis—a man in his 30s—after approximately 2.8 million third doses for individuals aged 12+. As a result of limitations in the available data, VaST outlined a plan to continue monitoring and reviewing safety data related to third doses. ACIP voted to recommend a 30-microgram third dose of the Pfizer-BioNTech vaccine for individuals 65+, residents of long-term care facilities, those aged 50–64 with underlying medical conditions, and individuals aged 18–49 with underlying medical conditions based on an individual benefit–risk assessment, all to be administered at least 6 months after completion of the primary series. |
| October 21, 2021 | VST presented updated data on myocarditis (Shimabukuro and ACIP, 2021). VAERS data showed that 402,469,096 doses had been administered as of October 6, 2021, resulting in 2,459 reports of myopericarditis (Su, 2021b). The patterns of myocarditis after vaccination were consistent with prior reports. VSD indicated that both mRNA vaccines were linked to an increased risk in individuals aged 18–39, with the Pfizer-BioNTech vaccine also showing a higher risk in those aged 12–17 (Klein, 2021). Head-to-head comparisons suggested that the risk of myocarditis was greater after the Moderna compared to the Pfizer-BioNTech vaccine. The VaST assessment noted that safety data for the reduced 50-microgram Moderna booster dose were based on a small clinical trial and that the risk after this booster might be lower than that associated with the original, 100-microgram dose (Talbot and Hopkins, 2021). ACIP voted to recommend Pfizer-BioNTech and Moderna third doses to individuals 65+ years and those 18+ years who live in long-term care settings, have underlying medical conditions, or work or live in high-risk settings, all at least 6 months after completion of the primary series (CDC, 2021b). |
| Meeting Date | Summary |
|---|---|
| November 2, 2021 | Updated VAERS and VSD data regarding myocarditis in individuals aged 12+ were presented (Oster, 2021a). The plans to use safety monitoring systems to track myocarditis, along with VaST’s plan to review data for individuals aged 5–11 years, were also shared (Shimabukuro, 2021b). Key counseling points for HCPs regarding the risk in children aged 5–11 were highlighted: the benefits of vaccination outweigh the risks; individuals should seek medical care if they experience chest pain, shortness of breath, or elevated heart rate after an mRNA vaccine; no cases of myocarditis were reported in clinical trials for this age group; the risk is higher in adolescents aged 12–17 than in younger children; and the risk after mRNA vaccination is lower than that associated with COVID infection in adolescents and adults (Woodworth, 2021). It was discussed that the rate of myocarditis after vaccination in this age group was not yet known, but it was expected to be lower than in 12–15-year-olds due to the lower dose and observed epidemiologic differences in viral myocarditis between the two age groups (Oliver, 2021). ACIP recommended the Pfizer-BioNTech vaccine for all children ages 5–11, as a two-dose series of 10 micrograms each (CDC, 2024). |
| November 19, 2021 | The VST presented updated VAERS data on reports following booster doses (Shimabukuro, 2021a). There were 54 preliminary reports of myocarditis and myopericarditis, aligning with the recommended booster dose population (e.g., adults over 65). VaST assessment noted that the risk appeared lower after a booster dose of the Pfizer-BioNTech vaccine compared to dose two of the primary series based on data from Israel (Talbot and Hopkins, 2022c). There was insufficient data to assess the myocarditis risk following a Moderna booster dose. Accumulating evidence indicating a higher myocarditis risk after the Moderna primary series compared to Pfizer-BioNTech was noted; however, the Moderna booster was a lower dose than the primary series (50 micrograms vs. 100 micrograms). ACIP expanded the recommendation for a booster dose to all individuals ≥18 years (CDC, 2021a). |
| December 16, 2021 | ACIP heard updates on AEs being reported to VAERS and VSD in children aged 5–11 following the COVID vaccination primary series (Su, 2021a). Fourteen cases of myocarditis were reported to VAERS, eight of which had been verified, with no confirmed cases in VSD in the 7 and 21 days following vaccination. |
| Meeting Date | Summary |
|---|---|
| January 5, 2022 | VST presented updated VAERS and VSD data on myocarditis (ACIP, 2022b). As of December 19, 2021, VAERS had 265 confirmed myocarditis reports following Pfizer-BioNTech vaccine administration among children and adolescents ages 12–15 out of 18.7 million doses. There were 12 confirmed reports among children ages 5–11 out of 8.7 million doses and 13 preliminary reports of myocarditis following booster vaccination among adults 16–24 with approximately 1 million doses. VSD data continued to demonstrate an elevated risk of myocarditis in 12–17-year-olds in the 7 days following dose 2. The excess risk was 70 cases per million second doses compared to 0.3 cases per million first doses. Data from Israel on myocarditis reports after a third dose in children aged 12–15 years were also presented. No cases were reported with over 6,000 vaccine doses administered. ACIP voted to recommend a 30-microgram booster dose of the Pfizer-BioNTech vaccine in adolescents 12–17 years at least 5 months after completion of the primary series. |
| February 4, 2022 | Updated VAERS data on myocarditis following administration of the Moderna vaccine, along with findings from the VSD RCA and a head-to-head comparison of mRNA vaccines, were presented. As of January 13, 2022, 359 myocarditis cases that met the case definition had been reported to VAERS among individuals 18+ within 7 days after Moderna vaccination, out of 164 million doses (Shimabukuro, 2022b). The VSD analysis with vaccinated concurrent comparators continued to show both mRNA vaccines were associated with increased risk of myocarditis in 18–39-year-olds (Klein, 2022). A head-to-head comparison of the vaccines using VSD data provided evidence that the risk of myocarditis may be higher after the Moderna vaccine compared to the Pfizer-BioNTech. VaST reported that its evaluation of updated data did not indicate any safety concerns related to myocarditis following the Moderna vaccine in individuals 18+ years beyond those already recognized (Talbot and Hopkins, 2022a). |
| Meeting Date | Summary |
|---|---|
| April 20, 2022 | Updated data from VSD and VAERS on the safety of the first booster doses were presented (ACIP, 2022a). As of April 11, 2022, there were 100 cases of myocarditis in VAERS following a first mRNA COVID vaccine booster dose out of 93 million doses. Reporting rates were highest among male recipients ages 12–29, exceeding background rates but lower than those observed after the second dose of the primary series. The only safety signal noted after a first booster dose in VSD was myocarditis, primarily occurring within a week after a first booster dose in individuals aged 12–39. The VaST assessment was that the risk following a booster dose continued to appear lower than after the second dose of the primary series. |
| May 19, 2022 | VST updated ACIP on myocarditis reports following the Pfizer-BioNTech primary series in children aged 5–11 (Shimabukuro, 2022a). As of April 24, 2022, 20 verified cases were reported in VAERS, out of 18.1 million doses, primarily after the second dose. The VSD RCA did not detect a statistically significant safety signal. VaST concluded that the data did not indicate any safety concerns with the Pfizer-BioNTech booster dose for children aged 5–11 beyond those already identified in older age groups (Talbot and Hopkins, 2022b). ACIP voted in favor of recommending the booster dose for this age group (ACIP, 2022e). |
| June 17–18, 2022 | Representatives from Moderna and Pfizer presented updates on the effectiveness and safety of both mRNA COVID vaccines from clinical trials for young children (ACIP, 2022d). Myocarditis was not reported during clinical trials for either vaccine. The ACIP COVID-19 Work Group concluded that both the Moderna and Pfizer-BioNTech mRNA COVID vaccines for young children had favorable safety profiles, with common mild to moderate side effects similar to other routine childhood vaccines. ACIP voted to recommend the Moderna vaccine as a two-dose primary series of 25 micrograms per dose for children aged 6 months to 5 years and the Pfizer-BioNTech vaccine as a three-dose primary series of 3 micrograms per dose for children aged 6 months to 4 years. |
| Meeting Date | Summary |
|---|---|
| June 23, 2022 | VST presented updated data from VAERS and VSD on myocarditis in children and adolescents aged 6–11 and 12–17 following primary series vaccination with Pfizer-BioNTech (ACIP, 2022g). As of May 26, 2022, VAERS had 635 verified myocarditis reports among 5–17-year-olds out of 54.8 million doses. No safety signals were present in VSD for myocarditis in children aged 5–11; however, people ≥12 years had a statistically significant safety signal for both the primary series and booster doses. A head-to-head comparison of the two mRNA COVID vaccines in individuals aged 18–39 using VSD data provided evidence that the risk of myocarditis may be higher following the Moderna vaccine. The VaST assessment noted a risk of myocarditis after mRNA COVID vaccination in adolescents and adults, with ongoing evaluation and monitoring in children under 12. ACIP voted favorably to recommend the Moderna vaccine as a two-dose series of 50 micrograms per dose in children aged 6–11 and a two-dose series of 100 micrograms per dose in children and adolescents aged 12–17. |
| July 19, 2022 | VST gave an update on myocarditis following mRNA COVID vaccination in adults ≥18 years based on VAERS and VSD data (ACIP, 2022c). As of May 26, 2022, VAERS had 1,321 verified myocarditis reports in individuals 18+ after 491.9 million doses. Evidence continued to show consistent patterns with previously reported data: cases were most likely within the first week postvaccination, with the highest risk in male adolescents and young adults, particularly after the second dose of the primary series. |
| September 1, 2022 | VST presented on the safety of the primary series with a mRNA COVID vaccine in children ages 6 months to 5 years and the safety of mRNA COVID booster doses in people 5+ years (ACIP, 2022f). VAERS or VSD had no evidence of a higher risk of myocarditis in children aged 6 months to 5 years following their primary series. Data did show an increased risk of myocarditis following a first booster dose with a mRNA vaccine in people aged 5+, particularly among male adolescents and young adults. There were 131 reports of myocarditis in individuals aged 5+ after over 123 million booster doses. This safety signal was not significant for individuals aged 5–11. VAERS reports of myocarditis were lower after the first booster than after dose 2 of the primary series. In contrast, VSD found similar rates but with small case numbers, leading to wide confidence intervals and uncertainty. ACIP voted to recommend the Pfizer-BioNTech bivalent booster at a dose of 30 micrograms for individuals ≥12 years and Moderna bivalent booster at a dose of 50 micrograms in people ≥18 years. |
| Meeting Date | Summary |
|---|---|
| October 21, 2022 | VST provided an update on vaccine safety, which included myocarditis (ACIP, 2022h). Multiple monitoring systems continued to provide evidence of increased myocarditis risk among male adolescents and young adults within a few days following dose 2, including the VAERS, VSD, and Department of Defense systems. FDA data did not show a significant variation in risk between the Pfizer-BioNTech and Moderna vaccines. The VA system reported few cases of myocarditis, likely due to its older patient population. Canada, Israel, and other European countries were reporting similar findings regarding myocarditis risk. Canada and select countries in Northern Europe were observing greater myocarditis risk for the Moderna compared to the Pfizer-BioNTech vaccine. The VaST assessment found a slightly higher risk of myocarditis in men aged 18–29 after the Moderna primary series compared to the Pfizer-BioNTech series and highlighted the limited data available on myocarditis risk following Moderna booster doses. |
NOTES: This list was generated based on ACIP documentation archived on the CDC Stacks website and may not include information that was not preserved in the archive. ACIP = Advisory Committee on Immunization Practices; AE = adverse event; CDC = Centers for Disease Control and Prevention; FDA = Food and Drug Administration; RCA = rapid-cycle analysis; VA = Department of Veterans Affairs; VAERS = Vaccine Adverse Event Reporting System; VaST = Vaccine Safety Technical Work group; VSD = Vaccine Safety Datalink; VST = Vaccine Safety Team.
who filed a VAERS report between January 12, 2021, and November 5, 2021. Data collection occurred between August 24, 2021, and January 12, 2022. The study methodology included a two-component survey completed at least 90 days after myocarditis symptoms began. One component was completed by the patient or their guardian and the other by their HCP.
The study followed 519 patients (Kracalik et al., 2022). The median age was 17 years, and 88 percent were male. HCPs indicated that the majority (81 percent) were considered recovered, though 26 percent remained on daily medication related to myocarditis. Some patients reported ongoing issues, including depression (46 percent) and pain (30 percent), but overall quality-of-life scores were similar to prepandemic levels. Most cardiac diagnostic tests showed improvement, with a high percentage of patients returning to normal or baseline values. While 54 percent of follow-up cardiac MRIs showed abnormalities, only 13 percent had findings consistent with active myocarditis, and 68 percent were cleared for full physical activity.
ACIP received updates from VST on the follow-up study. Updates on enrollment and data collection were provided at the October 21, 2021,
meeting (Shimabukuro and ACIP, 2021). Preliminary data were reported at the February 4, 2022, meeting (Kracalik, 2022). ACIP was provided preliminary data specifically regarding patients aged 5–17 at the June 23, 2022, meeting (Shimabukuro, 2022e). The results of the HCP survey were presented at the July 19, 2022 meeting (Shimabukuro, 2022d). Final results were published in The Lancet in September 2022 (Kracalik et al., 2022). CDC also launched a webpage about the study in August 2021, including how people would be contacted to participate in the study and how the information would be used (NCIRD, 2021d).
Public Interest and Vaccine Confidence
ISO receives vaccine safety questions from HCPs, public health officials, and the public through multiple communication channels (Miller et al., 2023). Between December 1, 2020, and August 31, 2022, ISO received 1,655 inquiries about COVID vaccine safety; myocarditis was the second most common concern, accounting for 9 percent of inquiries. Inquiries on myocarditis were most commonly made by HCPs about the risk following vaccination across age cohorts and CDC’s benefit–risk assessment of myocarditis following vaccinations. Inquiries from the public were commonly requesting medical advice for treating myocarditis following vaccination.
CDC regularly published State of Vaccine Confidence Insights Reports throughout the COVID PHE, analyzing factors affecting U.S. vaccine uptake and hesitancy. These reports drew data from social media, web searches, media inquiries, polls, and scientific literature. The first report, covering January 24–February 6, 2021, was released on February 12, 2021. Myocarditis was first mentioned in a special report on June 14, 2021, following the authorization and recommendation of the Pfizer-BioNTech vaccine for adolescents aged 12–15. The report highlighted a surge in discussions on social and news media regarding COVID vaccination and myocarditis in adolescents. Parents raised concerns about vaccine safety, the risk of myocarditis compared to its general prevalence, its severity and long-term effects, and whether to proceed with the second dose. Myocarditis remained a recurring topic in these reports throughout the PHE as a factor influencing vaccine confidence and hesitancy, particularly for mRNA COVID vaccines for children and adults (CDC, 2021f,g,h,i, 2022a,b,c,e,f,g, 2023a).
TINNITUS CASE STUDY
Tinnitus is defined as “the perception of sound without an external source” (Tunkel et al., 2014). It is estimated that about one-quarter of the U.S. population experiences tinnitus at any given point in time. People with tinnitus often describe hearing ringing, buzzing, or clicking, among other
sounds, in one or both ears. It can be idiopathic, be associated with sensorineural hearing loss, or result from another system disorder, such as cochlear or vascular abnormalities. It is most prevalent in individuals with loud noise exposure. It can significantly impact quality of life and may result in insomnia, depression, or anxiety, among other psychiatric conditions.
Tinnitus was not reported as a postvaccination event for BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) in the U.S. clinical trial data used for initial EUA (Baden et al., 2021; Polack et al., 2020). It was reported in the clinical trial data for Ad26.COV2.S (Janssen) (Sadoff et al., 2021). It occurred in six participants in the vaccine group (out of 3,356 participants in the safety subpopulation) compared to zero participants in the placebo group. As a result, Janssen indicated that tinnitus would undergo postmarketing monitoring (Sadoff et al., 2021). Tinnitus was not designated as an AESI warranting proactive monitoring via the U.S. COVID vaccine safety monitoring systems (Gee et al., 2024). It has been reported with other vaccines, including the hepatitis, rabies, measles, and H1N1 vaccines (Harpaz et al., 2022).
Timeline of Events
VaST first reviewed tinnitus and hearing loss associated with COVID vaccines on November 14, 2022 (Markowitz et al., 2024) in response to public interest and concerns following reports of tinnitus in the Janssen vaccine trial. It reviewed data from VAERS and VSD. Reports of tinnitus were rare following Pfizer-BioNTech and Moderna vaccines, with 21.6 and 22.7 cases per million doses administered, respectively. The VSD analysis estimated an incidence of tinnitus per 10,000 person-years of 78, 107, and 85 following the Pfizer-BioNTech, Moderna, and Janssen vaccines, respectively, based on 140 days of follow-up after vaccination. These observed rates were all below the expected background incidence (approximately 116 cases per 10,000 person-years among the general population). VaST determined that, based on the data reviewed through the April 2023 meeting, no safety concerns were identified. Based on a review of summary minutes from public meetings available via the CDC archives website, tinnitus was not included in any VaST assessments presented to ACIP during the PHE.
In 2024, ISO participated in publication of a peer-reviewed study of tinnitus following COVID vaccine (Yih et al., 2024). The study used data from VAERS and VSD and showed no disproportionate reporting of tinnitus in either monitoring system for any vaccine using similar methods to those that had identified the myocarditis safety signal. Although the study did not find strong evidence of increased risk, researchers acknowledged limitations in adjusting for confounding factors, meaning a definitive conclusion could not be reached.
Public Interest and Vaccine Confidence
Between December 2020 and August 2022, approximately 2 percent (n = 28) of 1,655 inquiries about COVID vaccine safety received by ISO were about tinnitus (Miller et al., 2023). It made one appearance in the CDC State of Vaccine Confidence Insights Reports. Tinnitus It was identified as a new and emerging theme that may be affecting vaccine confidence in the June 10, 2022, edition reflecting the March 14–April 4, 2022, time frame. A World Health Organization Pharmaceuticals newsletter had recently highlighted that the Uppsala Monitoring Centre observed tinnitus after COVID vaccination frequently enough to merit further study (CDC, 2022h). There were 367 reported cases of post-vaccination tinnitus across 10 countries as of February 22, 2022 linked to the Pfizer/BioNTech, Moderna, and AstraZeneca vaccines (CDC, 2022h; WHO, 2022).
MENSTRUAL IRREGULARITIES CASE STUDY
Menstrual irregularities refer to disruptions in the menstrual cycle (NIH, 2017a) and affect approximately 14–25 percent of women (Whitaker and Critchley, 2016). The most common include missed or infrequent periods, heavy or prolonged bleeding, or severe cramps (NIH, 2017b). Menstruation is controlled by a complex balance of hormones, inflammation, and tissue changes (Wong et al., 2022). Since COVID vaccines can cause temporary inflammation, it is biologically plausible that they could briefly disrupt the menstrual cycle and trigger unexpected bleeding.
Menstrual irregularities were not identified as a postvaccination occurrence in the clinical trial data for the Pfizer-BioNTech, Moderna, or Janssen vaccines that supported their initial EUA (Baden et al., 2021; Polack et al., 2020; Sadoff et al., 2021). While vaccination during pregnancy and pregnancy outcomes were AESIs, menstrual irregularities was not predetermined to be an AE warranting proactive safety monitoring (Polack et al., 2020).
Timeline of Events
Reports of menstrual irregularities following COVID vaccination emerged in 2021 via social media and in the news (NIH, n.d.a). VaST reported reviewing outcomes related to menstrual irregularities or vaginal bleeding (Markowitz et al., 2024). The data reviewed were published as an observational cohort study in August 2022 (Markowitz et al., 2024; Wong et al., 2022) that identified 63,815 reports of menstrual irregularities or vaginal bleeding from 62,679 female respondents in V-safe from December 14, 2020 to January 9, 2022. These reports represented 1 percent of all female respondents ≥18 years in V-safe. Menstruation timing (83.6 percent) and menstrual system severity (67 percent) were most commonly reported.
A review of summary minutes from public meetings available on the CDC archives website found no mention of menstrual irregularities in any VaST assessments presented to ACIP during the PHE. During the ACIP meeting on September 1, 2022, menstrual irregularities was identified as a pregnancy and reproductive health outcome being monitored following COVID vaccination in the presentation by VST (Shimabukuro, 2022c); the slides did not include any additional information on menstrual irregularities.
CDC did release information to the public on its website about the impact of COVID vaccination on menstruation and reproductive health in 2021 and 2022 (NCIRD, 2021g, 2022a,b). The “Myths and Facts about COVID-19 Vaccines” webpage addressed the question, “Can being near someone who received a COVID-19 vaccine affect my menstrual cycle?” (NCIRD, 2021g) The “COVID-19 Vaccines for People Who Would Like to Have a Baby” webpage discussed the limited research on the impact of vaccination on the menstrual cycle, noting that while minor, temporary changes—such as variations in cycle length, intervals, and heavier bleeding—had been observed, no evidence suggested it affected fertility (NCIRD, 2022a). The “Frequently Asked Questions about COVID-19 Vaccination” webpage also answered the question, “Do COVID-19 vaccines affect your menstrual cycle?” (NCIRD, 2022b).
In May 2021, the National Institutes of Health (NIH) announced funding for research studies exploring potential links between the COVID vaccine and menstruation (NIH, n.d.b). In August of the same year, NIH announced the five institutions that received funding (NIH, 2021). Research published to date from this funding has found a link between COVID vaccination and small, temporary menstrual changes (Edelman et al., 2022; Ramaiyer et al., 2024). Two studies found an increase in menstrual cycle length (Edelman et al., 2022; Wesselink et al., 2023). A third study found a small increase in menses length (Ramaiyer et al., 2024).
Public Interest and Vaccine Confidence
About 1 percent of 1,666 COVID vaccine safety inquiries made to ISO between December 2020 and August 2022 were related to irregular menses (Miller et al., 2023). Menstrual irregularities first appeared in the CDC State of Vaccine Confidence Insights Report on April 28, 2021 (CDC, 2021c). Report #6 stated reports of “atypical menstruation” from women following COVID vaccination had “been co-opted and incorporated into misinformation narratives that warn of a link between COVID-19 vaccination and infertility.” Multiple reports in May 2021 highlighted growing concerns about the impact of COVID vaccination on menstrual cycles and social media, including “viral shedding,” whereby the menstrual cycle of unvaccinated individuals could be influenced through exposure to
vaccinated individuals (CDC, 2021d,e). The State of Vaccine Confidence Insight Reports consistently highlighted consumer concerns about menstrual changes, potential effects on fertility, and likely impact on vaccine hesitancy through mid-2022 (CDC, 2021g,i, 2022b,c,d, 2023a).
CHIKUNGUNYA VACCINE CASE STUDY
Chikungunya is a viral illness transmitted by mosquitoes (WHO, 2025). It was first detected in Tanzania in 1952 and later identified in various countries across Africa and Asia. Since 2024, outbreaks have become more frequent and widespread, largely due to viral mutations that have enhanced its ability to spread through Aedes albopictus mosquitoes. The disease has now been documented in 110 nations across Africa, Asia, Europe, and the Americas. It typically begins with a sudden fever, often accompanied by joint pain that can be debilitating. Although it is rarely fatal, some cases involve eye, heart, and neurological complications.
Between 2006 and 2013, an average of 28 U.S. cases per year were identified (WHO, 2025). The first local transmission in the Americas was recorded in the Caribbean in late 2013, leading to subsequent cases in the United States. It became a nationally notifiable disease in 2015. In 2024, 199 U.S. cases were reported, all travel associated; no locally acquired cases have been reported since 2019.
On November 9, 2023, FDA approved a live, attenuated vaccine (CHIK-LA) “for the prevention of disease caused by chikungunya virus in individuals 18 years of age and older who are at increased risk of exposure to chikungunya virus” under statutory provisions and regulations for accelerated approval (Kaslow, 2023). On February 28, 2024, ACIP recommended it “for persons aged ≥18 years traveling to a country or territory where there is a chikungunya outbreak” and “laboratory workers with potential for exposure to chikungunya virus” (ACIP, 2024). CHIK-LA vaccine is administered intramuscularly as a single dose (CDC, 2025b). Headache, fatigue, myalgia, arthralgia, injection-site pain, pyrexia, and nausea occurred in ≥10 percent of clinical trial participants (Schneider et al., 2023). Serious AEs identified during the Phase 3 clinical trial of adults were infections and infestations (0.3 percent of intervention participants); injury, poisoning, and procedural complications (0.3 percent); psychiatric disorders (0.2 percent); and cardiac disorders (0.2 percent). The vaccine package insert contains a warning for severe or prolonged chikungunya-like adverse reactions (FDA, n.d.).
Timeline of Events
In February 2025, CDC reported that five individuals aged 65+ were hospitalized with cardiac or neurological symptoms after recently receiving CHIK-LA vaccine (Howard, 2025; Twenter, 2025). On February 25, 2025, CDC posted an update to its webpage on the vaccine for HCPs (CDC, 2025b; Howard, 2025): “CDC is currently investigating five hospitalizations for cardiac or neurologic events following vaccination with [CHIK-LA] among people 65 years of age and older. This topic will be discussed at an upcoming meeting of ACIP. Health care providers should discuss the benefits and risks of vaccination with individual travelers based on their age, destination, trip duration, and planned activities.”
The ACIP meeting scheduled for February 26–28, 2025, was postponed “to accommodate public comment in advance of the meeting.” The rescheduled meeting occurred on April 15–16, 2025 (CDC, 2025a) and included a presentation on postlicensure surveillance for AEs following CHIK-LA based on data from VAERS by the Chikungunya Vaccines Work Group (Hills, 2025). VAERS had 28 AE reports from May through December 2024, including 22 nonserious and six serious events. Among the serious AEs, five resulted in hospitalization and one was an “other medically important event.”
The presentation included deidentified case summaries of the six serious AEs reported to VAERS (Hills, 2025), which all involved men aged 67–86 with comorbidities. All received CHIK-LA vaccine for upcoming travel. Three had received coadministered vaccines, either the inactive Japanese encephalitis or oral, live typhoid vaccines. Symptom onset began within 3–5 days following vaccine administration. Among the five individuals who were hospitalized, three were discharged with encephalopathy diagnoses, one with aseptic meningitis, and one with atrial flutter and non-ST segment elevation myocardial infarction. The sixth individual was not hospitalized but was diagnosed with worsened and prolonged hypotension with preexisting cardiomyopathy and hypotension by an internist.
The presentation described how the Clinical Immunization Safety Assessment (CISA) Project was consulted (Hills, 2025). For each report, at least one CISA expert assessed association of the serious AE and CHIK-LA vaccine. Several factors supported possible causality: events began 3–5 days after vaccination; association with other vaccines was less likely for the three patients with coadministration; clear alternate etiologies were not identified; discharge summaries of the five hospitalized patients noted potential association with vaccination; and laboratory testing resulted suggested an association with CHIK-LA vaccine for two patients.
The presentation also described how VAERS reports and IQVIA data were used to calculate risk estimates for serious AEs and hospitalizations
among persons 65+ (Hills, 2025). The analysis yielded an estimated rate of serious AEs of 82 per 100,000 doses or one serious AE per 1,220 doses and an estimated rate of hospitalization of 68 per 100,000 doses or one hospitalization per 1,471 doses.
The Chikungunya Vaccine Work Group’s assessment that being age 65+ should be a precaution for CHIK-LA vaccine (Hills, 2025). It proposed revising the ACIP recommendations for the use of the vaccine among travelers—specifically, by removing adults over 65 from the group for whom the vaccine may be considered when traveling to areas with chikungunya transmission within the last 5 years but no current outbreak. ACIP voted to accept this change to the chikungunya vaccine recommendations (BroadcastCDC, 2025).
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