Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices — United States, June 2021

In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine and the Moderna COVID-19 (mRNA-1273) vaccine,† and the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for their use in persons aged ≥16 years and ≥18 years, respectively.§ In May 2021, FDA expanded the EUA for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12-15 years; ACIP recommends that all persons aged ≥12 years receive a COVID-19 vaccine. Both Pfizer-BioNTech and Moderna vaccines are mRNA vaccines encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. Both mRNA vaccines were authorized and recommended as a 2-dose schedule, with second doses administered 21 days (Pfizer-BioNTech) or 28 days (Moderna) after the first dose. After reports of myocarditis and pericarditis in mRNA vaccine recipients,¶ which predominantly occurred in young males after the second dose, an ACIP meeting was rapidly convened to review reported cases of myocarditis and pericarditis and discuss the benefits and risks of mRNA COVID-19 vaccination in the United States. Myocarditis is an inflammation of the heart muscle; if it is accompanied by pericarditis, an inflammation of the thin tissue surrounding the heart (the pericardium), it is referred to as myopericarditis. Hereafter, myocarditis is used to refer to myocarditis, pericarditis, or myopericarditis. On June 23, 2021, after reviewing available evidence including that for risks of myocarditis, ACIP determined that 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. The EUA has been modified to include information on myocarditis after receipt of mRNA COVID-19 vaccines. The EUA fact sheets should be provided before vaccination; in addition, CDC has developed patient and provider education materials about the possibility of myocarditis and symptoms of concern, to ensure prompt recognition and management of myocarditis.

In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine and the Moderna COVID-19 (mRNA-1273) vaccine, † and the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for their use in persons aged ≥16 years and ≥18 years, respectively. § In May 2021, FDA expanded the EUA for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12-15 years; ACIP recommends that all persons aged ≥12 years receive a COVID-19 vaccine. Both Pfizer-BioNTech and Moderna vaccines are mRNA vaccines encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. Both mRNA vaccines were authorized and recommended as a 2-dose schedule, with second doses administered 21 days (Pfizer-BioNTech) or 28 days (Moderna) after the first dose. After reports of myocarditis and pericarditis in mRNA vaccine recipients, ¶ which predominantly occurred in young males after the second dose, an ACIP meeting was rapidly convened to review reported cases of myocarditis and pericarditis and discuss the benefits and risks of mRNA COVID-19 vaccination in the United States. Myocarditis is an inflammation of the heart muscle; if it is accompanied by pericarditis, an inflammation of the thin tissue surrounding the heart (the * These authors contributed equally to this work. † All EUA documents for COVID-19 vaccines, including fact sheets, are available at https://www.fda.gov/emergency-preparedness-and-response/coronavirusdisease-2019-covid-19/covid-19-vaccines. § ACIP recommendations for all COVID-19 vaccines are available at https:// www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. ¶ COVID-19 Vaccine Safety Technical Work Group Reports are available at https://www.cdc.gov/vaccines/acip/work-groups-vast/index.html. pericardium), it is referred to as myopericarditis. Hereafter, myocarditis is used to refer to myocarditis, pericarditis, or myopericarditis. On June 23, 2021, after reviewing available evidence including that for risks of myocarditis, ACIP determined that 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. The EUA has been modified to include information on myocarditis after receipt of mRNA COVID-19 vaccines. The EUA fact sheets should be provided before vaccination; in addition, CDC has developed patient and provider education materials about the possibility of myocarditis and symptoms of concern, to ensure prompt recognition and management of myocarditis.
Since June 2020, ACIP has convened 15 public meetings to review data on COVID-19 epidemiology and use of COVID-19 vaccines. The ACIP COVID-19 Vaccines Work Group, comprising experts in infectious diseases, vaccinology, vaccine safety, public health, and ethics, has held weekly meetings since April 2020 to review COVID-19 surveillance data, evidence for vaccine efficacy and safety, and implementation considerations for COVID-19 vaccination programs. After reports of myocarditis, the work group met twice to review clinical trial and postauthorization safety data for myocarditis after receipt of mRNA COVID-19 vaccines. The work group also reviewed a benefit-risk assessment of myocarditis events after receipt of mRNA COVID-19 vaccines, considering recent epidemiology of COVID-19 and sequelae of COVID-19, including myocarditis and multisystem inflammatory syndrome in children (MIS-C).** The ACIP COVID-19 Vaccines ** https://www.cdc.gov/mis/hcp/index.html Safety Technical (VaST) Work Group, comprising independent vaccine safety expert consultants, had also reviewed safety data on myocarditis after receipt of mRNA COVID-19 vaccines at its weekly meetings. The findings from the VaST and the ACIP COVID-19 Vaccines Work Group assessments, including a summary of the data reviewed, were presented to ACIP during its meeting on June 23, 2021.
Myocarditis typically occurs more commonly in males than in females, and incidence is highest among infants, adolescents, and young adults (1,2). The clinical presentation and severity of myocarditis vary among patients. Symptoms typically include chest pain, dyspnea, or palpitations, although other symptoms might be present, especially in younger children (3). Diagnostic evaluation might reveal an elevated troponin level or abnormal findings on electrocardiogram, echocardiogram, or cardiac magnetic resonance imaging (Table 1). Supportive therapy is a mainstay of treatment, with targeted cardiac medications or interventions as needed. Current guidelines from the American Heart Association and American College of Cardiology recommend exercise restriction until the heart recovers. † † As of June 11, 2021, approximately 296 million doses of mRNA COVID-19 vaccines had been administered in the United States, with 52 million administered to persons aged 12-29 years; of these, 30 million were first and 22 million were second doses. Within the Vaccine Adverse Event Reporting System (VAERS) (4), the national vaccine safety passive monitoring system, 1,226 reports of myocarditis after mRNA vaccination were received during December 29, 2020-June 11, 2021. Among persons with reported myocarditis after mRNA vaccination, the median age was 26 years (range = 12-94 years), with median symptom onset interval of 3 days after vaccination (range = 0-179). Among 1,194 reports for which patient age was known, 687 were among persons aged <30 years and 507 were among persons aged ≥30 years; of 1,212 with sex reported, 923 were male, and 289 were female. § § Among 1,094 patients with number of vaccine doses received reported, 76% occurred after receipt of dose 2 of mRNA vaccine; cases were reported after both Pfizer-BioNTech and Moderna vaccines. Informed by early reports, CDC prioritized rapid review of myocarditis in persons aged <30 years reported during May 1-June 11, 2021; the 484 patient records in this subset were evaluated by physicians at CDC, and several reports were also reviewed with Clinical Immunization Safety Assessment Project investigators, ¶ ¶ including cardiologists. At the time of this report, 323 of these 484 cases were determined to meet † † https://www.ahajournals.org/doi/10.1161/CIR.0000000000000239?url_ ver = Z39.88-2003&rfr_id = ori:rid:crossref.org&rfr_dat = cr_pub%20%20 0pubmed#d3e785 § § Age was not reported for 32 patients, and sex was not reported for 14 patients. ¶ ¶ https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html Using myocarditis cases reported to VAERS with onset within 7 days after dose 2 of an mRNA vaccine, crude reporting rates (i.e., using confirmed and unconfirmed cases) per million second dose recipients were calculated using national COVID-19 vaccine administration data as of June 11, 2021. Myocarditis reporting rates were 40.6 cases per million second doses of mRNA COVID-19 vaccines administered to males aged 12−29 years and 2.4 per million second doses administered to males aged ≥30 years; reporting rates among females in these age groups were 4.2 and 1.0 per million second doses, respectively.*** The highest reporting rates were among males aged 12−17 years and those aged 18−24 years (62.8 and 50.5 reported myocarditis cases per million second doses of mRNA COVID-19 vaccine administered, respectively). Myocarditis rates from Vaccine Safety Datalink (VSD), based on electronic health records, were also evaluated. Although numbers were too small to show rates in all subgroups by age, VSD data indicated increased risk of myocarditis in the 7 days after receipt of dose 1 or dose 2 of an mRNA COVID-19 vaccine compared with the risk 22-42 days after the second dose, particularly among younger males after dose 2 (5).
To assess the benefit-risk balance of mRNA vaccines in adolescents and young adults, ACIP reviewed an individuallevel assessment that compared the benefits (i.e., COVID-19 infections and severe disease prevented) to the risks (number of cases of myocarditis) of vaccination, using methods similar to those described previously. † † † Specifically, the benefits per million second doses administered (i.e., the benefits of being fully vaccinated in accordance with the FDA EUA) were assessed, including 1) COVID-19 cases prevented based on *** Data collection for race/ethnicity of myocarditis cases is ongoing. † † † https://www.cdc.gov/vaccines/covid-19/info-by-product/janssen/riskbenefit-analysis.html rates the week of May 29, 2021 § § § ; 2) COVID-19 hospitalizations prevented based on rates the week of May 22, 2021 ¶ ¶ ¶ ; and 3) COVID-19 intensive care unit (ICU) admissions and deaths prevented based on the proportion of hospitalized patients who were admitted to the ICU or died.**** The risks were assessed as the number of myocarditis patients reported to VAERS that occurred within 7 days of receipt of a second dose of an mRNA COVID-19 vaccine per million second doses administered through the week of June 11, 2021. † † † † The benefit-risk assessment was stratified by age group and sex. The analysis assumed 95% vaccine effectiveness § § § § of 2 doses of a mRNA COVID-19 vaccine in preventing COVID-19 cases and hospitalization and assessed outcomes for a 120-day period. The 120-day period was selected because 1) no alternative vaccine options currently exist for persons aged <18 years or are expected to be available during this period, and 2) inputs regarding community transmission have high uncertainty beyond this period, particularly in the context of circulating variants. ¶ ¶ ¶ ¶ The benefits (prevention of COVID-19 disease and associated hospitalizations, ICU admissions, and deaths) outweighed the risks (expected myocarditis cases after vaccination) in all populations for which vaccination has been recommended. However, the balance of benefits and risks varied by age and sex because cases of myocarditis were primarily identified among males aged <30 years, and the risks of poor outcomes related to COVID-19 increase with age. Per million second doses of mRNA COVID-19 vaccine administered to males aged 12-29 years, 11,000 COVID-19 cases, 560 hospitalizations, 138 ICU admissions, and six deaths due to COVID-19 could be prevented, compared with 39-47 expected myocarditis cases after COVID-19 vaccination ( Table 2). Among males aged ≥30 years, 15,300 COVID-19 cases, 4,598 hospitalizations, 1,242 ICU admissions, and 700 deaths could be prevented, compared with three to four expected myocarditis cases after COVID-19 vaccination. This analysis did not include the potential benefit of preventing post-COVID-19 conditions, such as prolonged symptoms and MIS-C (6,7). § § § https://covid.cdc.gov/covid-data-tracker/#demographicsovertime. Data were used for the most recent week not subject to reporting delays prior to the ACIP meeting. ¶ ¶ ¶ https://gis.cdc.gov/grasp/COVIDNet/COVID19_3.html. Data were used for the most recent week not subject to reporting delays prior to the ACIP meeting. **** https://gis.cdc.gov/grasp/COVIDNet/COVID19_5.html † † † † Because of uncertainty in the accuracy of myocarditis reporting, given that reviews are ongoing, and some cases might not have been reported yet, myocarditis reporting rates are presented as a range of values, calculated as ±10% of the observed reporting rates. § § § § https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fullyvaccinated-people.html ¶ ¶ ¶ ¶ https://covid.cdc.gov/covid-data-tracker/#variant-proportions

TABLE 2. Individual-level estimated number of COVID-19 cases and COVID-19-associated hospitalizations, intensive care unit admissions, and deaths prevented after use of 2-dose mRNA COVID-19 vaccine for 120 days and number of myocarditis cases expected per million second mRNA vaccine doses administered, by sex and age group* -United States, 2021
Sex/Benefits and harms from mRNA vaccination ACIP also reviewed population-level considerations regarding vaccination. No alternatives to mRNA COVID-19 vaccines for adolescents will be available for the foreseeable future, and vaccination of adolescents offers protection against COVID-19 that can be important for returning to educational, social, and extracurricular activities. Higher levels of vaccination coverage can reduce community transmission, which can protect against development and circulation of emerging variants. Regarding health equity considerations, racial and ethnic minority groups have higher rates of COVID-19 and severe disease*****; potential changes in vaccine policy, or anything that would affect vaccination coverage for adolescents or young adults, might disproportionately affect those groups with the highest rates of poor COVID-19 outcomes.

No. per million vaccine doses administered in each age group (yrs) †
The ACIP discussion concluded that 1) the benefits of vaccinating all recommended age groups with mRNA COVID-19 vaccine clearly outweigh the risks of vaccination, including the risk of myocarditis after vaccination; 2) continuing to monitor outcomes of myocarditis cases after COVID-19 vaccination is important; and 3) providers and the public should be informed about these myocarditis cases and the use of COVID-19 vaccines. Based on ACIP's conclusion regarding the benefit-risk assessment on June 23, 2021, COVID-19 vaccination continues to be recommended for all persons aged ≥12 years under the FDA's EUA. ACIP emphasized the importance of informing ***** https://covid.cdc.gov/covid-data-tracker/#demographics vaccination providers and the public about the benefits and the risks, including the risk for myocarditis after COVID-19 vaccination, particularly for males aged 12-29 years.
CDC has provided guidance regarding evaluation and management of myocarditis after mRNA COVID-19 vaccine (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html), as well as considerations for a second vaccine dose in persons who develop myocarditis after a first dose (https://www.cdc.gov/vaccines/covid-19/ info-by-product/clinical-considerations.html). FDA has added information to the Pfizer-BioNTech † † † † † and Moderna § § § § § COVID-19 vaccine EUA and fact sheets regarding myocarditis cases that have been reported among vaccine recipients. In addition, CDC has updated patient education and communication materials reflecting this information for the Pfizer-BioNTech ¶ ¶ ¶ ¶ ¶ and Moderna****** COVID-19 vaccines; these are important to ensure that vaccine recipients, especially males aged 12-29 years, are aware of increased risk for myocarditis and to seek care if they develop symptoms of myocarditis. The vaccine product-specific EUA fact sheet should be provided to all vaccine recipients and their caregivers before vaccination with any authorized COVID-19 vaccine. † † † † † https://www.fda.gov/media/144413/download § § § § § https://www.fda.gov/media/144637/download ¶ ¶ ¶ ¶ ¶ https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/index.html ****** https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/index.html CDC and FDA will continue to closely monitor reports of myocarditis after receipt of the mRNA COVID-19 vaccines and will bring any additional data to ACIP for consideration. The benefit-risk analysis can be updated as needed to reflect changes in the COVID-19 pandemic and additional information on the risk for and outcomes of myocarditis after COVID-19 vaccination. The ACIP recommendation for use of mRNA COVID-19 vaccines under an EUA is interim and will be updated as additional information becomes available.

Reporting of Vaccine Adverse Events
FDA requires that vaccine providers report to VAERS vaccination administration errors, serious adverse events, † † † † † † cases of multisystem inflammatory syndrome, and cases of COVID-19 that result in hospitalization or death after administration of a COVID-19 vaccine under an EUA. CDC also encourages reporting of any additional clinically significant adverse event, even if it is not clear whether a vaccination caused the event. Information on how to submit a report to VAERS is available at https://vaers.hhs.gov/index.html or 1-800-822-7967. In addition, CDC has developed a voluntary smartphone-based online tool (v-safe) that uses text messaging and online surveys to provide near real-time health check-ins after receipt of a COVID-19 vaccine. In cases of v-safe reports that include possible medically attended health events, CDC's v-safe call center follows up with the vaccine recipient to collect additional information for completion of a VAERS report. Information on v-safe is available at https://www.cdc.gov/vsafe.