Myocarditis is an inflammatory disorder of the heart muscle and pericarditis is inflammation of the pericardial layers. Myocarditis and pericarditis can be caused by variety of different infectious and non-infectious etiologies. Viruses are a common cause of both conditions. SARS-CoV-2 infection has been associated with myocarditis. As such, myocarditis and pericarditis are among a list of Adverse Events of Special Interest (AESIs) for COVID-19 vaccine surveillance among National Regulatory Authorities of many countries.
The Centers for Disease Control and Prevention (CDC) issued a report of the Advisory Committee on Immunization Practices (ACIP) COVID-19 Vaccine Safety Technical (VaST) Work Group on May 17, 2021, describing a review of myocarditis and pericarditis after COVID-19 vaccine in the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) – two of CDC’s vaccine safety surveillance systems – and the Department of Defense (DoD) vaccine safety surveillance system. The VaST reported relatively few reports of myocarditis to date and the cases seemed to occur predominately in adolescents and young adults, more often in males than females and after the 2nd rather than 1st dose, and typically within 4 days after vaccination. Additionally, among CDC safety monitoring systems reported rates of myocarditis following COVID-19 vaccination, observed rates of myocarditis and pericarditis were not higher than expected baseline rates. A second VaST report was released by CDC on May 23, 2021, indicating that data from VAERS showed in the 30-day post Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines window there was a higher number of observed than expected cases of myocarditis/pericarditis among 16-24 year-olds.
CDC presented an update to the Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) on June 10, 2021, including 216 myocarditis and pericarditis VAERS reports after dose 1 and 573 myocarditis and pericarditis VAERS reports after dose 2 among persons receiving the Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines. Among these cases, the median age was 30 for dose 1 and 24 for dose 2, with the median time to symptom onset 3 days for dose 1 and 2 days for dose 2, and 65% among males for dose 1 and 79% among males for dose 2. Among persons aged 12-15, 16-17 and 18-24 the observed cases (which suffers from under-reporting) was higher than the expected number of cases based upon population-based background rates published in the literature. Early VSD analyses suggested more cases after dose 2 vs. dose 1 with a rate of about 16 cases per million 2nd doses. COVID 19 disease caused by the SARS-CoV-2 virus is known to cause myocarditis at a rate much higher than the rates reported following mRNA vaccines and the infections cause many other ser. CDC continues to recommend these vaccines for all eligible persons.
CDC and the COVID-19 VaST) Work Group provided an update to the ACIP on June 23, 2021. Myocarditis/pericarditis among persons receiving the Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines were reported from VAERS and the VSD.
As of June 11, 2021, VAERS had received reports of 267 myocarditis/pericarditis cases following the first doses of mRNA COVID-19 vaccines and 827 reported cases following the second dose of mRNA vaccines. Among cases after the first dose, median age was 30 and 66% were male; median age was 24 and 79% were male in the cases that occurred after the second dose. Most cases after the first and second dose were within 5 days after vaccination. Among 484 reports in persons younger than 29 years of age, 323 met a standardized case definition, 309 were hospitalized, 295 were discharged from the hospital, 218 were known to have recovered from symptoms, 9 were still hospitalized (2 in the ICU), 14 were not hospitalized, and outcomes were not available for 6 persons. The number of cases occurring 7 days after vaccine receipt reported to VAERS was higher than would be expected for males based on the rates of myocarditis/pericarditis published in the literature for persons 12-29 years of age after the first dose, and higher for persons 12-49 for males and age 12-29 among females after the second dose. The reporting rate of myocarditis/pericarditis by dose, gender and age group per million doses administered is provided in table presented to the ACIP below. However, VAERS suffers from under-reporting so we do not know the true number of cases occurring after vaccination but rather the number reported to VAERS (reported rate).
The VSD had captured about 4.6 million doses of Moderna vaccine and about 5.8 million doses of Pfizer-BioNTech vaccine, including about 243,000 first and second doses among 12-15 year-olds and about 230,000 first and second doses among 16-17 year olds. Chart confirmed myocarditis/pericarditis cases in 12-39 year olds and adjusted rate ratios in the 7 days after vaccinated are provided in the table presented to the ACIP below.
Translating these risk ratios into the risk attributable to vaccination, resulted in 2.6 (first dose) and 8.0 (second dose) cases per million doses (21 days risk window) for 12-39 years olds of both genders after the Pfizer-BioNtech vaccine and 7.5 (first dose) and 19.8 (second dose) cases per million doses (21 days risk window) for 12-39 years olds of both genders after the Moderna vaccine. As can be seen in the table presented to the ACIP below, the risk of myocarditis/pericarditis was highest among males aged 12-39 years after the second dose of Moderna vaccine (47.7 cases per million vaccines or 1 case per 21,000 vaccinees).
The COVID-19 VaST Work Group reported “the risk of myocarditis/pericarditis following mRNA vaccination in adolescents and young adults aged 12-39 years is notably higher after dose 2 and in males”. The VaST also noted that the ICD10 rates in VSD among males were similar to the crude reporting rates among males in VAERS.
The CDC considered the benefits-risks for two doses vs. no doses of mRNA vaccines among adolescents and young adults. The CDC concluded the benefits of vaccination outweigh the risks based upon the scientific literature and CDC data regarding burden of COVID-19, efficacy of COVID-19 mRNA vaccines, and VAERS reporting rates of myocarditis/pericarditis following mRNA vaccination. As the figure presented to the ACIP below illustrates, the benefits for two doses versus no doses of mRNA vaccines are greater than the reported rates of myocarditis/pericarditis to VAERS, even for males 12-17 years who are the highest risk group.
CDC and the COVID-19 VaST Work Group provided another update to the ACIP on October 21, 2021. VSD data showed a signal for myocarditis/pericarditis in the 21 days after both doses of both mRNA vaccines, and suggested more than double the risk of myocarditis (adjusted rate ratio: 2.26) in 18-39 year old males comparing Moderna to Pfizer-BioNTech vaccine.
As presented to the ACIP on November 2, 2021, data from the VSD (as of October 23rd, 2021) estimated a rate of 108.5 per million second doses of Pfizer-BioNTech vaccine administered to adolescent males 12-15 years of age.
As presented to the ACIP on November 19, 2021, 25.9 million mRNA and 334 thousand Janssen vaccine booster doses had been administered between September 22 and November 5, 2021. During this time period, there were 12 reports to VAERS of myocarditis/myopericarditis following booster doses that met the CDC case definition. All 12 were after mRNA vaccines. Most booster dose recipients during this time were older adults, so more cases are likely to be reported especially as more younger persons receive booster doses. Initial estimates of the risk of myocarditis following a booster dose of Pfizer-BioNTech vaccine appeared lower than after dose 2. Limited data were available to assess risk of myocarditis after a booster dose of Moderna vaccine at this time.
The CDC continues to update their interim clinical considerations for COVID-19 vaccines to include the latest information and guidance about myocarditis.
On June 2, 2021, the Israeli Ministry of Health issued a press release indicating an extended epidemiological team had been appointed to investigate myocarditis following Pfizer-BioNTech COVID-19 vaccination. This report describes 275 cases of myocarditis after COVID-19 vaccine reported between December 2020 and May 2021, more frequently after the 2nd dose than the 1st dose and mostly among younger men aged 16-19. The majority of cases (95%) were considered to be mild. Secondary reporting from news agencies reported about 1 case of myocarditis in 5,000 men vaccinated and 1 in 3-6,000 among men ages 16-24 years of age.
A peer reviewed publication analyzing data from the largest health care organization in Israel identified 54 cases of myocarditis among the more than 2.5 million persons receiving Pfizer-BioNTech vaccine, most of which were mild or moderate in severity; the rate of myocarditis was highest among males 16-29 years of age (10.69 cases per 100,000 persons; 95% CI: 6.93-14.46). Israeli MOH data updated through September 25 2021 and specifying rates of myocarditis after COVID-19 vaccination by age and sex were presented to the VRBPAC and are shown below.
European Medicine Agency
The European Medicine Agency (EMA) provided highlights form a Pharmacovigilance Risk Assessment Committee (PRAC) on July 9, 2021. The PRAC has concluded that “myocarditis and pericarditis can occur in very rare cases following vaccination with Comirnaty [mRNA vaccine by BioNtech] and Spikevax (previously COVID-19 Vaccine Moderna).” They recommended warnings be placed in the label of both products.
World Health Organization
The WHO Global Advisory committee on Vaccine Safety (GACVS) has reviewed the safety information regarding myocarditis after mRNA vaccine. They also concluded that the “benefits of mRNA COVID-19 vaccines outweigh the risks in reducing hospitalizations and deaths due to COVID-19 infections.”