Large-scale COVID-19 vaccination using mRNA technology revealed a small but real risk of vaccine-associated myocarditis (VAM). Presenting at rates of less than 4 per 100,000 in the general population, the incidence of VAM was too small to be detected in the vaccine safety and efficacy trials. Large-scale epidemiological and adverse event studies, conducted in multiple countries and using a variety of methodological approaches, have better characterized this risk according to vaccine type and subpopulation. Of particular note, VAM is most common among adolescent and young males between the ages of 12 and 24 years, with rates as high as 10.7 per 100,000. The clinical course of VAM is generally mild in both pediatric and adult populations.

While the benefits and risks of COVID vaccination are well-reported, this summary is intended to place the most recent COVID vaccine research in context, particularly the rates of VAM adverse events in comparison to COVID-associated hospitalization, myocarditis, multi-inflammatory syndrome in children (MIS-C), and death. This summary is not a formal meta-analysis but rather a topline review of the current published evidence.

What is the risk of vaccine-associated myocarditis?

Accurately quantifying VAM risk at the cases-per-million rate remains difficult, particularly given that VAM risk in the general population can be as low as 0.0006% for the commonly administered Pfizer-BioNTech vaccine.¹ In June 2021 the U.S. Centers for Disease Control and Prevention (CDC) estimated a VAM rate of 32.4 per million for all doses and 66.7 per million after the second dose of mRNA vaccine in males between the ages of 12 and 17 years based on then-available data from the vaccine adverse events reporting system (VAERS). VAM rates declined significantly with increasing age and were substantially lower for females of all ages.²

These data were used for official decision-making during CDC's Advisory Committee on Immunization Practices on June 23, 2021, and were later published by Bozkurt, et al.³ Five recently released peer-reviewed or preprint studies from Israel, Denmark, the U.S., the United Kingdom and Hong Kong collectively enable a more confident characterization of risk, largely confirming early CDC estimates. (Risk reporting as cases per million or cases per 100,000 is consistent with that used in the cited paper.)

• Witberg, et al., find a VAM rate of 2.13 per 100,000 in the general population and 10.69 in the 16-29-year-old population in a study of 2.5 million vaccinated Israelis.⁴
• In a preprint study from the U.K. on more than 42 million vaccinated Britons, including over 10 million receiving a third dose, Patone, et al., found:¹
  • In the general population, 2 excess cases of myocarditis per million for each dose of Pfizer-BioNTech, including booster doses. The Moderna vaccine was associated with 36 excess myocarditis cases per million after the second dose.
  • In males younger than 40 years, a cumulative 28 cases per million across 3 doses of Pfizer-BioNTech and 113 cases across 2 doses of Moderna.
  • ChADOx1, an adenoviral vector vaccine, was associated with 1 excess myocarditis case per million in the general population and 14 cases per million in the under-40 male population.
• According to Gellad, a comprehensive study of VAM in Denmark suggested similar rates of VAM in the general population, with 1.4 cases per 100,000 for Pfizer-BioNTech and 4.2 cases per 100,000 for Moderna; interestingly, in the male population between 12 and 39 years of age the rate was only 1.8 per 100,000.⁵
• In a comprehensive analysis of 1,626 myocarditis cases in the U.S. VAERS, Oster, et al., concluded the highest rates of VAM are concentrated in young males, as follows:⁶
  • 70.6 per million in males 12-15 years
  • 105.9 per million in males 16-17 years
  • 52.4 per million for Pfizer-BioNTech and 56.3 million for Moderna per million in males 18-24 years.
• A small, published abstract by Chua, et al., found much higher VAM rates in Hong Kong among all 12-17-year-old adolescents at 18.5 per 100,000, rising to 37.2 per 100,000 for males of the same age; it should be noted that this study only includes 33 cases of confirmed myocarditis.⁷

Although this review does not attempt to directly compare these studies due to the different approaches to detecting and classifying VAM, the varying age cutoffs used in subpopulation analysis, and the methodological differences in calculating excess vs. absolute myocarditis risk, the totality of the evidence is reassuring.

Across nearly 250,000,000 million patients studied on three continents, the individual risk of VAM in the general population is between 0.002% and 0.004%, depending on vaccine. Even among the highest risk subpopulation of teenage males, the individual risk of VAM is approximately 0.011%.

The studies surveyed here consistently report a mild-to-moderate clinical course for VAM, with 87% of symptoms resolving prior to hospital discharge on a common treatment of nonsteroidal anti-inflammatory drugs.⁶ In the largest case review to date, Kohli, et al., report "excellent short-term outcomes" among 465 adolescent VAM cases treated at 57 major pediatric hospitals, with only a single case experiencing life-threatening complications.⁸

How should VAM risk be interpreted in the context of vaccine protection against COVID-19 risk?

While VAM is a rare but real side effect of mRNA COVID vaccines across all ages, it is necessary to place these risks in the context of the risk from COVID infection itself. A study by Patone, et al., of the U.K. population concluded that the rate of COVID-associated myocarditis with 28 days of exposure was 30 cases per million for the general population, rising as high as 73 cases per million in males older than age 40.¹ This suggests the rate of COVID-associated myocarditis alone matches or well exceeds the rate of VAM in most populations. The one exception is younger males. Particularly during the mid-teenage years, VAM risk appears to significantly exceed the rate of post-infection myocarditis of 7 cases per million.¹ Nonetheless, when balanced against a small but measurable mortality rate of SARS-CoV-2 infection (0.1-1 per 100,000 in young adults ages 12-29¹), as well as risk of hospitalization, the overall benefit of the vaccine outweighs the risk of contracting VAM. In an analysis by Gargano, et al., for every 39-47 cases of VAM in vaccinated men between the ages of 12 and 29 years, approximately 11,000 COVID-19 cases, 560 hospitalizations, 138 ICU admissions and 6 deaths could be prevented.⁹

Recent research has identified additional benefits to vaccination in preventing MIS-C. MIS-C occurs at a rate of 316 per 1 million cases of SARS-CoV-2, presenting within 2-6 weeks post infection.¹⁰ It can occur in COVID infection of any severity, including mild or asymptomatic. Over 30% of MIS-C cases occur between the ages of 12 and 20 years, and most of the balance in children between the ages of 5 and 11 years.¹¹ According to the CDC, 61% of cases are male.¹¹ MIS-C frequently results in an extended hospitalization with high percentages of patients requiring intensive care and advanced life support, a stark contrast to the generally mild course of most VAM. Zambrano, et al., recently demonstrated the Pfizer-BioNTech mRNA vaccination is 91% effective against MIS-C in children between the ages of 12 and 18 years and additionally protective against the most severe clinical courses of the syndrome.¹² In their study, 95% of all children hospitalized with MIS-C were unvaccinated and no vaccinated child required life support. This finding was confirmed by additional research published in JAMA from a French population.¹³

Does the omicron era change the risk-benefit calculation regarding VAM?

The rise of the omicron variant and its enhanced immune escape from both natural and vaccine-acquired immunity should prompt open-minded evaluation of whether the pre-omicron benefit-to-risk equation continues to hold in populations with the highest vaccine adverse event rate, particularly adolescent males. Specifically, some parents are reasonably asking whether the added protection of a mRNA booster shot still exceeds the potential risk of VAM in their teenage children.

A series of recently published studies now enable a more precise quantification of the risk-benefit ratio in the omicron era, concluding that mRNA vaccination, especially when boosted with a third dose, remains highly effectively against severe COVID, hospitalization, and death, though symptomatic breakthroughs are more common than with prior variants.¹⁴ According to Thompson. et al., mRNA boosters are 82% effective against urgent care and emergency department visits and 90% effective against hospitalization.¹⁵ This represents a doubling in protection against urgent care and emergency department visits and up to a 50% increase in protection against hospitalization vs. non-boosted populations. Accorsi, et al., further find that boosters are associated with a 66% reduction in symptomatic COVID infection vs. a standard two-dose mRNA regimen.¹⁶ Boosters afforded additional protection against severe illness from both omicron and delta variants, with likely greater effectiveness against delta.

Conclusion

VAM is a rare but real side effect of mRNA vaccination against COVID-19. Large-scale observational studies on hundreds of millions of vaccine recipients across 3 continents have identified the highest risk of VAM in adolescent males, with rates as high as 107 cases per million in the teenage years. Across the general population, in comparison, COVID-associated myocarditis is likely greater than VAM, though VAM exceeds COVID-associated myocarditis for adolescent males. The clinical course of VAM is generally mild, with most symptoms resolving prior to hospital discharge. Even in the adolescent male population, the entirety of the protective effect of COVID vaccination, particularly in preventing severe COVID, hospitalization, MIS-C, and death, continues to clearly exceed the risk of VAM. Specific data are not yet available regarding the risk-benefit and timing considerations of a booster dose for adolescent males.¹⁷

References

1. Patone M, Mei XW, Handunnetthi L, et al. Risk of myocarditis following sequential COVID-19 vaccinations by age and sex. medRxiv. Published online December 25, 2021. doi:10.1101/2021.12.23.21268276.
2. Daley M, Oster M, Shimabukuro T, Lee G, Wallace M, Oliver S. Coronavirus disease 2019 (COVID-19) vaccines. Presented at: CDC Advisory Committee on Immunization Practices; June 23, 2021. https://www.cdc.gov/vaccines/acip/meetings/slides-2021-06.html. Accessed July 6, 2021.
3. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with COVID-19 mRNA vaccines. Circulation. 2021;144(6):471-484. doi:10.1161/circulationaha.121.056135.
4. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med. 2021;385(23). doi:10.1056/nejmoa2110737.
   
5. Gellad WF. Myocarditis after vaccination against COVID-19. BMJ. 2021;375(8319):n3090. doi:10.1136/bmj.n3090.
6. Oster ME, Shay DK, Su JR, et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the U.S. from December 2020 to August 2021. JAMA. 2022;327(4):331. doi:10.1001/jama.2021.24110.
7. Chua GT, Kwan MYW, Chui CSL, et al. Epidemiology of acute myocarditis/pericarditis in Hong Kong adolescents following Comirnaty vaccination. Clin Infect Dis. Published online November 28, 2021. doi:10.1093/cid/ciab989.
8. Kohli U, Desai L, Chowdhury D, et al. mRNA coronavirus-19 vaccine-associated myopericarditis in adolescents: A survey study [published online ahead of print, 2021 Dec 22]. J Pediatr. 2021;S0022-3476(21)01231-2. doi:10.1016/j.jpeds.2021.12.025.
9. Gargano JW, Wallace M, Hadler SC, et al. 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. MMWR Morb Mortal Wkly Rep. 2021;70(27). doi:10.15585/mmwr.mm7027e2.
10. Payne AB, Gilani Z, Godfred-Cato S, et al. Incidence of multisystem inflammatory syndrome in children among U.S. persons infected with SARS-CoV-2. JAMA Netw Open. 2021;4(6):e2116420. doi:10.1001/jamanetworkopen.2021.16420.
11. CDC COVID Data Tracker. Centers for Disease Control and Prevention. Published March 28, 2020. https://covid.cdc.gov/covid-data-tracker/#mis-national-surveillance.
12. Zambrano LD, Newhams MM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA vaccination against multisystem inflammatory syndrome in children among persons aged 12–18 years — U.S., July–December 2021. MMWR Morb Mortal Wkly Rep. 2022;71(2). doi:10.15585/mmwr.mm7102e1.
13. Levy M, Recher M, Hubert H, et al. Multisystem inflammatory syndrome in children by COVID-19 vaccination status of adolescents in France. JAMA. 2021;327(3):281-283. doi:10.1001/jama.2021.23262.
14. Johnson AG, Amin AB, Ali AR, et al. COVID-19 incidence and death rates among unvaccinated and fully vaccinated adults with and without booster doses during periods of delta and omicron variant emergence — 25 U.S. Jurisdictions, April 4–December 25, 2021. MMWR Morb Mortal Wkly Rep. 2022;71(4):132-138. doi:10.15585/mmwr.mm7104e2.
15. Thompson MG, Natarajan K, Irving SA, et al. Effectiveness of a third dose of mRNA vaccines against COVID-19–associated emergency department and urgent care encounters and hospitalizations among adults during periods of delta and omicron variant predominance — VISION network, 10 States, August 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(4). doi:10.15585/mmwr.mm7104e3.
16. Accorsi EK, Britton A, Fleming-Dutra KE, et al. Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 omicron and delta variants. JAMA. Published online January 21, 2022. doi:10.1001/jama.2022.0470.
17. European Centre for Disease Prevention and Control. COVID-19 vaccine effectiveness in adolescents aged 12– 17 years and interim public health considerations for administration of a booster dose. 8 February 2022. ECDC: Stockholm; 2022.

Clinical Topics: Cardiovascular Care Team, COVID-19 Hub, Heart Failure and Cardiomyopathies, Prevention

Keywords: COVID-19, COVID-19 Vaccines, SARS-CoV-2, Myocarditis, Adverse Drug Reaction Reporting Systems, Hong Kong, Hospitals, Pediatric, Israel, RNA, Messenger, Centers for Disease Control and Prevention, U.S., Anti-Inflammatory Agents, United Kingdom, Immunization, Vaccination, Technology, Denmark, Pharmaceutical Preparations, Adaptive Immunity, Critical Care, Ambulatory Care

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