Conclusion
Myocarditis can be induced by either viral or bacterial infection, most notably developing in up to two thirds of persons infected with diphtheria. Thus, diphtheria vaccine prevents myocarditis by protecting against natural infection. Smallpox vaccine can very rarely cause myocarditis and myocardiopathy/cardiomyopathy, but is not routinely recommended to the general population in the United States. mRNA COVID-19 vaccines can rarely cause myocarditis among adolescent males and can very rarely cause myocarditis among females and among males in other age groups. mRNA COVID-19 vaccines also very rarely cause pericarditis. However, SARS-COV-2 infection also causes myocarditis and pericarditis, and that risk is lowered with COVID-19 immunization [129]. Additionally, the prognosis of myocarditis and pericarditis from mRNA vaccines is generally good, with most persons recovering quickly [810]; vaccine induced myocarditis appears less severe that myocarditis caused by other factors (including SARS-COV-2 infection) [134, 811]. Other vaccines that are currently routinely recommended to the general population in the U.S.* have not been shown to cause myocarditis or myocardiopathy/cardiomyopathy.
Epidemiological Evidence
The 2012 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), found no relevant studies of quality in the literature assessing myocarditis and diphtheria, tetanus or pertussis vaccines 5.
One study published since this report of 193,083 adults at least 50 years of age found no association between zoster vaccine and myocarditis using both case-centered and self-controlled case series analyses 6. A VSD study of 438,487 live births between 2007 and 2013 found no increased risk of cardiac events such as cardiomyopathy, myocarditis, pericarditis, or heart failure among pregnant individuals receiving Tdap vaccination 7.
U.S. military personnel administered smallpox vaccine had almost 7.5 times higher incidence of myopericarditis in the 30 days post vaccination than non-vaccinated active-duty military personnel (16.11 per 100,000 vaccinees versus 2.16 per 100,000 non-vaccinees) 8. A 2015 prospective cohort study also found an increased risk of myocarditis/pericarditis after smallpox vaccine, but no cases of myocarditis after receipt of trivalent inactivated influenza vaccine 9.
mRNA COVID-19 vaccines have been shown to rarely cause myocarditis, most frequently among adolescent males after their second dose. Estimates of incidence vary by study but have mostly ranged between about 1 case per 2,500 to 1 case per 10,000 among males aged 12-17 after their second dose. Estimates of incidence are lower after the first and booster doses, among males of other age groups, and among females. Estimates of incidence are also higher after SARS-CoV-2 infection than after vaccination 1, 10-13.
A Canadian study of adolescents 12-17 years of age found the highest risk among males 16 and 17 years old after dose 2 (15.7 per 100,000) 14. Analyses of safety surveillance data from the Vaccine Safety Datalink found no significant associations between mRNA COVID-19 vaccines and 23 serious health outcomes (including myocarditis/pericarditis) when including all ages 13. However, supplemental analyses restricted to individuals 12 to 39 years of age found an increased risk of myocarditis/pericarditis in the week after mRNA vaccination (RR: 9.83; 95% CI: 3.35-35.77), corresponding to an estimated 6.3 additional cases per million doses 13.
Data from the US Vaccine Safety Datalink (VSD) as of October 23rd, 2021, estimated a rate of 11 per 100,000 second doses of Comirnaty among adolescent males 12-15 years of age 11, 12. A California cohort study found an increased risk of myocarditis within 10 days of the second dose of mRNA vaccination (incidence rate ratio: 2.7; 95% CI: 1.4-4.8) 15. Of over 2.5 million Israelis receiving Comirnaty, the Pfizer-BioNTech COVID-19 vaccine, 54 cases of myocarditis were identified, most of which were mild or moderate in severity; the rate of myocarditis was highest among males 16-29 years of age (11 per 100,000 vaccinated persons) 16.
Of over 400,000 adolescents 12-15 years of age receiving Comirnaty in Israel, 13 cases of myocarditis were identified, all of which were mild in severity; the rate of myocarditis after the second dose was 8 per 100,000 adolescents 12-15 years of age 17. Analyses of observational data from the largest health care organization in Israel found an increased risk of myocarditis after vaccination with Comirnaty 18, especially among young males (16 to 39 years of age) who had 8.6 additional cases per 100,000 vaccinations (95%CI: 2.8-14.6) 19. Retrospective analysis of Israeli national active surveillance found an increased risk of myocarditis within 30 days of the second dose of Comirnaty (rate ratio: 2.35; 95%CI: 1.10-5.02); especially among males 16-19 years of age (RR: 8.96; 95% CI: 4.50-17.83) 20.
A self-controlled case series analysis of hospital admissions in England found an increased risk of myocarditis within a week after mRNA vaccination, especially after the second dose among males younger than 40 21.
A Danish national cohort study found an increased risk of myocarditis and myopericarditis after vaccination with Spikevax, particularly among individuals 12 to 39 years of age (hazard ratio: 5.24; 95%CI: 2.47-11.12) 22. A meta-analysis of four cohort studies using national data from Denmark, Finland, Norway, and Sweden found an increased risk of myocarditis among males 16 to 24 years of age receiving their second dose of Comirnaty (IRR: 5.31; 95%CI: 3.68-7.68) or Spikevax (IRR:13.83; 95%CI: 8.08-23.68) 23. A self-controlled risk interval analysis nested in a population-based cohort study using healthcare data from four European countries (Italy, Spain, Netherlands, and Denmark) found an increased risk of myocarditis among persons less than 30 years old receiving their second dose of Comirnaty (IRR: 7.8; 95%CI: 2.6-23.5) or Spikevax (IRR: 6.1; 95%CI: 1.1-33.5) 24.
A self-controlled case series and case-control study of electronic health records in Hong Kong found increased risks of carditis after vaccination with Comirnaty (specifically among males and persons younger than 30), but not after CoronaVac 25.
The risk of myocarditis seems to be about twice as high for Spikevax (Moderna) compared to Comirnaty (Pfizer-BioNTech) COVID-19 vaccines 11, 12, 22, 23. However, it is difficult to make direct comparisons and combine data between studies on this topic, due to variability in the populations and vaccines studied, the methods used for case ascertainment and study design, how associations are reported, and study limitations. In particular, much of the available data are not adequately stratified by age and sex. An increased risk of pericarditis has also been shown after second and booster doses of mRNA COVID-19 vaccines, though less common than myocarditis and more evenly distributed between sexes and age groups 13, 21.
Proposed Biological Mechanism
Myocarditis often results from a prolonged immune response induced by viral infection 26. In particular, myocardiopathy/cardiomyopathy develops in up to two thirds of persons infected with Corynebacterium diphtheria, due to the effects of the exotoxin released by the bacteria. However, the diphtheria vaccine does not contain active toxin. Other mechanisms that could contribute to myocarditis include autoantibodies or T cells 5. The IOM concluded that there was no mechanistic evidence for an association between myocarditis and tetanus or pertussis containing vaccines 5.
The mechanism through which the mRNA vaccines lead to myocarditis are not well understood. While viral infections, including infection with SARS-CoV-2 can lead to myocarditis, in some cases due to infection of the myocardial cells with the virus 27, this is not true of the vaccine, which is not a live virus. The few cardiac biopsies performed in people with myocarditis after an mRNA SARS-CoV-2 vaccine did not find evidence of the vaccine mRNA or spike protein in the affected heart muscles 20, 28. Several hypotheses are proposed. The first is that in a very small number of people, there is molecular mimicry- that is the immune response to the vaccine is targeting proteins within the heart that are not targeted in most persons 29-31. Another is that, again, very rarely, the vaccine stimulates overactivation of the immune system that leads to inflammation of the heart muscle.
As noted above, the smallpox vaccine, which is not routinely recommended, has been shown to cause myocarditis. The mechanism is thought to be due to a strong inflammatory response to the live, replicating vaccine, leading to myocardial damage and myonecrosis 32. This has not been seen following the non-replicating monkeypox vaccine.
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.
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