Myocarditis can be induced by either viral or bacterial infection, 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 myocardopathy, but smallpox vaccine is not routinely recommended to the general population in the United States. mRNA-based COVID-19 vaccines can rarely cause myocarditis among males 12-17 and can very rarely cause myocarditis among females and among males in other age groups. mRNA-based COVID-19 vaccines also very rarely cause pericarditis after the booster dose. However, SARS-COV-2 infection also causes myocarditis and pericarditis, and that risk is lowered with COVID-19 immunization. Additionally, the prognosis of myocarditis and pericarditis from mRNA vaccines is generally good, with most persons recovering quickly . Vaccine induced myocarditis appears less severe that myocarditis caused by other factors .
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 .
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 . 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 women receiving Tdap vaccination .
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) . 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 .
mRNA COVID-19 vaccines have been shown to rarely cause myocarditis, most frequently among males aged 12-17 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. 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). Estimates of incidence are lower after the first and booster doses, among males of other age groups, and among females. The risk of myocarditis seems to be about twice as high for Moderna compared to Pfizer vaccines [9, 10]. 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 the second dose of mRNA Covid-19 vaccines, though less common than myocarditis and more evenly distribute between sexes and age groups .
Proposed Biological Mechanism
Myocarditis often results from a prolonged immune response induced by viral infection . In persons infected with Corynebacterium diphtheria, myocarditis due to the effects of the exotoxin released by the bacteria occurs in up to half or more, and increases the risk of death. As the diphtheria vaccine does not contain active toxin, there is no risk of myocarditis through that mechanism. Other mechanisms that could contribute to myocarditis include autoantibodies or T cells .
The IOM concluded that there was no mechanistic evidence for an association between myocarditis and tetanus or pertussis containing vaccines .
COVID-19 mRNA Vaccine
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  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 [14, 15]. 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 [16-18]. 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 . This has not been seen following the non-replicating monkeypox vaccine.
- Jain SS, Steele JM, Fonseca B, Huang S, Shah S, Maskatia SA, Buddhe S, Misra N, Ramachandran P, Gaur L, et al: COVID-19 Vaccination-Associated Myocarditis in Adolescents. Pediatrics 2021, 148.
- Patel T, Kelleman M, West Z, Peter A, Dove M, Butto A, Oster ME: Comparison of Multisystem Inflammatory Syndrome in Children-Related Myocarditis, Classic Viral Myocarditis, and COVID-19 Vaccine-Related Myocarditis in Children. J Am Heart Assoc 2022, 11:e024393.
- Institute of Medicine: In Adverse Effects of Vaccines: Evidence and Causality. Edited by Stratton K, Ford A, Rusch E, Clayton EW. Washington (DC): National Academies Press (US); 2012
- Tseng HF, Liu A, Sy L, Marcy SM, Fireman B, Weintraub E, Baggs J, Weinmann S, Baxter R, Nordin J, et al: Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study. J Intern Med 2012, 271:510-520.
- Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Klein NP, Cheetham TC, Naleway AL, Lee GM, Hambidge S, Jackson ML, Omer SB, et al: Maternal Tdap vaccination: Coverage and acute safety outcomes in the vaccine safety datalink, 2007-2013. Vaccine 2016, 34:968-973.
- Poland GA, Grabenstein JD, Neff JM: The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program. Vaccine 2005, 23:2078-2081.
- Engler RJ, Nelson MR, Collins LC, Jr., Spooner C, Hemann BA, Gibbs BT, Atwood JE, Howard RS, Chang AS, Cruser DL, et al: A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. PLoS One 2015, 10:e0118283.
- Buchan SA, Alley S, Seo CY, Johnson C, Kwong JC, Nasreen S, Thampi N, Lu D, Harris TM, Calzavara A, Wilson SE: Myocarditis or Pericarditis Events After BNT162b2 Vaccination in Individuals Aged 12 to 17 Years in Ontario, Canada. JAMA Pediatr 2023.
- Husby A, Hansen JV, Fosbol E, Thiesson EM, Madsen M, Thomsen RW, Sorensen HT, Andersen M, Wohlfahrt J, Gislason G, et al: SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study. BMJ 2021, 375:e068665.
- Klein NP. ACIP Presentation: Myocarditis Analyses in the Vaccine Safety Datalink: Rapid Cycle Analyses and “Head-to-Head” Product Comparisons [https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-04/10-COVID-Klein-508.pdf]
- Oliver S. ACIP Presentation: Updates to the Evidence to Recommendation Framework: Pfizer-BioNTech COVID-19 booster in children aged 5-11 years [https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-05-19/06-COVID-Oliver-508.pdf]
- Biesbroek PS, Beek AM, Germans T, Niessen HW, van Rossum AC: Diagnosis of myocarditis: Current state and future perspectives. Int J Cardiol 2015, 191:211-219.
- Xu SC, Wu W, Zhang SY: Manifestations and Mechanism of SARS-CoV2 Mediated Cardiac Injury. Int J Biol Sci 2022, 18:2703-2713.
- Amemiya K, Kobayashi T, Kataoka Y, Iwai T, Nakagawa S, Morita Y, Ohta-Ogo K, Matsumoto M, Ikeda Y, Katano H, et al: Myocarditis after COVID-19 mRNA vaccination in three young adult males: Significance of biopsy in vaccine-associated myocarditis. Pathol Int 2022, 72:385-387.
- Mevorach D, Anis E, Cedar N, Bromberg M, Haas EJ, Nadir E, Olsha-Castell S, Arad D, Hasin T, Levi N, et al: Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel. N Engl J Med 2021, 385:2140-2149.
- Power JR, Keyt LK, Adler ED: Myocarditis following COVID-19 vaccination: incidence, mechanisms, and clinical considerations. Expert Rev Cardiovasc Ther 2022, 20:241-251.
- Switzer C, Loeb M: Evaluating the relationship between myocarditis and mRNA vaccination. Expert Rev Vaccines 2022, 21:83-89.
- Bozkurt B, Kamat I, Hotez PJ: Myocarditis With COVID-19 mRNA Vaccines. Circulation 2021, 144:471-484.
- Murphy JG, Wright RS, Bruce GK, Baddour LM, Farrell MA, Edwards WD, Kita H, Cooper LT: Eosinophilic-lymphocytic myocarditis after smallpox vaccination. Lancet 2003, 362:1378-1380.
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