Risk of myocarditis after three doses of COVID-19 mRNA vaccines in the United States, 2020–2022: A self-controlled case series study

Abstract

Aim: Myocarditis is a recognized safety concern following COVID-19 mRNA vaccination. However, there is limited research quantifying the risk associated with the third dose or comparing the risk between the three doses. The US Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system that monitors rare adverse events after US-licensed vaccination. However, studies analyzing VAERS data have often faced criticism for underreporting cases and lacking a control group to assess the increase in baseline risk.

Methods: The temporal association between myocarditis onset and COVID-19 vaccination was studied. To overcome limitations, a novel modified self-controlled case series method was employed, explicitly modeling the case reporting process in VAERS data.

Results: We found an increased risk of myocarditis during the 1- to 3-day period following the second and third doses of both the BNT162b2 vaccine and the mRNA-1273 vaccine. Following the second dose, the relative incidence (RI) was 4.89 (95% confidence interval (CI), 2.39–10.08) for the BNT162b2 vaccine and 2.86 (95% CI: 1.18–7.03) for the mRNA-1273 vaccine. Similarly, following the third dose, the RI was 9.04 (95% CI: 2.79–40.99) for the BNT162b2 vaccine and 4.71 (95% CI: 1.42–19.09) for the mRNA-1273 vaccine. No significant increase in risk was observed during other periods. Notably, our analysis also identified a similar increased risk of myocarditis among individuals aged below 30.

Conclusions: These findings raise safety concerns regarding COVID-19 mRNA vaccines, provide insights into the quantification of myocarditis risk at different postvaccination periods, and offer a novel approach to interpreting passive surveillance system data.

Keywords

COVID-19 / drug-related side effects and adverse reactions / mRNA vaccines / myocarditis / passive surveillance system / self-controlled case series study

References

[1] O'Callaghan KP, Blatz AM, Offit PA. Developing a SARS-CoV-2 vaccine at warp speed. J Am Med Assoc. 2020; 324(5), 437–438.

[2] Oster ME, Shay DK, Su JR, et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the US from December 2020 to August 2021. J Am Med Assoc. 2022; 327: 331–340.

[3] Mevorach D, Anis E, Cedar N, et al. Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel. N Engl J Med. 2021; 385: 2140–2149.

[4] Shimabukuro TT, COVID-19 Vaccine safety updates. Advisory Committee on Immunization Practices. 2021.

[5] 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), 2132–2139.

[6] Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. 2021; 6: 1202–1206.

[7] Massari M, Spila Alegiani S, Morciano C, et al. Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: a multi-database, self-controlled case series study. PLoS Med. 2022; 19:e1004056.

[8] Knudsen B, Prasad V. COVID-19 vaccine induced myocarditis in young males: a systematic review. Eur J Clin Invest. 2023; 53:e13947.

[9] Simone A, Herald J, Chen A, et al. Acute myocarditis following a third dose of COVID-19 mRNA vaccination in adults. Int J Cardiol. 2022; 365: 41–43.

[10] Patone M, Mei XW, Handunnetthi L, et al. Risk of myocarditis after sequential doses of COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Circulation. 2022; 146: 743–754.

[11] Stowe J, Miller E, Andrews N, et al. Risk of myocarditis and pericarditis after a COVID-19 mRNA vaccine booster and after COVID-19 in those with and without prior SARS-CoV-2 infection: a self-controlled case series analysis in England. PLoS Med. 2023; 20:e1004245.

[12] Blumenthal KG, Phadke NA, Bates DW. Safety surveillance of COVID-19 mRNA vaccines through the vaccine safety Datalink. J Am Med Assoc. 2021; 326: 1375–1377.

[13] Shimabukuro TT, Nguyen M, Martin D, et al. Safety monitoring in the vaccine adverse event reporting system (VAERS). Vaccine. 2015; 33: 4398–4405.

[14] Farrington P, Whitaker H, Weldeselassie YG. Self-controlled case series studies: a modelling guide with R. Chapman and Hall/CRC; 2018.

[15] Farrington P. The self-controlled case series method and covid-19. Br Med J (Clin Res Ed). 2022; 377.

[16] Bate A. Bayesian confidence propagation neural network. Drug Saf. 2007; 30: 623–625.

[17] Fram DM, Almenoff JS, DuMouchel W, Empirical Bayesian data mining for discovering patterns in post-marketing drug safety. Proceedings of the Ninth ACM SIGKDD International Conference on Knowledge Discovery and Data Mining. 2003.

[18] Escolano S, Hill C, Tubert-Bitter P. A new self-controlled case series method for analyzing spontaneous reports of adverse events after vaccination. Am J Epidemiol. 2013; 178: 1496–1504.

[19] Lai D, Zhang YD, Lu J. Venous thromboembolism following two doses of COVID-19 mRNA vaccines in the US population, 2020–2022. Vaccines. 2022; 10: 1317.

[20] Escolano S, Hill C, Tubert-Bitter P. Intussusception risk after RotaTeq vaccination: evaluation from worldwide spontaneous reporting data using a self-controlled case series approach. Vaccine. 2015; 33: 1017–1020.

[21] Escolano S, Farrington CP, Hill C, et al. Intussusception after rotavirus vaccination—spontaneous reports. N Engl J Med. 2011; 365: 2139–2139.

[22] Vaccine Adverse Event Reporting System. [Accessed at May 16, 2023]. Available at:

[23] Farrington C. Relative incidence estimation from case series for vaccine safety evaluation. Biometrics. 1995:51; 228–235.

[24] Haber P, Patel M, Pan Y, et al. Intussusception after rotavirus vaccines reported to US VAERS, 2006–2012. Pediatrics. 2013; 131: 1042–1049.

[25] Verstraeten T, Baughman AL, Cadwell B, et al. Enhancing vaccine safety surveillance: a capture-recapture analysis of intussusception after rotavirus vaccination. Am J Epidemiol. 2001; 154: 1006–1012.

[26] Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2022; 28: 410–422.

[27] Woo EJ, Mba-Jonas A, Dimova RB, et al. Association of receipt of the Ad26. COV2.S COVID-19 vaccine with presumptive Guillain-Barré syndrome February-July 2021. J Am Med Assoc. 2021; 326: 1606–1613.

[28] Hippisley-Cox J, Patone M, Mei XW, et al. Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study. Br Med J (Clin Res Ed). 2021; 374.

[29] Pawlowski C, Rincón-Hekking J, Awasthi S, et al. Cerebral venous sinus thrombosis is not significantly linked to COVID-19 vaccines or non-COVID vaccines in a large multi-state health system. J Stroke Cerebrovasc Dise. 2021; 30:105923.

[30] Hviid A, Hansen JV, Thiesson EM, et al. Association of AZD1222 and BNT162b2 COVID-19 vaccination with thromboembolic and thrombocytopenic events in frontline personnel: a retrospective cohort study. Ann Intern Med. 2022; 175: 541–546.

[31] Buchan SA, Seo CY, Johnson C, et al. Epidemiology of myocarditis and pericarditis following mRNA vaccination by vaccine product, schedule, and interdose interval among adolescents and adults in Ontario, Canada. JAMA Netw Open. 2022; 5:e2218505. -e05.

[32] Heymans S, Cooper LT. Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms. Nat Rev Cardiol. 2021; 19: 75–77.

[33] Li X, Ostropolets A, Makadia R, et al. Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study. Br Med J (Clin Res Ed). 2021; 373:n1435.

[34] Sharff KA, Dancoes DM, Longueil JL, et al. Myopericarditis after COVID-19 booster dose vaccination. Am J Cardiol. 2022; 172: 165–166.

[35] Sharff KA, Dancoes DM, Longueil JL, et al. Risk of myopericarditis following COVID-19 mRNA vaccination in a large integrated health system: a comparison of completeness and timeliness of two methods. Pharmacoepidemiol Drug Saf. 2022; 31(8), 921–925.

[36] Haber P, Parashar UD, Haber M, et al. Intussusception after monovalent rotavirus vaccine—United States, Vaccine Adverse Event Reporting System (VAERS), 2008–2014. Vaccine. 2015; 33: 4873–4877.

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