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

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.