Myocarditis associated with SARS-CoV-2 vaccines by dose and brand in three European countries using large electronic health care data sources: a self-controlled risk interval study  in the COVID-19 vaccine monitor study

Background: Literature suggests mRNA-based COVID-19 vaccines elevate the risk of myocarditis in young individuals, with a higher risk after second dose. There is less clarity for third doses and adenovirus-platform vaccines.

Objectives: Report the risk of myocarditis associated with dose 1, 2, and 3 of four EMA-approved COVID-19 vaccines.

Methods: We conducted a self-controlled risk interval (SCRI) study using primary and secondary healthcare data from Italian (ARS), Spanish (BIFAP, FISABIO, SIDIAP) and British (CPRD) datasources (DS). Exposed cases with ≥1 year of follow-up before 1 September 2020 (study start) were eligible. Data were extracted from study start to the end of data availability (December 2021 (ARS) - April 2022 (BIFAP)). Exposures were doses 1, 2, and 3 of the Pfizer (PF), Moderna (MO), AstraZeneca (AZ), and Janssen (JJ) COVID-19 vaccines. Outcome was myocarditis (MC) based on diagnosis codes. The SCRI used a 60-day control window starting 90 days before dose 1 and dose-specific 28-day (main analysis) and 7-day (sensitivity analysis) risk windows. Analyses were stratified by vaccine brand and dose, adjusted for calendar time in 30-day periods, and pooled across DS with random effects meta-analysis.

Results: The study population comprised 578 MC cases among 29,563,667 vaccinated individuals. The median distance between doses was 21-42 days for dose 1&2 and 189-197 days for dose 2&3. The MC risk was significantly increased in the 28 days after dose 2 of mRNA vaccines (PF IRR=1.85, 95%CI: 1.32-2.60; MO IRR=2.39, 95%CI 1.40-4.10) but not dose 1 or 3. The 7-day sensitivity analysis suggested higher risks for MC during weeks 1 and 2 after PF dose 1, and during week 1 after dose 2. For MO vaccine, during weeks 1 and 4 after dose 2. For AZ vaccine, during week 2 after dose 1 and during week 2 after dose 2. For JJ, during week 4 after dose 1. Risks were higher in men below 30 years for mRNA vaccines, but not for AZ. In PF vaccine, dose 3 was not associated with an increased risk of myocarditis in either below or above 30 years. For MO vaccine, the risk is elevated (not significantly) after dose 3 in those under 30 years, but not above 30.

Conclusions: We observed an increased risk of myocarditis following mRNA-based vaccines as well as adenovirus platform vaccines in weekly intervals. The weekly pattern of myocarditis risk following adenovirus platform vaccines differs from the pattern in mRNA platform vaccines. Pfizer vaccine is not associated with an increased risk of myocarditis after dose 3. For Moderna, the risk might be increased.