How do myocarditis risks compare after SARS-CoV-2 infection versus mRNA vaccination by age and sex in large cohort studies?
Executive summary
Large cohort meta-analyses and population studies find that myocarditis risk is, on average, substantially higher after SARS‑CoV‑2 infection than after mRNA COVID‑19 vaccination, but that risk varies sharply by age, sex, vaccine type, and dose — with young males facing the highest relative risk from vaccination compared with other demographic groups [1] [2] [3]. Policy and clinical guidance therefore balance a small, concentrated vaccine-associated myocarditis risk against a larger and more prolonged myocarditis risk from infection [4] [5].
1. Overall comparison: infection >> vaccination in pooled cohorts
A systematic review and meta‑analysis pooling >58 million people reported a relative risk for myocarditis roughly seven times higher after SARS‑CoV‑2 infection than after vaccination (infection RR ≈15, vaccine RR ≈2), concluding overall myocarditis risk is substantially greater following infection [1] [6]. Other large observational networks and reviews reach a concordant conclusion: myocarditis or pericarditis incidence after COVID‑19 infection exceeds that seen after mRNA vaccines across broad age and sex strata [3] [7].
2. Age and sex are decisive modifiers of vaccine risk
Multiple large studies and meta‑regressions show myocarditis after mRNA vaccination concentrates in younger males; the English self‑controlled case series found associations strongest in men under 40, and excess events per million after certain doses (notably mRNA‑1273) in young men sometimes exceeded numbers after infection for that subgroup [2]. Population surveillance and cohort studies likewise report the highest observed‑to‑expected ratios after the second dose among males aged 18–29, especially with mRNA‑1273 [8] [9].
3. Dose, product, and timing matter
Risks rise after sequential doses for some products: the English study documented increased myocarditis incidence 1–28 days after first and successive BNT162b2 doses and a particularly high IRR after a second dose of mRNA‑1273 in younger males [2]. Observational analyses and regulatory bodies therefore note vaccine type (mRNA‑1273 vs BNT162b2) and interdose interval as practical levers to modify risk, with some jurisdictions preferring BNT162b2 for younger adults [10] [11].
4. Absolute risk framing: rare events, different magnitudes
Although relative risks can be large for small subgroups, absolute excess cases remain low: consensus documents cite roughly 2.7 excess myocarditis cases per 100,000 vaccinated individuals aged ≥16 years, versus about 11 excess cases per 100,000 after infection in one national comparison — illustrating that infection produces more myocarditis at the population level [5]. National surveillance similarly reported myocarditis incidence after vaccination across age/sex groups in ranges that are small in absolute terms (e.g., up to tens per 100,000 in the highest male age bands) [3].
5. Outcomes and clinical course: generally milder post‑vaccine myocarditis in reports
Systematic reviews and clinical reports note that myocarditis following mRNA vaccination often has a relatively benign short‑term course compared with typical viral myocarditis, with low hospitalization and death percentages in pooled data, though longer‑term outcomes require further standardized follow‑up [1] [7]. Authors caution that heterogeneous definitions, surveillance intensity, and follow‑up lengths limit direct outcome comparisons across studies [5].
6. What the evidence does not resolve and why context matters
Despite consistent patterns, studies differ in case definitions, background ascertainment, vaccine mixes, and circulating SARS‑CoV‑2 exposure, so estimates for specific age/sex/product combinations can diverge and evolve with new data; several authors explicitly flag these limitations and call for standardized, long‑term surveillance [5] [12]. Public‑health recommendations therefore weigh small concentrated vaccine risks against larger infection risks, and some jurisdictions have adjusted product choice or dosing intervals accordingly [10] [9].