Cardiac outcomes following SARS-CoV-2 infection versus BNT162b2 vaccination in adolescents and young adults: a cohort study of 4 million individuals.

Background

Concerns about myocarditis and mortality after COVID-19 vaccination in pediatrics persist despite limited direct comparisons with SARS-CoV-2 infection risks. We compared risks of myocarditis, pericarditis, and mortality between infection and BNT162b2 vaccination in adolescents and young adults.

Methods

This retrospective cohort study used TriNetX data (December 2020-September 2025) for 4,072,375 individuals aged 16-25 years, categorized as uninfected/unvaccinated (n = 3,572,000), infected/unvaccinated (n = 248,546), vaccinated/uninfected (n = 241,152), or hybrid immunity (n = 10,677). We used competing risk analysis, propensity-score matching, and Cox regression, and sex-stratified analyses to assess 6-month outcomes.

Findings

The infected/unvaccinated group had the highest cumulative incidence of myocarditis (0.116%). After 1:1 propensity-score matching, SARS-CoV-2 infection was associated with significantly higher risks of myocarditis (relative risk [RR] = 4.91; 95%CI = 3.11-7.77), pericarditis (RR = 1.93; 95%CI = 1.39-2.67), and mortality (RR = 1.33; 95%CI = 1.04-1.71) versus no infection. In direct comparison, vaccination was associated with 85% lower myocarditis risk, 79% lower pericarditis risk, and 72% lower mortality versus infection. Protection was consistent across sexes. The absolute risk difference for myocarditis was 0.0354%, corresponding to one fewer recorded myocarditis event per 2827 individuals in the vaccinated/uninfected group compared with the infected/unvaccinated group.

Interpretation

Recorded SARS-CoV-2 infection was associated with higher short-term risks of myocarditis, pericarditis, and all-cause mortality than recorded BNT162b2 vaccination in adolescents and young adults. These findings support a favorable benefit-risk profile for BNT162b2 vaccination relative to documented infection, although the observational all-cause mortality comparison should be interpreted as descriptive rather than causal.