Multiorgan Outcomes Following COVID-19 Vaccine vs Infection: 30M Analysis

BackgroundCardiovascular and cerebrovascular risks of SARS-CoV-2 infection and mRNA vaccination remain incompletely defined and lacking comparative outcomes such as sex-specific vulnerabilities. MethodsUsing the TriNetX Research Network (December 2020-December 2024), we identified four mutually exclusive cohorts: uninfected/unvaccinated (naive), infected/unvaccinated, vaccinated-only, and infected/vaccinated (hybrid immunity). We compared 50 prespecified cardiovascular, cerebrovascular, and mortality outcomes across four pairwise cohort comparisons, with analyses stratified by sex and time of event windows (0-3, 3- 6, 6-9, and >9months). Different vaccine dosing strategies were analyzed. ResultsAmong 30.3 million individuals, infection was associated with a 4.5-fold increased mortality in males and 4.0-fold in females (p<0.001) as well as marked increases in myocarditis, myocardial infarction, and pulmonary embolism. Inflammatory cardiac complications occurred four times more often after infection than vaccination. Vaccination alone conferred a 76% reduction in major adverse cardiovascular events (MACE) in males and 69% in females, with no detectable cardiovascular toxicity. Post-infection vaccination provided an additional 36-38% MACE reduction, though males with hybrid immunity had a late increased risk of pericarditis. Completing the two-dose vaccine series maximally reduced mortality (by 77%) and myocarditis (by 62%) versus single dosing; further doses gave minimal additional benefit but sustained the benefit of the primary vaccination series. Females had higher infection-linked myocarditis risk despite lower mortality. ConclusionsSARS-CoV-2 infection confers substantially greater and sustained cardiovascular and cerebrovascular risk than mRNA vaccination, confirming a highly favorable benefit-risk profile for vaccination. These findings support extended cardiovascular surveillance after infection and targeted, risk-based vaccination strategies.