COVID-19 mRNA Vaccination and 4-Year All-Cause Mortality Among Adults Aged 18 to 59 Years in France.

Importance: While several studies have assessed the impact of COVID-19 vaccination on short-term mortality, none have compared long-term mortality by vaccination status, particularly in young individuals who are less likely to experience severe disease following SARS-CoV-2 infection. Objective: To compare 4-year all-cause mortality in individuals aged 18 to 59 years vaccinated with the mRNA COVID-19 vaccine vs unvaccinated individuals. Design, Setting, and Participants: This cohort study used data from the French National Health Data System for all individuals in the French population aged 18 to 59 years who were alive on November 1, 2021. Data analysis was conducted from June 2024 to September 2025. Exposure: Exposure was defined as receiving a first mRNA dose between May 1 and October 31, 2021. Individuals who were unvaccinated by November 1, 2021, were assigned a random index date based on vaccinated individuals' vaccination dates. Main Outcomes and Measures: Cox models weighted for sociodemographic characteristics and 41 comorbidities were used to estimate 4-year all-cause mortality. Time to event was censored at all-cause death, COVID-19 vaccination for unexposed individuals, or study termination on March 31, 2025. Complementary analyses were performed, including a comparison of the main causes of death available up to December 31, 2023. Follow-up began 6 months after the index date in both groups to address immortal time bias. Short-term mortality within 6 months after vaccination was assessed in a separate, independent study using adapted self-controlled case series models. Results: A total of 22 767 546 vaccinated and 5 932 443 unvaccinated individuals were followed up for a median (IQR) of 45 (44-46) months. Vaccinated individuals were older than unvaccinated individuals (mean [SD] age, 38.0 [11.8] years vs 37.1 [11.4] years), more frequently women (11 688 603 [51.3%] vs 2 876 039 [48.5%]) and had more cardiometabolic comorbidities (2 126 250 [9.3%] vs 464 596 [7.8%]). During follow-up, 98 429 (0.4%) and 32 662 (0.6%) all-cause deaths occurred in the vaccinated and unvaccinated groups, respectively. Vaccinated individuals had a 74% lower risk of death from severe COVID-19 (weighted hazard ratio [wHR], 0.26 [95% CI, 0.22-0.30]) and a 25% lower risk of all-cause mortality (wHR, 0.75 [95% CI, 0.75-0.76]), with a similar association observed when excluding severe COVID-19 death. Sensitivity analysis revealed that vaccinated individuals consistently had a lower risk of death, regardless of the cause. Mortality was 29% lower within 6 months following COVID-19 vaccination (relative incidence, 0.71 [95% CI, 0.69-0.73]). Conclusions and Relevance: In this national cohort study of 28 million individuals, the results found no increased risk of 4-year all-cause mortality in individuals aged 18 to 59 years vaccinated against COVID-19, further supporting the safety of the mRNA vaccines that are widely used worldwide.