Related Experiment Video
Updated: Jan 6, 2026
Synthesis and Characterization of mRNA-Loaded PolyBeta Aminoesters Nanoparticles for Vaccination Purposes
Published on: August 13, 2021
COVID-19 mRNA Vaccination and 4-Year All-Cause Mortality Among Adults Aged 18 to 59 Years in France
Laura Semenzato1, Stéphane Le Vu1, Jérémie Botton1,2
1EPI-PHARE Scientific Interest Group in Epidemiology of Health Products from the French National Agency for the Safety of Medicines and Health Products and the French National Health Insurance, Saint-Denis, France.
Insights
This study found no increased 4-year mortality risk in young adults vaccinated against COVID-19. mRNA COVID-19 vaccination was associated with a lower risk of all-cause mortality in this population.
Area of Science:
- Public Health
- Epidemiology
- Vaccinology
Background:
- Limited data exists on long-term mortality following COVID-19 vaccination in younger populations.
- Previous studies focused on short-term mortality, leaving a gap in understanding long-term safety.
- Younger individuals are less prone to severe COVID-19, necessitating specific long-term safety assessments.
Purpose of the Study:
- To compare the 4-year all-cause mortality rates between individuals aged 18-59 who received mRNA COVID-19 vaccines and unvaccinated individuals.
- To assess the long-term safety profile of mRNA COVID-19 vaccination in a large, adult population.
- To contribute evidence on the long-term mortality impact of COVID-19 vaccination in a demographic less likely to experience severe SARS-CoV-2 infection.
Main Methods:
- A French national cohort study utilized data from the National Health Data System, including over 28 million individuals aged 18-59.
- Cox models, weighted for sociodemographic factors and comorbidities, were employed to estimate 4-year all-cause mortality.
- Follow-up extended for a median of 45 months, with sensitivity analyses and complementary cause-of-death analyses performed.
Main Results:
- Vaccinated individuals (n=22,767,546) showed a 25% lower risk of all-cause mortality compared to unvaccinated individuals (n=5,932,443) (wHR, 0.75).
- A significantly lower risk of death from severe COVID-19 was observed in the vaccinated group (wHR, 0.26).
- Sensitivity analyses confirmed a consistently lower risk of death from any cause in vaccinated individuals.
Conclusions:
- The study found no increased 4-year all-cause mortality risk associated with mRNA COVID-19 vaccination in individuals aged 18-59.
- These findings support the established safety profile of widely used mRNA COVID-19 vaccines.
- The results reinforce the public health recommendation for COVID-19 vaccination across adult age groups.
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.
Related Concept Videos
01:51Vaccinations
02:31Nuclear Export of mRNA
01:29Bias in Epidemiological Studies
01:03Rous Sarcoma Virus (RSV) and Cancer
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...
01:30Cancer Vaccines
Cancer vaccines come in two categories: preventive (prophylactic) and treatment (active). Preventive vaccines, such as the Human Papillomavirus (HPV) vaccine, protect against viruses that cause certain...
02:51mRNA Stability and Gene Expression