French Study of 28 Million Adults Confirms Long-Term Safety of COVID-19 mRNA Vaccines
Key Insights
A nationwide French study of over 28 million adults under 60 found that those who received at least one dose of COVID-19 (search) mRNA vaccine had 25% lower all-cause mortality compared to unvaccinated individuals over a median follow-up of 45 months.
Vaccinated individuals were 74% less likely to die from COVID-19 (search) in hospitals and remained 24% less likely to die from any cause even when COVID-related deaths were excluded from the analysis.
The protective effect against mortality was strongest in the first 6-9 months after vaccination, with the weighted hazard ratio of 0.61, but gradually declined to 0.79 at 39-42 months of follow-up.
A comprehensive French study analyzing data from over 28 million adults has provided robust evidence for the long-term safety and effectiveness of COVID-19 (search) mRNA vaccines, with vaccinated individuals showing significantly lower mortality rates compared to their unvaccinated counterparts over nearly four years of follow-up.
The nationwide cohort study, published in JAMA Network Open by researchers from the Epi-Phare (search) team, examined all French residents aged 18 to 59 as of November 1, 2021. Among the study population, 22.8 million people received their first dose of mRNA vaccine between May 1 and October 31, 2021, while 5.9 million remained unvaccinated by November 1, 2021.
Significant Mortality Reduction Observed
After a median follow-up period of 45 months, the incidence of all-cause mortality was notably lower among vaccinated individuals at 0.4% compared to 0.6% in the unvaccinated group. Following standardization of characteristics between the two groups, researchers found that all-cause mortality incidence was 25% lower in those who had received an mRNA shot, with a weighted hazard ratio of 0.75 (95% CI 0.75-0.76).
The protective effect was particularly pronounced for COVID-19 (search)-related deaths, with vaccinated people being 74% less likely to die in a hospital due to COVID-19 compared to unvaccinated individuals (weighted hazard ratio 0.26, 95% CI 0.21-0.32). Remarkably, even when COVID-related hospital deaths were excluded from the analysis, vaccinated individuals maintained a 24% lower risk of death from any cause during the follow-up period (weighted hazard ratio 0.76, 95% CI 0.75-0.77).
Time-Dependent Protection Patterns
The study revealed that the protective association between vaccination and lower all-cause mortality diminished over time. The weighted hazard ratio favoring vaccination was strongest at 0.61 (95% CI 0.58-0.64) during the first six to nine months of follow-up but gradually increased to 0.79 (95% CI 0.75-0.82) at 39 to 42 months.
This decline corresponded with changing patterns of COVID-19 (search)-related mortality. In the initial six to nine months of follow-up, 10.5% of deaths among unvaccinated individuals were COVID-19-related, compared to just 1.9% among vaccinated people. By 24 to 27 months of follow-up, these percentages had dropped to 0.5% and 0.3%, respectively, reflecting the impact of increasing vaccine-induced protection and changes in circulating SARS-CoV-2 variants.
Demographic and Clinical Characteristics
The study population showed distinct demographic patterns between vaccinated and unvaccinated groups. Vaccinated individuals were slightly older on average (38 years versus 37.1 years) and more frequently women (51.3% versus 48.5%). They were also less likely to live in the most disadvantaged socioeconomic areas (19.1% versus 27%) and less likely to be covered by complementary state health insurance (9.2% versus 20.9%).
Interestingly, vaccinated adults had higher rates of certain comorbidities, including cardiac conditions (9.3% versus 7.8%), chronic respiratory diseases (search) (3.3% versus 3.1%), and cancer (search) (1.5% versus 1.4%). Despite these factors that would typically bias toward higher mortality in the vaccinated group, the opposite pattern was observed.
Cause-Specific Mortality Analysis
Among the 59% of study participants for whom cause of death could be determined, the main causes of mortality were similar between groups but occurred at different rates. Cancer (search) was the leading cause of death, affecting 769 cases per million among vaccinated individuals compared to 853 per million among unvaccinated people. External causes of mortality, including unintentional and self-inflicted injuries, accounted for 493 cases per million in the vaccinated group versus 597 per million in the unvaccinated group. Circulatory system diseases (search) caused 282 deaths per million among vaccinated individuals compared to 367 per million among unvaccinated people.
Study Implications and Limitations
According to Professor Mahmoud Zureik, director of Epi-Phare (search) and lead researcher, the findings help counter misinformation about mRNA vaccines while supporting confidence in future vaccine development for other viruses and diseases. The research team noted that vaccinated individuals were generally more socioeconomically advantaged and likely had better healthcare management, factors that may partly explain the observed negative association between vaccination and mortality.
The researchers acknowledged several study limitations, including the potential impact of socioeconomic status on both vaccination decisions and mortality outcomes, which could not be completely accounted for in the available data. Additionally, people who chose vaccination may have other unmeasured factors that differentiate them from those who remained unvaccinated, potentially creating confounding bias in the results.
The study's publication comes at a time when vaccine policies are under renewed scrutiny, with recent changes in U.S. health authority recommendations and funding decisions affecting mRNA vaccine research and implementation.