Safety and Efficacy of COVID Vaccine in a large French Study
I know this will bring out all sorts of attackes on me, personally, but this is so important a study that I am willing to be subjected to it.
JAMANetworkOpen.2025;8(12):e2546822.doi:10.1001/jamanetworkopen.2025.46822
COVID-19mRNA Vaccination and 4-YearAll-Cause Mortality Among Adults
Aged 18 to 59 Years in France
LauraSemenzato,PhD,MSc;StéphaneLeVu,PhD;JérémieBotton,PhD,PharmD,MPH;MarionBertrand,MSc;Marie-JoelleJabagi,PhD,PharmD,MPH;
JérômeDrouin,MSc;FrançoisCuenot,PhD;ValérieOlié,PhD;RosemaryDray-Spira,PhD,MD;AlainWeill,MD;MahmoudZureik,PhD,MD
Abstract
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
them RNACOVID-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 May1 and October31,
2021. Individuals who were unvaccinated byNovember1,2021, were assigned a randomindex date
based on vaccinated individuals’ vaccination dates.
MAIN OUTCOMES AND MEASURES Coxmodels weighted for sociodemographic characteristics
and 41 comorbidities were used to estimate 4-yearall-cause mortality. Time to event was censored at
all-cause death, COVID-19 vaccination for unexposed individuals, or study termination on March31,
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 22767546 vaccinated and 5932443 unvaccinated individuals were followed up
for a median (IQR)of45(44-46) months. Vaccinated individuals were older than unvaccinated
individuals (mean[SD]age,38.0[11.8]yearsvs37.1[11.4]years), more frequently women(11688603
[51.3%]vs2876039[48.5%])and had more cardiometabolic comorbidities (2126250[9.3%] vs
464596[7.8%]).Duringfollow-up,98429(0.4%)and32662(0.6%)all-cause deaths occurred in
the vaccinated and unvaccinated groups, respectively. Vaccinated individuals had a 74% lower risk of
death from severeCOVID-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 with in 6
months following COVID-19 vaccination (relativeincidence,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-yearall-cause mortality in individuals aged 18 to59 years vaccinated against COVID-19, further supporting the safety of the mRNA vaccines that are widely used
worldwide
JAMANetworkOpen.2025;8(12):e2546822.doi:10.1001/jamanetworkopen.2025.46822
COVID-19mRNA Vaccination and 4-YearAll-Cause Mortality Among Adults
Aged 18 to 59 Years in France
LauraSemenzato,PhD,MSc;StéphaneLeVu,PhD;JérémieBotton,PhD,PharmD,MPH;MarionBertrand,MSc;Marie-JoelleJabagi,PhD,PharmD,MPH;
JérômeDrouin,MSc;FrançoisCuenot,PhD;ValérieOlié,PhD;RosemaryDray-Spira,PhD,MD;AlainWeill,MD;MahmoudZureik,PhD,MD
Abstract
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
them RNACOVID-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 May1 and October31,
2021. Individuals who were unvaccinated byNovember1,2021, were assigned a randomindex date
based on vaccinated individuals’ vaccination dates.
MAIN OUTCOMES AND MEASURES Coxmodels weighted for sociodemographic characteristics
and 41 comorbidities were used to estimate 4-yearall-cause mortality. Time to event was censored at
all-cause death, COVID-19 vaccination for unexposed individuals, or study termination on March31,
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 22767546 vaccinated and 5932443 unvaccinated individuals were followed up
for a median (IQR)of45(44-46) months. Vaccinated individuals were older than unvaccinated
individuals (mean[SD]age,38.0[11.8]yearsvs37.1[11.4]years), more frequently women(11688603
[51.3%]vs2876039[48.5%])and had more cardiometabolic comorbidities (2126250[9.3%] vs
464596[7.8%]).Duringfollow-up,98429(0.4%)and32662(0.6%)all-cause deaths occurred in
the vaccinated and unvaccinated groups, respectively. Vaccinated individuals had a 74% lower risk of
death from severeCOVID-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 with in 6
months following COVID-19 vaccination (relativeincidence,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-yearall-cause mortality in individuals aged 18 to59 years vaccinated against COVID-19, further supporting the safety of the mRNA vaccines that are widely used
worldwide
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