How Study Design Manufactured a Vaccine Mortality Benefit in French Data

A large French study that appeared to show COVID-19 vaccination was associated with a roughly 25 percent reduction in all-cause mortality among adults aged 18 to 59 has been challenged in a new analysis published in Frontiers in Epidemiology. The critique, written by Michael Günther of the University of Stuttgart and colleagues, argues that the celebrated mortality benefit may be an artifact of who was included in the analysis in the first place—a phenomenon the authors describe as a healthy vaccinee effect created by the study’s own design.

The original study, led by Ludovic Semenzato and colleagues and published in JAMA Network Open, drew on the French National Healthcare Data System, known as SNDS, which records healthcare reimbursements for nearly the entire population. The researchers followed more than 33 million adults aged 18 to 59 from November 2021 onward and compared all-cause death rates between those who had received an mRNA vaccine and those who had not. Over 39 months of follow-up, the vaccinated group showed a substantially lower annual mortality rate than the unvaccinated group, and this difference has been widely cited as evidence that the French vaccination campaign saved lives.

Günther and his colleagues did not dispute the raw numbers. Instead, they asked a deceptively simple question: do the mortality rates in the study’s two groups match what is known about mortality in the French population as a whole? Using official demographic and mortality data from the French statistics institute Insee, they calculated that the nationwide all-cause mortality rate for 18 to 59 year olds in 2022 was approximately 0.001715 per person per year. The unvaccinated group in the study, with a mean annual rate of 0.001694, sat almost exactly at this national average. The vaccinated group, however, showed a rate of just 0.001330—far below what the national figures would predict.

The discrepancy, the authors argue, points to a systematic distortion introduced at the very start of the study. Approximately 4 million people aged 18 to 59 who were vaccinated before May 2021 were excluded from the analysis, along with smaller groups who were vaccinated later or who received non-mRNA vaccines. These excluded individuals, according to the age distribution reported in the original study, were on average older than those who remained. Because mortality risk rises steeply with age even within this relatively young adult range, removing the oldest and presumably most vulnerable vaccinated individuals from the analyzed cohort would mechanically lower the death rate observed among the vaccinated group.

To quantify this effect, the team performed a conservation calculation. They reasoned that the roughly 33.9 million people actually analyzed should be representative of the full French population of 35.3 million in that age bracket. If the unvaccinated and vaccinated groups in the study had mortality rates of 0.001694 and 0.001330 respectively, then the excluded group—about 5.16 million people who were vaccinated early, vaccinated during a six-month lag period, or received non-mRNA vaccines—must have had a mortality rate roughly twice the national average to make the total number of deaths add up. This is not, the authors stress, a claim that vaccination doubled mortality risk in that group; rather, it reflects that the excluded individuals were older and more vulnerable on average, which is precisely why they were vaccinated first.

The authors also tested whether their conclusion was sensitive to assumptions about people who moved between groups during follow-up. About 642,000 individuals initially classified as unvaccinated received their first vaccine dose after October 2021 and thus crossed into the vaccinated category during the study period. When the researchers adjusted for this movement by ignoring the first three months of follow-up, the unvaccinated group’s mortality rate rose to 0.001832, and the implied mortality rate of the excluded vaccinated group remained approximately 1.83 times the national average. The overall conclusion held under this alternative accounting.

When the excluded vaccinated individuals are folded back into the vaccinated group, the apparent mortality advantage largely disappears. The combined mortality rate of all vaccinated people, including those excluded from the original analysis, would be close to or above the national average rather than substantially below it. The hazard ratio that the original study reported—a measure of relative risk between vaccinated and unvaccinated groups—would shift from the favorable range of roughly 0.73 to 0.79 toward values consistent with no meaningful difference in all-cause mortality between the two groups.

This pattern is a variant of what epidemiologists call the healthy vaccinee effect, a well-documented bias in observational vaccine research. People who choose to get vaccinated, or who are prioritized for vaccination in ways that exclude the frail, tend to differ systematically from those who do not. In this case, the bias was not primarily a matter of individual health-seeking behavior but of study design: the decision to exclude everyone vaccinated before May 2021 removed a disproportionate share of older and sicker individuals from the vaccinated group being analyzed. The comparison group was therefore not comparable in the way the study’s conclusions assumed.

The authors acknowledge limitations in their approach. The original study’s published data do not include detailed information about how the age profile of the unvaccinated group shifted over time as younger people got vaccinated and left that group, which introduces some uncertainty into the corrected estimates. Nevertheless, they argue that the direction and approximate magnitude of the distortion are clear enough to undermine the central claim that vaccination was associated with a 25 percent reduction in all-cause mortality in this population.

The critique arrives at a moment when claims about vaccine benefits and risks continue to generate intense public debate. The authors emphasize that their analysis concerns a specific methodological question about one observational study, not a judgment about whether COVID-19 vaccines prevent severe disease or death from infection—outcomes that randomized trials and other evidence have addressed separately. But they contend that when observational studies are held up as evidence of population-level mortality benefits, the composition of the groups being compared must be scrutinized as carefully as the headline numbers. In this case, they conclude, the apparent benefit dissolves once the full vaccinated population is accounted for, and the study’s design, rather than the vaccine itself, produced the celebrated result.

Subject of Research: Healthy vaccinee bias in observational studies of COVID-19 vaccination and all-cause mortality in France

Article Title: Healthy vaccinee effect by study design

Article References: Günther, M., Walach, H., Rockenfeller, R., Reitzner, M., & Meyer, C. (2026). Healthy vaccinee effect by study design. Frontiers in Epidemiology, 6, Article 1837295. https://doi.org/10.3389/fepid.2026.1837295

Image Credits: AI Generated

DOI: 10.3389/fepid.2026.1837295

Keywords: healthy vaccinee effect, COVID-19 vaccination, all-cause mortality, observational study bias, France, SNDS database, mRNA vaccines, epidemiological methods, hazard ratio, study design, Frontiers in Epidemiology, Semenzato study