A new study reinforces the evidence for the safety and efficacy of the mRNA COVID-19 vaccines. That’s the TLDR, but let’s dive into the details.

Medical evidence is always rolled out in stages. First there is what we would consider preclinical evidence, or basic science. This could be initial uncontrolled clinical observations, or mechanistic animal or in vitro research. At some point we have sufficient evidence to generate a hypothesis that a specific treatment could be effective in treating a specific disease, enough to progress to human research. For FDA qualifying research, there are four specific phases. Phase I trials look at the safety of the intervention in usually healthy controls, while also answering basic questions and mechanism and effects. If there are no safety red-flags then the research progressed to a phase II trial, which look for preliminary evidence of efficacy, and further safety data. Again, if that data continues to look encouraging we can progress to a phase III trial, which is a larger and more rigorous trial designed to be definitive. Usually the FDA requires several phase III trials to grant approval of a drug for a specific indication. Then, once on the market there is phase IV trials, which look at data from more widespread use to confirm safety and effectiveness in the real world.

Looked at another way, we do research in the lab, then on dozens of people, then score to hundreds of people, then hundreds to thousands of people, and then finally on thousands to millions of people. Each step of the way we gain the ability to detect less and less common side effects in a broader set of people. Further, the types of evidence are designed to be complementary. Phase III trials, for example, are rigorously experimental, with highly defined populations with randomization to control as many variables as possible. Phase IV trials, on the other hand, are generally observational, designed to look at very large numbers of people in an uncontrolled setting – to determine how safe and effective the treatment is in real-world conditions.

The mRNA vaccines for COVD all went through phase I-III trials before getting approval. Operation Warp Speed to accelerate the process was not about cutting corners, but about doing the trials more in parallel rather than sequentially (they could at least begin to recruit for the phase III trial while the phase II data was still being analyzed) and streamlining the red tape, but the science still had to get done. Since the vaccine has been in use we have the opportunity to gather phase IV type data. Billions of people have received at least one dose of COVID-19 vaccine, so that is a lot of data to pour through.

In the recent study:

“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.”

Some countries have socialized medicine including centralized health data banks, which allows for very convenient sources for such observational research. This study was able to compare 22 ,767, 546 vaccinated and 5, 932, 443 unvaccinated individuals. The strength of this kind of study is that it is very representative, because it is so inclusive, and it is statistically robust. The challenge is that it is uncontrolled, so there is always potential confounding factors – differences between those who choose to get vaccinated or not get vaccinated. So how do the researchers deal with these confounding factors? Through weighting of the evidence.

They looked at sociodemographic characteristics and 41 comorbidities and then weighted the results accordingly. They could still be missing something, but that is a pretty thorough analysis. Their main outcomes were death due to COVID-19 and all-cause mortality over a four year period. They also did a separate analysis for all-cause mortality in the six months following vaccination. For the unvaccinated group, another end-point was getting vaccinated (after which, of course, they were no longer considered vaccinated).

The results are fairly dramatic. The vaccinated group had a 74% lower risk of death from COVID-19, indicating that the vaccine is effective in preventing death from COVID. But also, over the four year period the vaccinated group had a 25% lower risk of all-cause mortality, even when you eliminate death from COVID. Mortality was 29% lower in the first six months after getting vaccinated.

This data pretty clearly reflects that the mRNA vaccines were effective, at least in preventing death from severe COVID. The data is also very reassuring that the vaccines are safe. There could still be extremely rare, one in a million type side effects, but there does not appear to be any significant negative effects from the vaccine that could contribute to the risk of death. Medical interventions are all about risk vs benefit – no intervention is risk free, so having zero risk is not a rational or reasonable criterion. What we like to see is a robust increased benefit vs risk.

The bottom line is that if you chose to get an mRNA COVID-19 vaccine in 2021 you were much less likely to die of either COVID-19 or all-cause mortality. Clearly there is significant benefit in excess of any risk, which all the data indicates is tiny.