A new scientific study titled †Serious Adverse Reactions of Special Concern Following mRNA Vaccination in Randomized Trials† provides the best evidence to date regarding the safety of the mRNA Covid vaccines. For most vaccines in common use, the benefits far outweigh the risks, but that may not be the case for the mRNA-covid vaccines, according to this study by Joseph Fraiman and his colleagues. It depends on your age and medical history.
The randomized controlled clinical trial is the gold standard for scientific evidence. When regulators approved Pfizer and Moderna’s mRNA vaccines for emergency use in December 2020, two randomized trials showed that the vaccines reduced symptomatic covid infection by more than 90% during the first few months after the second dose.
Pfizer and Moderna did not design the studies to evaluate long-term efficacy or the more important outcomes of preventing hospitalization, death, or transmission.
The randomized trials collected data on adverse events, including the presence of mild symptoms (such as fever) and more serious events resulting in hospitalization or death. Most vaccines cause some mild side effects in some people, and there were significantly more such side effects after the mRNA vaccines compared to the placebo.
That’s annoying, but not a big problem. We care about serious health outcomes. The key question is whether the efficacy of the vaccine outweighs the risks of serious side effects.
The Fraiman study uses data from the same Pfizer and Moderna-sponsored randomized trials submitted to the FDA for vaccine approval, but with two innovations that provide additional information.
First, the study collects data from both mRNA vaccines to increase the sample size, thereby decreasing confidence intervals and uncertainty about estimated harm.
Second, the study focuses only on the serious side effects that are likely to be caused by the vaccines. Serious side effects such as gunshot wounds, suicide, animal bites, foot fractures and back injuries are unlikely to be due to a vaccine, and cancers within months of vaccination are unlikely to be due to a vaccine. Removing such random noise increases the ability (statistical power) to detect real problems. If there is no undue risk, shorter confidence intervals strengthen confidence in the safety of the vaccines.
Classifying adverse events into the two groups is not a trivial task, but Fraiman et al. do an excellent job of avoiding bias. They rely on the predefined Brighton Collaboration Adverse Events of Special Concern (AESI) definitions. Founded in 2000, the Brighton Collaboration has two decades of experience using rigorous science to define clinical outcomes for vaccine safety studies.
In addition, Fraiman and colleagues blinded the process in which they classified the clinical events as AESIs. The judges didn’t know whether the person had received the vaccine or the placebo. Therefore, any criticism of so-called p-hacking is unjustified.
So, what are the results? There were 139 AESIs among the 33,986 people who were vaccinated, one for every 244 people. That may sound bad, but those numbers mean nothing without comparison to a control group. There were 97 AESIs among the 33,951 people who received a placebo. The combination of these numbers implies 12.5 vaccine-induced AESIs for every 10,000 people vaccinated, with a 95% confidence interval of 2.1 to 22.9 per 10,000 people. In other words, there is one additional AESI for every 800 people vaccinated (95% CI: 437-4762).
That is very high for a vaccine. No other vaccine on the market comes close.
The numbers for the Pfizer and Moderna vaccines are 10 and 15 additional events per 10,000 people, respectively, so both vaccines contributed to the finding. The numbers are similar enough that we can’t say for sure that one is safer than the other. Most of the excess AESIs were coagulation disorders. Before the Pfizer vaccine, there was also an excess of cardiovascular AESIs.
While these safety results are worrisome, let’s not forget the other side of the equation. Unfortunately, the study does not calculate composite estimates that include reductions in severe covid infections, but we have such estimates for mortality.
dr. Christine Benn and her colleagues calculated a combined estimate of the effect of vaccination on all-cause mortality using the same randomized trial data as Fraiman et al. They found no mortality reduction for the mRNA vaccines (relative risk 1.03, 95% CI: 0.63-1.71).
An important limitation of both Fraiman’s and Benn’s studies is that they do not distinguish between the side effects by age, comorbidity or medical history. That’s not their fault. Pfizer and Moderna have not released that information, so outside researchers can’t access it.
We know that the benefits of the vaccine are not equally distributed among the people, as the covid deaths among the elderly are more than a thousand times higher. Risk-benefit calculations therefore need to be done separately for different groups: with and without previous covid infection, by age and for the first two doses versus boosters.
- People recovering from Covid have natural immunity that is stronger than vaccine-induced immunity. So the benefit of vaccination is minimal at best. If the risk of side effects is the same as in the randomized studies, there is a negative risk-benefit difference. Why do we force people in this group to get vaccinated? It is both unethical and harmful to public health.
- While anyone can become infected, children have a miniscule risk of covid death. There are very limited safety data from the studies in children. If the risk of side effects is the same as in adults, the risks outweigh the risks. Children should not be given these vaccines.
- Older people over 70 have a much higher risk of covid death than the population in the Fraiman study. If their risk of a side effect is the same, the benefits outweigh the drawbacks. Therefore, older people who have never had covid and have not yet been vaccinated may benefit from these vaccines. However, we don’t know if they are better than the Johnson & Johnson and Astra-Zeneca vaccines.
- It is unclear, based on the data from clinical trials, whether the benefits outweigh the risks for adults of working age who have not been vaccinated and who have not yet had Covid. This is true both historically, for the original covid variants, and currently for the newer ones.
- The Fraiman study analyzes data after the first and second doses. Both risks and benefits may differ for booster shots, but no randomized trial has properly evaluated the interaction.
These results refer only to Pfizer and Moderna mRNA vaccines. Fraiman et al. did not analyze data on the adenovirus vector vaccines marketed by Johnson & Johnson and Astra-Zeneca. Ben et al. found they reduced all-cause mortality (RR=0.37, 95% CI: 0.19-0.70), but none have used trial data to analyze AESIs for these vaccines.
Critically, Fraiman and Benn’s studies were followed only a few months after the second dose, because unfortunately Pfizer and Moderna ended their randomized studies a few months after receiving emergency use consent. Of course, a longer-term benefit can provide a basis for tolerating negative or neutral short-term risk-benefit differences. However, this is unlikely as we know from observational studies that the efficacy of the mRNA vaccine deteriorates several months after the second dose.
There may also be long-term side effects of the vaccine that we don’t know about yet. Because the randomized trials ended early, we need to look at observational data to answer that question. The publicly available data from the Vaccine Adverse Event Reporting System is of low quality, with both under- and over-reporting. The best observational data comes from CDC’s Vaccine Safety Datalink (VSD) and FDA’s Biologics and Effectiveness Safety System (BEST), but there are only limited reports of these systems.
Fraiman and colleagues have provided the best evidence to date regarding the overall safety of the mRNA vaccines. The results are alarming. It is the responsibility of the manufacturers and the FDA to ensure that the benefits outweigh the drawbacks. They have not succeeded.