The Serious Adverse Events of mRNA Covid-19 Vaccine Trials

By Maryanne Demasi, PhD

In December 2020, the US FDA authorised the Moderna and Pfizer mRNA covid-19 vaccines, claiming “the benefits outweighed the harms.”

Now, a group of international researchers has gone back to re-analyse the original trial data upon which that claim was made.

A valid claim?

A pre-print study (not yet peer-reviewed) by Fraiman and colleagues contradicts the FDA’s claim that the benefits outweigh the harms of the mRNA vaccines. In fact, the authors conclude that the vaccines are associated with an “increased risk of serious adverse events” that surpass the “risk reduction for covid-19 hospitalisation” relative to the placebo group.

The conclusion is provocative. While some have criticised the study for fuelling ‘anti-vax’ sentiment, many have welcomed the independent scrutiny of the trial data. The researchers focused on analysing serious adverse events -- specifically, they narrowed it to serious adverse events of “special interest” which were derived from a predefined list by the Brighton Collaboration, an established framework for vaccine safety used for over two decades.

The advantage of this method is that it removes adverse events that are unlikely to be vaccine-related such as gunshot wounds and car accidents, thereby removing ‘noise’ from the analysis.

They also pooled the trial data for the two mRNA vaccines which increased the sample size and achieved higher confidence in the results (more precision).

The upshot of the analysis was that mRNA vaccines were associated with an absolute risk increase of serious adverse events of 12.5 per 10,000 vaccinated people (95% CI 2.1 to 22.9) over placebo.

Put another way, 1 in 800 people experienced a serious adverse event following either one of the mRNA vaccines (95% CI: 437 to 4762).

“That is very high for a vaccine. No other vaccine on the market comes close,” says Martin Kulldorff, professor of medicine at Harvard (on leave) and former CDC vaccine safety committee member who was not involved in the study.

Kulldorff says the closest any other vaccine on the US market comes to this is the MMRV vaccine which is no longer recommended for 1-yr-olds because they found the excess risk of febrile seizures was 1 in 2300 compared to separate MMR and Varicella vaccines (no excess risk in 5-yr olds).

The Fraiman study found that coagulation disorders and cardiovascular problems were driving most of the serious adverse event in the trials, which seems to corroborate reports in the pharmacovigilance databases. Kulldorff says that while randomised trials offer high level evidence for a causal association between the vaccine and harms, we can acquire valuable information from pharmacovigilance data which are based on millions of vaccinations.

The superior databases for recording adverse events come from the CDCs Vaccine Safety Datalink (VSD) and the FDA’s Biologics and Effectiveness Safety System (BEST). But there’s a problem -- the agencies do not analyse the data and present them to the public.

“It’s a scandal” says Kulldorff. “In July 2021, the FDA came out with a press release saying that it had found a signal with cardiovascular problems but there’s been no published follow up. A signal may be real or an artifact, but it’s the FDA and CDC’s obligation to be open and transparent with the public, showing that vaccines are safe when they are safe and to be honest when there are adverse reactions” he adds.

Kulldorff says these agencies have been derelict in their duty and the result has been vaccine hesitancy. “That’s why we do this vaccine safety work, to build trust for the vaccines - measles, polio, rotavirus vaccines, the list is long. The way that the FDA and CDC have fumbled with the covid-19 vaccine, I think has had extremely bad consequences on the trust in other vaccines as well as in public health generally,” says Kulldorff.

Do the harms outweigh the benefits?

Jay Bhattacharya, professor of Medicine at Stanford University says that determining whether the benefits outweigh the harms is not black and white. It depends on a person’s age since there’s a 1000-fold difference in the infection fatality rate between young and old. Looking back at the pivotal mRNA trials, Bhattacharya says, “There’s no firm age cut-off, but for an immune naïve patient facing the alpha or delta variant, I’d say the balance of risks and benefits favoured vaccinating everyone over 65 and not recommending it for most people below 30.” What about those aged between 30 and 65 years? Bhattacharya says, “For the ages in between, it was a grey area where vaccination made sense for some and not others, depending on risk factors like diabetes and morbid obesity and, of course, prior infection. As a population wide recommendation for young people, I think it was a mistake.” Kulldorf agrees. “The right thing to have done at the time was to authorise the vaccines for older people who are at higher risk of dying from covid-19, people in their 70s, 80s and 90s – not for younger people. But we still don’t know where the cut-off should have been.”

It’s one reason why Kulldorff has argued against mandating the vaccines. “If you don’t know the risks, you should let people make their own decision, give all the information you have and not force people to take it,” says Kulldorff. “Also, the FDA should have demanded that the original trials be designed for important outcomes, like hospitalisations, and deaths, and they should have done the trial with older people because they were poorly represented in the original trials,” adds Kulldorff.

In 2020, only a small proportion of subjects in the original clinical trials had prior exposure to the virus, but today the situation has changed -- a large proportion of people in the west have natural immunity.

“If people have been previously exposed to the virus and recovered, they have better immunity than the vaccine itself can provide, and I think now it’s going to be of limited use, population wise, compared to 2021,” says Bhattacharya.

Upon reflection...

The Fraiman analysis has revealed that the FDA and the CDC underplayed the harms of the mRNA vaccines in Dec 2020.

By authorising and recommending a population-wide vaccination campaign, authorities neglected to focus on protecting the elderly, and exposed many younger people to unnecessary harm.

As the pandemic progresses, and new variants emerge, the benefits of the mRNA vaccines will continue to diminish, while the harms are likely to compound.