Article 3/3: Vaccine safety paved with uncertainties

DOSSIER “Covid-19: from the Belgian vaccination strategy to the vaccine passport”

While there are other dimensions to vaccine safety at production level and at the global level, including the environment, in this article we will look at the risks of adverse effects after injection. No vaccine is ever perfectly safe. It is impossible to guarantee the safety of a product for everyone, for natural and synthetic products alike.

The four vaccines available in Europe, under a conditional marketing authorisation, followed an accelerated development scheme to respond to an emergency situation, under the leadership of the WHO and the regions/governments. The EU considered it justified to take a measured risk by deploying these vaccines, without certainty as to their efficiency or safety.

These vaccines are all different: the available data and the effects differ, including between population subgroups for the same vaccine. Each covid vaccine is therefore more or less safe depending on the context. Medium- and long-term studies have not been completed. And requests for additional analyses are multiplying as knowledge progresses.

Incidentally, safety should not be confused with quality assurance, which consists of testing and monitoring the production chain as well as the composition and use of the product. When the American FDA reacts to a problem at a production site, or a problem is identified at a vaccination site, it means that the quality control system is working, even if rushed development and distribution have increased the risk of error. The reaction of certain politicians and media points to a lack of knowledge of the sector on the part of many, or even a highly politicised discourse on the part of some. But while the quality of the vaccines is controlled, this does not guarantee that they are free of adverse effects.

More adverse effects

The clinical study reports submitted by the companies indicate that all covid vaccines induce short-term effects that are greater in number and intensity than “classic” vaccines on the market. These effects reported during the trials were not atypical and were mostly considered “mild”, that is, without serious consequences. But “mild” can be painful and does not mean mild for everyone.

Moreover, risks affecting fewer than one person in 1,000 are often underestimated or undetermined during studies. A rare risk of 1/1,000 scaled up to the world population can still affect 7 million people! To assess the safety of vaccines, it is therefore the minority that one must look at.

Possible medium- and long-term effects, as well as rare and indirect effects, have certainly not been properly assessed, for lack of means. Because it takes several years to assess this type of effect. It thus happens that a vaccine that is promising in the short term is withdrawn or its indications limited, because adverse effects are observed in the medium and long term, sometimes indirect, targeting a subpopulation,… This explains, for example, why the DengVaxia vaccine is registered with restricted indications.

Establishing a causal link for a rare effect remains a challenge, especially after marketing. However, the fact that these effects have not been assessed does not mean that they exist: we are in the realm of the unknown here.

Essential pharmacovigilance

Given the status of conditional authorisations, “pharmacovigilance” is even more essential than for ordinary medicines. This system serves to identify or reassess the level of risk as quickly as possible, and to formulate recommendations for health policies.

Beware! There are major methodological differences between post-marketing pharmacovigilance and clinical studies: the latter are carried out under controlled conditions, they include a limited number of people, and there are exclusion criteria for methodological reasons. Monitoring of effects is active and systematic.

Here, national authorities are responsible for setting up and promoting pharmacovigilance. The European Medicines Agency (EMA) and the companies seem to be fulfilling their role, in a very complex context. However, the risk of political and societal pressure on (inter)national agencies should not be underestimated. Scientists pointed out these risks before the products were placed on the market. And certain statements are troubling, both from politicians and from some people within the agencies.

Pharmacovigilance also helps doctors give their patients the best advice and guarantee free and informed consent. Anything that undermines pharmacovigilance can lead to lives being needlessly wasted.

A surprising number of reported effects

Technically, the pharmacovigilance system for covid vaccines seems to be working: the number of reported effects is surprising. Compared with the 2019 flu vaccination campaign, at an equivalent vaccination rate, since December there have been more than 20 times more effects reported in the United States, including more than 30 times more severe effects.

Does that mean these vaccines are so risky? On the one hand, not all reported effects are necessarily linked to the vaccines, the proportion of reported effects is always higher in the first months of monitoring, these vaccines are certainly scrutinised far more than others (by patients and doctors) and the proportion of effects is always biased.

But on the other hand, the pharmacovigilance process depends essentially on the quality of the data, that is, it relies on the contribution of health professionals and patients. Yet it is established that doctors have poor knowledge and perception of the system. This is one of the reasons that led Europe to open up the possibility for patients to participate in the system. Admittedly, we are still far from countries like Australia, which proactively contact all vaccinated people. Monitoring social networks is considered a complementary avenue of surveillance.

Not giving the “anti-vaxxers” ammunition

And what is happening on social networks and in the media should alarm health officials. Many doctors and citizens do not hesitate to declare that they do not report severe effects so as not to give the “anti-vaxxers” ammunition. While safety should be at the heart of concerns, given the inevitable uncertainties, the mainstream media relay statements that trivialise the seriousness of the effects, and even do not hesitate to castigate people who are worried about the vaccination strategy.

Yet the very first sentence of the package leaflets encourages everyone to contribute to pharmacovigilance. In April, the Superior Health Council also stressed the importance of diagnosing and escalating adverse effects.

The word “sacrifice”, which now seems accepted by many, is nevertheless not compatible with the principle of safety. There are still people, however, who take safety seriously and defend patients’ right to be concerned.

Possible implications yet to be determined

As these vaccines are still in the evaluation phase, their risks are being discovered as we go along. Certain recently reported effects associated with covid vaccines have already led to a review of their indications, in particular for two of the four vaccines in Europe. The EMA is not idle: it has asked each laboratory to analyse the effects attributed to the Spike protein (the target antigen of all four vaccines) in the infection and its complications.

What are the risks with regard to variants? The vaccines on the market in Europe all share the same flaw: they target a single antigen, subject to wide genetic variation. Vaccine expert Geert Van Den Bossche has alerted the public to certain risks. His position is alarmist, but it is nevertheless based on known facts, such as the “bias” effect in immune memory, forever influenced by the first version of the antigens it encountered. For vaccinated people, this could influence resistance to future variants of the virus. This kind of effect seems to play a role in the seasonal epidemic variations of influenza. New vaccines with other antigens would then be needed to enrich an overly narrow vaccine immunity.

More generally, the retrospective analysis of mass vaccination programmes has also revealed “cascade effects” that had not been anticipated. This hypothesis does not seem to be taken into account in covid vaccination.

Another grey area: researchers have recently demonstrated an effect of vaccination with the Pfizer/BioNTech vaccine on innate immunity. Its possible implications remain to be determined and the authors mention various possibilities that need to be checked as quickly as possible.

Incidentally, the beliefs of the health authorities are hardly reassuring: injecting a vaccine causes inflammation, but whatever one may think, more inflammation does not mean better immunisation. Likewise, low positivity figures (based on PCR tests) in the short term do not mean that the circulation of the virus is under control.

Vaccination, an irreversible act

Health policies normally take into account both uncertainties and overall impact. In other words, the overall safety of vaccination establishes the risks one is prepared to take in the light of the characteristics of the disease, the target population, the pathogen and the available vaccines.

For this other dimension of vaccine safety, hindsight is a key variable. The American health agency (CDC) indeed states that “the better we understand a pathogen and the disease it causes, the more efficient vaccine development can be”.

Vaccination is an irreversible act, and the countries that resort to it seem very quick to neglect the weight of risks in their vaccination strategy. The WHO’s position is more cautious, calling for a focus above all on people at risk worldwide.

So, are these covid vaccines safe? The question is wrongly framed. All one can say is that these vaccines are as safe as possible given the circumstances. They are, however, far from the usual standards. Given the little hindsight we have on these vaccines, the disease and the virus, the lessons of the past are currently the only established truths.

Rationally, nothing more can be said, except to remember the first principle of caution in Hippocrates’ treatise on epidemics: primum non nocere (first, do no harm), even if some place great hope in vaccinating populations that have nothing to gain from it, which is flimsy to say the least as a defence of an (inter)national vaccination strategy.

Quotations from English-language sources are translated back here from the French.