Covid-19: Could future variant vaccines be less effective?

Today, vaccines are the main hope for getting rid of Sars-CoV-2. However, there is still concern: will they be effective against variants, these strains of the virus which mutate and can escape, at least partially, the immune response generated by the body after a “natural” infection or after the injection of a vaccine? ? Several responses are being considered in order to counter the evolution of the coronavirus, such as the injection of new doses of vaccines adapted to the variants. However, experts worry that these future vaccines will not be as effective as those of today, this because of a quirk of the immune system called “the original antigenic sin”.

This mechanism refers to the fact that when our immune system is first confronted with an infectious agent, such as a virus, it will build a response against it and remember it through immune memory. This mechanism is useful most of the time, but it can sometimes backfire, for example when the immune system encounters a slightly different version of the same infectious agent. In this case, our memory can “trap” itself by favoring the defenses erected during the first, rather than a new response more suited to the mutant virus.

When immune memory fails

“When we are infected, B cells [des globules blancs, NDLR] of the immune system will produce antibodies against the virus. When the virus has disappeared, the cells that produced these antibodies become memory cells, explains Morgane Bomsel, virologist and CNRS researcher at the Cochin Institute. If the pathogen returns to the body, these cells recognize it, reactivate very quickly, multiply and thus make more antibodies. “But if this pathogen comes back into the body in a slightly different form, several cases can occur. Either the B cells produce antibodies which recognize the threat and are able to fight it, or they recognize it in part, and produce antibodies which are not necessarily protective, or they do not recognize the antigen, because it is too different, and see it as a new threat against which they are making new antibodies. “The problem is that sometimes the immune response that recognized the pathogen the first time prevents the production of a new one. response more suited to the new pathogen “, points out the researcher.

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This phenomenon has for example been observed in the case of the human papillomavirus. One of the first vaccines created against him aimed to generate an immune response against four antigens [des parties du virus qui engendrent la création d’anticorps, NDLR]. Then, as the virus evolved, researchers created a new vaccine containing the four starting antigens, plus five new antigens, to target the papillomavirus variant. “People who had received the first vaccine were entitled to a booster dose with the new vaccine, but the researchers found that they did not produce an immune response against the five new antigens, details Morgane Bomsel. people who had received only the second vaccine had formed a response against all nine antigens. ” A perfect illustration of the original antigenic sin.

A debate that agitates the scientific world

Could this mechanism occur in the case of Sars-CoV-2? In the research community, the debate is far from settled. And for good reason, the coronavirus appeared only a little over a year ago, and the first forms of variants have only existed for a few months: the lack of hindsight is still too important to comment. “Revaccinating against a variant is not complicated, but we do not yet know which immune response will be expressed: will it strengthen the immune response against the classic strain rather than revealing new antibodies against the variants? at this level “, summarizes Yves Gaudin virologist and researcher at the CNRS. In an interview with the specialized media Stat, American researchers who have observed the original antigenic sin at work in various influenza viruses believe that the phenomenon could recur for Sars-CoV-2. “I think that’s something we need to be concerned about,” said Michael Worobey, professor of evolutionary biology at the University of Arizona. still stuck in immune memory from memories of the first Sars-CoV-2 “. For Morgane Bomsel, original sin indeed deserves special attention. “This happens for some viruses, but that does not mean that it is the case for all pathogens, she nevertheless stresses, cautiously. All this is not yet well understood and it must be remembered that the immunology is not physics or chemistry, it is a whole series of black boxes. ”

Bruno Pitard, research director at the CNRS in the Nantes-Angers immunology oncology research center, is optimistic. This specialist in messenger RNA vaccines reminds us that immune memory knows how to stack different information. “Of course, immune memory is built with the first infectious episode, but if you are vaccinated again or infected with a variant, the body will create a new specific memory.” Above all, even if the coronavirus mutates, it does not transform drastically either, he insists. Indeed, the S protein of the coronavirus, the famous spicule which surrounds the virus and which researchers use to create vaccines, does not mutate entirely: only certain parts evolve and deceive the antibodies. Therefore, even if the “original sin” turns against us and slows down the construction of a response more suited to a variant, Bruno Pitard believes that the immune system will still be better armed after a first infection or a first vaccine than if he has never encountered Sars-CoV-2.

Other researchers are even more critical. This is the case of Christine Rouzioux, professor emeritus in virology at the Faculty of Medicine of Necker and member of the Academy of Medicine, who is not far from calling fake news the idea that original sin could apply to Sars-CoV-2. “Definitely, I do not think that this flag of original sin should be waved. First because, concerning the flu, it is a question of long-term hypotheses which are more or less confirmed, then because the viruses of influenza and Sars-CoV-2 do not compare: the diversity of the protein S of the coronavirus is much less important than that of the hemagglutinin H of the influenza, without forgetting that the influenza dies in summer every year and that a a new form arrives in winter, which is not the case with the coronavirus which persists everywhere on the planet. Finally, because messenger RNA vaccines are much more powerful than what has never existed for influenza ” . According to her, part of the answer lies in the technology used by vaccines, and in particular their ability to make the immune system recognize not part of the S protein, but its entirety, which is, according to her, is the the case of the Pfizer vaccine. Like Bruno Pitard, Christine Rouzioux believes that the different immune responses induced by the different strains will overlap, and not cancel each other out.

In an interview with BFMTV, Ugur Sahin, CEO of BioNTech, indicates that his company has already studied more than 30 variants to verify whether their mRNA vaccine – which they are developing with Pfizer – is effective. “Even for the variants that cause a weaker immune response, we still get a sufficient response, this is the case with the South African variant, he explains. And against the British variant, which is the one that spread the most in the world, we have a 97% success rate, which is more than against the original Wuhan variant. ” If these results are encouraging, it should nevertheless be emphasized that they were carried out in the laboratory and are not necessarily representative of what will happen inside human bodies. “We must remain very careful in our statements today, because phenomena that we do not see or that we do not understand can occur, analyzes Morgane Bomsel. Anyway, I do not believe that the 100% vaccine solution will be viable because of all the variability in immunological issues? We also have to focus on drugs. I think it’s probably the combination of the two that will get us out of the pandemic. ”



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