By announcing the abandonment of its most advanced vaccine candidate on January 25, 2021, the Institut Pasteur cast a chill on the prospect of seeing a vaccine “made in France” by the end of the year. The disappointment is all the greater as the failure is that of a flagship technology of the institute: the use of the measles vaccine (MV) as a vector for other viral antigens. Since the early 2000s, this so-called Measles platform has used the live attenuated (non-pathogenic) measles virus vaccine to add pieces (antigens) of other viruses: AIDS, dengue, chikungunya, Lhasa virus … In fact, the measles vaccine is one of the best vaccines available, used for over 40 years, already administered to over 2 billion children for 95% protection without any side effects. By modifying it to make vaccines against other pathogens, it is a question of benefiting from all these advantages. Except that, against all odds, with SARS-CoV-2 responsible for Covid-19, the results of the phase 1 trial conducted on 90 volunteers were disappointing. To the point of convincing the Merck laboratory, a partner of the Institut Pasteur, to stop development. Bruno Hoen, director of medical research at the Institut Pasteur returns to Science and the Future on the scientific reasons for this failure and the many questions it poses.
Bruno Hoen, director of medical research at the Institut Pasteur
Sciences et Avenir: The bet made a year ago to opt for this technology was to go perhaps a little slower than others in development but with more guarantees in terms of safety and efficiency. What happened ?
Bruno Hoen: We were confident about safety and tolerability, and we weren’t disappointed on that side We also had a set of arguments suggesting that immunogenicity (the ability to induce a protective immune response) would be good she did too, but that’s where the formula failed. Our experience with vaccine candidates previously developed on the basis of this technology for other infectious agents showed that the immunogenicity was good in humans. This is particularly the case with the vaccine against chikungunya which is in phase 3 of clinical trial. For the Covid-19 vaccine candidate, the immunogenicity in mice was identical to what could be observed with other candidates. It was therefore reasonable to believe that what had been observed in humans with these other vaccines would be reproducible. We had also demonstrated with the chikungunya vaccine that the pre-existence of anti-measles immunity had no impact on the immunogenicity of the vaccine. The rational was therefore there …
What exactly are the data that led to the decision to stop development?
These are the data from the interim analysis conducted by Merck. This involves measuring the antibody titers of volunteers who have received the vaccine in order to compare them then with titers obtained in several populations of people cured after a natural infection as well as with the data published in the literature concerning vaccines already marketed or in the process of being. If we focus on the level of neutralizing antibodies, those associated with antiviral protection therefore, we have antibody titers two to three times lower than the averages observed in a group of convalescents from a natural infection. There were several groups, some had a low dose, others a higher one, at different times … So there is variability, but in the most optimal situation, after the second vaccine dose, the titers of The antibodies are significantly lower in a ratio of a quarter to a half compared to the titers measured in the sera of convalescents. And the difference is even greater when compared to the titers obtained with the messenger RNA vaccines from Pfizer and Moderna and, to a lesser extent, that of AstraZeneca. It’s completely unexpected, and nonetheless indisputable.
How to explain this very bad surprise?
We will have to find answers. We just received the full data from the 90-person trial, and now needs to be analyzed in detail. But there are several avenues that we have listed. For what we know so far – there is no problem on this side – but first we must make sure that there has not been a problem with the batch of vaccines. Next, could the subjects’ measles vaccination status have an impact on the recognition of the SARS-CoV-2 antigen? We will also have to see if there is a difference in response depending on the titer of the pre-existing measles antibody (if the immune response against measles is very strong, it could prevent the measles vector from adequately presenting the SARS-CoV-2 antigen, editor’s note.). But this is not what has been observed so far with the various vaccines developed thanks to this Measles platform. Could it be that the viral vector is alive? Is there a possible link between the immune boost to measles probably induced by the vector and the poorer response to SARS-CoV-2? For the moment we have listed the questions, but it’s a bit early to understand.
Measles technology finally abandoned against SARS-CoV-2?
We are in the usual model of a partnership with a vaccine industry since the Institut Pasteur is not intended to be a vaccine developer in the industrial sense of the term. From what we understand from Merck’s position, there are enough arguments today to think that the probability that this vaccine in its current form could be effective is too low in view of the immunogenicity observed so far. here. So they make a radical decision by saying “let’s stop”; both for the economic risk but also because we cannot hire other volunteers if we consider that the chances of success are not sufficient. To relaunch it, we would need another partner, and for now, we have not thought about it at all. That said, the Measles platform continues to develop other vaccines, in particular against chikungunya and the Lhasa virus.
Have the “new variants” of the coronavirus and more generally the natural evolution of SARS-CoV-2 which threatens to escape the antigens chosen so far played a role in this interruption?
This dimension was not taken into account by Merck to interrupt development. First, because the immunogenicity data cited is what it is. Secondly, because there is still too little data to provide a basis for reflection. There is some evidence that the probability that mRNA vaccines will see their effectiveness reduced is low on the variants known so far. But too many questions remain at this time: do antibodies sum up protection or are there other correlates such as mucosal immunity or cellular immunity?
The big winner in this vaccine race is messenger RNA. Will the Institut Pasteur in turn embark on this new technology?
Currently, there is no team specialized in the manufacture of messenger RNA biomedicines. But of course that’s a question we ask ourselves. And we must recognize that the story is incredible both on the side of Moderna and BioNtech who had the intuition that it was a real avenue to develop. They were right to have this intuition in January 2020, then the enthusiasm to develop the vaccine candidate very quickly. They had their messenger RNA code as early as January. It is an extraordinary scientific adventure, completely unexpected but which deserves to be greeted and savored. Almost nobody could imagine this a year ago.
For our part, we must put failure into perspective because it is despite everything a known hazard of a research project: we are never sure that it will succeed. We also know that more often than not, it fails. We would have preferred to succeed, of course, but this is the scientific process as it should be conducted.