And to think that exactly sixty years ago, in May 1961, the discovery of messenger RNA was published by François Gros and François Jacob, both of the Institut Pasteur, with several renowned American biologists, in two articles by the journal Nature. Witnesses of the time speak of a period of intense scientific excitement. In March, Jacob, Lwoff and Monod had already made known their fundamental work on the regulation of genes that would earn them the Nobel Prize four years later. A great technical skill was needed to specify what this mRNA was, a molecule very quickly destroyed by the organism, whose term of messenger reflects the role of intermediary in genetic mechanisms.
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An essential molecule of living things which it was at the time “unthinkable that use be made, because it is completely unstable”, recalls Maxime Schwartz, former Director General of the Institut Pasteur today. And to estimate that with their work, Ugur Sahin and Özlem Türeci, the founding couple of BioNTech (Mainz, Germany), have indeed made “an extremely risky bet”. But a successful bet. “I was too suspicious, I was not convinced that your anti-Covid vaccine could be injected before the end of the year”, confessed the bacteriologist Pascale
Cossart, perpetual secretary of the French Academy of Sciences and professor at the Institut Pasteur, on May 5, 2021, during a meeting of scientists who have received grants from the European Research Council (ERC). “You have to know how to take risks to make discoveries”, insists the French Jean-Pierre Bourguignon, at the head of the ERC. Could it be risk aversion that prevented such a breakthrough in France?
Challenges. What is the history of BioNTech’s mRNA vaccine?
Ugur Sahin. It’s a ten-month journey, an exceptional process, the fastest of vaccine developments. Less than a year, where the minimum was so far four and a half years. But which comes after a long journey of academic research and investment, for more than twenty years, with very many scientists whom I cannot all thank. One of our plans for 2020 was to launch several clinical trials on the validity of our mRNA treatments for cancer – we are specialists in this disease, not virologists. Except that one Friday evening, while reading the first article describing the epidemic in Wuhan in China, the key information that the Sars-Cov-2 virus had the ability to spread asymptomatically worried us a lot. This was an indication of the high potential of this disease to cause a pandemic.
With what implication?
We knew we had the wherewithal to make an mRNA vaccine quickly, so we felt responsible for initiating development. We studied the scientific literature on Sars-Cov-1 from twenty years ago, to determine which would be the right target to attack the new virus. It turned out to be the spicule (protein that forms the crown peaks of the coronavirus). We then decided to develop some twenty immunogens and assess their capacity to neutralize it in order to find the best vaccine candidate before clinical trials.
How were these conducted?
We started them two and a half months later with four candidates. A partnership with Pfizer ensured the speed of the process, and with Fosun for sourcing in China. We had to analyze the response of the cells of the immune system, estimate the right doses, determine the levels of neutralizing antibodies …
When did you have confidence in this process?
On July 24, 2020, we identified the right candidate – BNT162b2 – to launch phase 3 clinical trials. It caused a very high level of antibodies, higher even in people who had the disease. Based on our cancer results, we felt this was an extraordinary response.
And we were extremely happy to see how effective it was from the first injection, with the second injection boosting the immune response, resulting in 95% protection – 94% against symptomatic infections according to a February 2021 study after vaccination in Israel.
Does the vaccine remain effective against the variants?
The data are good, the neutralization of the variants is stable, including that against the English variant, currently dominant worldwide and responsible for 90% to 95% of cases in Europe. We could achieve collective immunity in July or maybe August, but obviously the problem is not just for Europe. We will only be safe if the whole world is safe. So the question is how to deliver even more doses. With Pfizer, we are forecasting 3 billion doses in 2021. And we are also continuing our research.
In which direction ?
One of the most exciting is that of a self-amplifying vaccine obtained with the help of an enzyme called replicase. This would reduce the required dose of mRNA. According to our preclinical tests, it would be a vaccine 100 times more powerful than the current one. If it works, we could go much faster and that may be a solution for a next generation of projects.
Is the vaccine for adolescents different from that for adults?
Ozlem Tureci. Scientifically speaking, it is no different, but for regulatory reasons we had to test it on 16-17 year olds and then 12-15 year olds. For the same doses, the reactogenicity is the same as in adults, and we even observed a better response of neutralizing antibodies. We are conducting the trials over 11 years-6 months with lower doses.
François Jacob, Jacques Monod and André Lwoff, Nobel Prize in Medicine 1965. Jacob, along with François Gros, published the discovery of mRNA in 1961, the basic research of which they developed at the Institut Pasteur.
Interview by Dominique Leglu