Health: the messenger RNA revolution is just beginning

Last year, she missed the boat. But by the end of the decade, it is hard to see how Katalin Kariko could escape the Nobel Prize for Medicine. The prestigious distinction is awarded to “persons who have brought the greatest benefit to humanity”. However, this biochemist of Hungarian origin, today vice-president of the German laboratory BioNTech, is the researcher who highlighted the extraordinary capacities of messenger RNA (mRNA).

His work led to the development of the first vaccines against the coronavirus. With the efficiency that we know. “This breakthrough opens up a new aspect of medicine. It is a revolution comparable to that brought about in the 1990s by monoclonal antibodies, with the appearance of biotherapies for the treatment of cancers and chronic inflammatory diseases”, Judge Chantal Pichon , researcher at the Center for Molecular Biophysics (CBM) of the CNRS in Orléans and recognized specialist in mRNA.

This is not the least of the paradoxes of the complicated period that the planet has just known: responsible for carnage (6.3 million deaths and 542 million people affected, according to the latest score from the American university Johns Hopkins ), the pandemic has also caused an electric shock… positive.

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First of all, it was at the origin, with the advent of mRNA, of a major technological breakthrough which gives hope for future novel therapeutic solutions in many fields. It then forced laboratories and health authorities to think about new operating patterns which, in the future, will make it possible to respond to crisis situations more effectively. Finally, it consecrated the rise of biotechs and accelerated the redistribution of the cards in a pharmaceutical sector where, tomorrow, “big” will no longer necessarily be synonymous with “beautiful”.

“Messenger RNA did not fall from the sky on a fine day in January 2020”, recalls Thomas Borel, scientific director of Leem, the business lobby of the pharmaceutical industry sector in France. In the labs, there is indeed a long time that we worked on it. Its role of “informant” with the cells so that they manufacture the proteins necessary for the functioning of the organism was described for the first time in 1961 by two French researchers, Jacques Monod and François Jacob (both Nobel Prize 1965) . But the idea of ​​using it to make a vaccine took time to take hold.

The story accelerated in 2005 thanks to Katalin Kariko. That year, the researcher and her immunologist partner Drew Weissmann succeeded in making slight modifications to the mRNA to avoid the strong inflammatory reactions seen when injecting mice. Ten years later, a new breakthrough: the researchers succeeded in encapsulating RNA in “lipid nanoparticles”, in order to prevent its rapid degradation and facilitate its penetration into the cell.

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It will be necessary to wait until 2020 and the eruption of Sars-Cov2 to really cause a revolution. For the first time, classic vaccination, which consists of inoculating an attenuated or inactivated infectious agent to trigger the immune response, was no longer predominant. In the race against the disease, American laboratories Pfizer – associated with BioNTech – and Moderna, as well as the German CureVac, have indeed embarked on the development of candidate vaccines based on mRNA.

All in record time, the development of serum does not require the cultivation of pathogens in the laboratory. The principle ? Inject a genetic sequence of the target virus inside the cells. In response, the body produces non-harmful viral proteins that it memorizes. If the person is then actually exposed to the virus, their immune system recognizes and destroys it.

Used for the first time in human vaccinology, the new weapon has kept its promises. And opened up vast prospects for the future. Because, if it knows how to attack Sars-Cov2, the mRNA can also track a host of other viruses on which the labs are now focusing their work: shingles, respiratory syncytial virus (RSV), very serious in infants, or even HIV, a target of Moderna…

“For diseases where effective vaccines already exist, such as those for hepatitis B or tetanus, there is no reason to change the approach. On the other hand, for new vaccines or if it is necessary to act quickly to adapt to the evolution of a viral strain, in the case of the flu for example, mRNA is a real plus”, comments Professor Jean-Daniel Lelièvre, head of the infectious diseases department at Henri Hospital -Mondor de Créteil (94).

Beyond viral diseases, the technology also raises immense hopes in the treatment of cancers. “The mRNA could be applied in immunotherapy. Instead of using a copy of a virus to make the immune defenses react, we will use antigens specific to cancerous tumors”, explains Rodolphe Renac, partner of the consulting firm in Alcimed innovation and director of its office in the United States.

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Thanks to the manna of anti-Covid vaccines (Moderna made 12.2 billion dollars in profits in 2021, against 747 million losses a year earlier, and BioNTech 10.3 billion euros), labs at the forefront of mRNA and which had already started oncology trials went into overdrive. “We have massively reinvested in vaccines, but also in solutions in oncology and rare diseases”, confirms Emmanuelle Blanc, medical director for vaccines at Pfizer in France. The German partner BioNTech has notably initiated promising developments in the treatment of solid tumors of the ovaries, bladder, kidneys, but also metastatic melanoma…

For its part, Moderna has also launched trials in cardiology to repair heart cells after a myocardial infarction. “Currently, there are 400 clinical trials in the world at different stages based on messenger RNA technology”, emphasizes Rodolphe Renac.

The main labs working on mRNA

Capital

When will these solutions be available? For the very strategic influenza vaccine, a global market estimated at 6.7 billion euros, Pfizer expects a date as close as 2025 or 2026. New serums against Covid and capable of covering a large number of variants will be ready before. As for oncology and rare diseases, we will have to wait a little longer.

“In three or four years, we will have validations of hypotheses, but establishing a timetable is very risky as the hazards of clinical research are numerous”, specifies Thomas Borel at Leem. Improvements in technology will be required. To facilitate the preservation of vaccines (today, they must be kept in the freezer), limit side effects, prolong the immune response, find a more precise delivery system…

One thing is certain: tomorrow, the lessons of the Covid crisis will be learned. The general mobilization it has aroused has in fact made it possible to shorten the time needed between the preclinical phases and the marketing authorizations by the health authorities as never before. The first vaccines were thus developed in the space of a year, whereas it usually takes ten! “It’s a record from all points of view. Since the end of 2020, 13.9 billion doses have been produced and 10 billion have been administered”, is amazed Thomas Borel. The lower complexity of manufacturing messenger RNA vaccines (no antigens to cultivate) partly explains this time saving. But the overhaul of the ways in which the laboratories and the ecosystem as a whole operate also played an enormous role.

“Clinical trials generally take several years because everything is done in sequence. At each stage, the results are submitted to the authorities who ask for time to decide. With Covid, on the contrary, developments were carried out in parallel on several candidate vaccines , until being able to produce and deliver them. The authorities, for their part, practiced “rolling reviews”, real-time evaluations”, explains Emmanuelle Blanc, at Pfizer.

According to observers, all these approaches have a good chance of being sustained. Just like the preponderant role of biotechs in developing the drugs of the future based on mRNA, now considered the Holy Grail of the pharmaceutical industry. “To respond to the Covid crisis, innovation did not come from large laboratories specializing in vaccines, but from small private or academic structures”, underlines health economist Pierre-Yves Geoffard.

The French Sanofi, unable to release a convincing product against the Covid in due time, swore to itself, but a little late, that it would no longer be taken. To catch up, he acquired last year for 3.2 billion dollars Translate Bio, a biotech expert in messenger RNA with which he had been collaborating since 2018. He also bought Tidal, an American company which uses a mRNA technology to reprogram immune cells in the body. The bill should amount to a total of 310 million dollars.

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“These acquisitions will allow us to expand the therapeutic areas in which we operate in oncology, inflammatory diseases and rare diseases”, specifies Jean-François Toussaint, the R&D world boss Sanofi Pasteur. Vaccines against acne or chlamydia would also be planned. A sign of its conversion to the virtues of mRNA, the lab, which for its serums relied instead on a competing approach called “recombinant protein-based” (it involves artificially creating virus proteins which, once injected, trigger the immune response), has just created a center of excellence dedicated to new technology. The group plans to invest 400 million euros per year over five years. No doubt: the messenger RNA revolution has only just begun.

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