Vaccines against the coronavirus responsible for Covid-19 have brought to light a biological molecule that holds great promise for the medical treatments and the pharmaceutical industry. However, the story of this discovery does not begin in 2020. “Messenger RNA (mRNA) vaccines are the result of 20 years of academic research,” says Marc Graille, an RNA specialist at the Structural Biology of the Cell Laboratory (CNRS/Ecole Polytechnique). These molecules exist naturally in all living species. “They convert information in DNA into proteins, which are the final products that ensure cellular functions,” explains the specialist. These molecules are ‘messengers’ because they make the link between the genetic information locked in the nucleus, and the rest of the cell. They are of great interest to the biomedical world as they control the manufacture of proteins, biological molecules responsible for effects; a family that includes both enzymes and receptors.
A fragile but promising molecule
Marc Graille explains, “mRNA vaccines are made possible thanks to two main discoveries. Firstly, the development of encapsulation systems to inject synthetic mRNA into cells. And secondly, the transformation of mRNA components to control their degradation,” Because these molecules, which are omnipresent in the living world, are rapidly degraded by the body. “Endogenous mRNAs [coming from within] in mammals have small chemical modifications that prevent them from being recognised as exogenous [coming from outside] by the immune system and therefore from being eliminated too quickly,” explains the specialist.
Katalin Karikó and Drew Weissman, two researchers from the University of Pennsylvania, discovered this phenomenon and proposed a strategy to modify synthetic mRNAs. For their work, they are favourites for the next Nobel Prize in medicine. “This discovery was decisive. If the pandemic had occurred five years earlier, we would not have been able to produce such effective mRNA vaccines,” says Marc Graille.
However, despite these chemical transformations, RNA remains a fragile molecule. This contributes to their biomedical significance. “It’s a bit crazy to try to inject such fragile molecules,” admits Marc Graille. “These molecules do not accumulate and break down naturally between a few tens of minutes and two days depending on the mRNA,” he adds. This short lifespan in the body reduces the risk of long-term adverse effects.
Applications beyond Covid-19
In the case of mRNA vaccines, it is the molecules encoded in the mRNA sequence that produce the immune response responsible for vaccination, i.e. the recognition and memorisation of a pathogen marker. It is a molecule of interest to vaccinology because “immunogenicity is inherent in the mRNA itself”, says Chantal Pichon, the French specialist in therapeutic mRNA, a CNRS researcher and professor at the University of Orléans. “Even using modified bases discovered by Katalin Karikó, synthetic mRNA does not quite resemble endogenous mRNA. It retains an immunostimulatory character, which makes it possible to make vaccines without the need for an adjuvant.” Thus, the mRNA molecule stimulates an immune response at the time of injection, thus improving effectiveness of the vaccine.
Chantal Pichon continues, “We know the structure of mRNAs. It takes the form of units whose sequence can be optimised according to the application. This structure makes it easy to build, rather like Lego bricks. For a given field of application, once the structure of the mRNA has been optimised, the coding sequence can easily be changed according to the protein that we want to produce in the cell.” In theory, this molecule can therefore be used for a wide range of applications.
Moreover, the virus responsible for Covid-19, Sars-Cov‑2, was not the first pathogen for which this strategy was envisaged. “We see examples of numerous preclinical studies testing mRNA vaccines against influenza, chikungunya, Zika, Ebola or HIV,” explains Chantal Pichon. “If SARS-Cov‑2 was the first to complete all the stages, it was because the context of the pandemic encouraged funding and risk-taking by testing several candidates which were in the clinical research phases. And several mRNA vaccines could be developed at the same time.”
A solution for dealing with new variants?
In the case of influenza, the mRNA vaccine is being considered for two strategies: for seasonal vaccines, i.e. vaccines prepared each year to target strains assumed to be in the majority in the following winter epidemic, or for a universal vaccine. “This is the type of vaccine we had to produce in my laboratory as part of a European project; one of the main avenues for creating mRNA vaccines against viral diseases without the problems of variants,” says the specialist. “It is a challenge because we need to find an mRNA that stimulates an effective response regardless of the viral variant.”
Other developments are concerned with encapsulation systems. In the future, they will assist in the slow release of RNA to produce long-term effects. Systems can also be created with the necessary hardware to amplify RNA. “This is already possible in research laboratories,” says Chantal Pichon. It may then be possible to use RNA to compensate for missing molecules to treat age-related diseases or genetic diseases. For the latter, “clinical trials are under way to treat myocardial ischaemia (heart attack) or cystic fibrosis”, she adds. The biomedical future of this molecule seems to be assured.