mRNA: these four letters, an acronym for messenger ribonucleic acid, have been the source of much hope for several months. This technology, which came into the spotlight with the covid-19 vaccines, holds other promises. What do we know so far? Here are some insights from experts.
The "lack of experience" with messenger RNA vaccines against Covid-19 is often pointed out by naysayers. Yet mRNA is far from being an unknown technology to scientists.
Messenger ribonucleic acid (also called messenger RNA, or mRNA) is a copy of DNA (deoxyribonucleic acid), which allows the synthesis of proteins within cells. It was discovered in 1961 by two French researchers at the Pasteur Institute: François Jacob and Jacques Monod. This scientific breakthrough earned them the Nobel Prize in Medicine in 1965.
The first evidence of its effectiveness was provided in 1993: French scientists demonstrated the effectiveness of the first mRNA vaccine against the influenza virus in mice. In 2008, a Franco-German team published the first clinical trial of an anti-cancer mRNA therapy in humans (in the context of research on melanoma).
Twelve years later, in 2020, a major milestone was reached with the approval of the first mRNA vaccines against covid-19 (Pfizer-BioNTech and Moderna), less than a year after the start of the pandemic.
Will messenger RNA cure all types of disease?
In theory, yes, says Prof. Steve Pascolo, a research immunologist at the University Hospital of Zurich (Switzerland):
"There is theoretically an mRNA solution for every disease, whether in the form of vaccines or therapies. Trials have begun with preventive vaccines against infectious diseases such as influenza, bronchiolitis, cytomegalovirus, Ebola or HIV, which could be validated in 2022 or 2023.
At BioNTech, curative cancer vaccines are also being studied, including Parkinson's, cystic fibrosis, COPD, regenerative therapies to repair organs... However, it is likely that the development of these applications will take a little more time.
In fact, mRNA has been tested as a drug in its synthetic form for about 30 years, but it has long been scorned by the academic and medical world on the grounds that it was too fragile to be effective.
A barrier that has fallen due to the success of coronavirus vaccines that use this approach, and the speed of their development."
mRNA: "a safe and highly effective vaccine weapon against Covid-19"
"Messenger RNA is a safe and very effective vaccine weapon against Covid-1," hammer the National Academy of Medicine, the National Academy of Pharmacy and the Academy of Sciences. In a joint press release published on August 5, 2021 (source 1), they denounce the "false information" circulating around vaccines based on messenger RNA (Pfizer/BioNTech vaccine and Moderna vaccine): "Issued and maintained by a small minority, these untruths are not based on any scientific data, but their wide dissemination, especially through social networks, maintains the doubt and confusion.
Also, the Academies recall several points:
- Scientists and industry have been developing and improving messenger RNA platform technology for more than 30 years, which has been shown to be highly effective for vaccination against SARS-CoV2. Messenger RNA vaccines induce more than 90% protection against symptomatic forms of Covid-19 and almost 100% protection against severe forms;
- These vaccines are remarkably safe; they have undergone pharmaceutical development and good practice clinical trials for marketing and have been validated in emergency pandemic procedures by health authorities in Europe and the United States;
- After the injection of billions of doses, vaccine efficacy and safety have been largely confirmed by all real-life epidemiological studies and by pharmacovigilance;
- Vaccine messenger RNA is rapidly degraded after translation into vaccine protein and, like physiological RNA, does not integrate into the human genome;
- Messenger RNA vaccines have the advantage that they can be produced rapidly in large quantities and could be easily modified, if necessary, in the face of possible escape mutations carried by new variants;
- SARS-CoV-2 variants have emerged in highly infected populations in countries with the lowest vaccination coverage rates;
- Many countries do not yet have enough vaccine to immunize their populations; when they can, they use other vaccines that are cheaper and easier to distribute. In wealthy countries such as France, which have enough messenger RNA vaccines to immunize their entire population, rhetoric that creates hesitation or even opposition to vaccination is no longer acceptable;
- The Covid-19 pandemic is likely to continue as long as the whole of humanity has not acquired immunity, either through infection, but with serious consequences, or through vaccines. Only a universal vaccination will make it possible to stop it.
And to conclude: "the development of new vaccines using messenger RNA is a huge success of science. It provides a very effective weapon without which it is currently impossible to defeat the Covid-19 pandemic".
How do Covid-19 messenger RNA vaccines work?
Pfizer/BioNTech and Moderna Laboratories were the first to announce preliminary efficacy results for their Covid-19 vaccine candidate (November 2021). These Covid-19 mRNA vaccines consist of an intramuscular injection of a messenger RNA, which will replicate the Spike protein (S protein), present on the surface of the SARS-CoV-2 coronavirus. "This protein constitutes the 'key' allowing the virus to cling to the cells then to penetrate them and infect them", explains Inserm (source 2). And to specify:
the choice of an RNA vaccine rather than a DNA vaccine was made so that the Spike protein could be produced directly in the cytoplasm of the vaccinated person's cells, without passing through the nucleus.
The principle is simple: push our cells to create targets: "the mRNA is encapsulated in positively charged lipid nanoparticles to enhance its stability, and to facilitate its penetration through the membrane (negatively charged) of the muscle cells where it is injected at very low dose. Once in the cytoplasm at the level of the ribosomes, the mRNA encodes the synthesis of viral S proteins. These migrate to the cell surface and are recognized by B lymphocytes which produce anti-Covid antibodies. Other Spike fragments are digested by dendritic cells (called antigen-presenting cells). These cells present these Spike fragments to T lymphocytes, which are responsible for immune memory," explains Jacques Augé, university professor of chemistry (CY Cergy Paris Université), in an article published on July 5, 2021 on The Conversation website (source 3). This salutary training of the immune system allows the rapid elimination of coronavirus in case of real infection.
Can mRNA vaccines change our DNA?
The RNA injected via the vaccine has no risk of modifying our genome, or of being transmitted to our descendants, insofar as it does not penetrate the nucleus of the cells. However, it is the nucleus of the cells that contains our genetic material.
"Moreover, the injection is local and the cells that receive the RNA coding for the Spike protein are mainly the muscle cells: in no case does the RNA go as far as the cells of the reproductive organs (the gonads). It cannot therefore be transmitted from one generation to the next", adds Inserm.
And to remind: "the cells producing the Spike protein following the injection of the vaccine are quickly destroyed by the immune system. The foreign RNA does not remain in the body for long: it produces just enough to train the immune system to react in case of a 'natural' infection by the virus before being eliminated.
Messenger RNA, a promising technology against cancer
Messenger RNA triggers "highly targeted responses against cancer," says Dr. Palma Rocchi, director of research at Inserm and head of the Nanoparticles and Therapeutic Targeting group at the Marseille Cancer Research Center (CRCM).
"In the field of cancer, mRNA technology opens the door to true personalized medicine, which we do not have at present. Where it takes ten years to develop a drug that specifically targets the genetic mutation that causes a tumor, this technique could make it possible to produce an individualized treatment in a few months, and thus to treat and prevent the risk of relapse more quickly and effectively.
To do this, two strategies are being explored: the first consists of directly blocking the expression of the mutated gene(s) in order to short-circuit the cancer; the second aims to stimulate anti-tumor immunity in order to better fight it. In addition to melanoma, we hope that this mRNA technique can be applied in the coming years to other frequent and/or very aggressive cancers, including those currently under study: breast, ovarian, prostate, certain digestive or lung cancers, and certain leukemias, to name a few."
As of January 1, 2021, 44 clinical trials exploring messenger RNA vaccines or therapies are underway, nearly half of which are in the field of cancer (source 4).
Messenger RNA against cancer: how does it work?
- Cancer cells are taken by biopsy to identify specific proteins of the tumor: these are the tumor antigens.
- The genetic code of these tumor antigens is analyzed to produce the corresponding messenger RNA in vitro, in the laboratory.
- This synthetic mRNA is injected into the patient's skin, muscle or blood. Tumor antigen is produced.
- This stimulates the patient's immune system to produce killer T-cells capable of destroying only the cancer cells.
How is messenger RNA made?
The mRNA used in vaccines or therapies is a synthetic molecule, produced in the laboratory.
- Researchers isolate in the genome (of a virus, a cell...) the DNA sequence coding a precise protein, for example the Spike protein of the coronavirus.
- From this sequence, they synthesize in the laboratory the mRNA, a kind of "instruction manual" that will be used by the cells to produce the targeted protein themselves.
- Before being injected, the mRNA is encapsulated in very small droplets of fat that protect it and allow its penetration into the cells.
While it is rather easy and quick to identify the mRNA that is needed, its manufacture remains complex and costly, according to Prof. Chantal Pichon, professor of cellular and molecular biology at the University of Orleans.
And the director of research at the CNRS ("Innovative Therapies and Nanomedicine") elaborates: "In fact, this molecule is made up of a structure with several parts that must be assembled one after the other, a bit like a Lego game. But to form all these 'bricks', we need at least five ingredients for which we have to buy the patents, which are expensive.
Another limitation is the quantity of mRNA that must be manufactured and injected. While very little is needed for vaccines, much more is likely to be needed for therapeutic applications, and other components may have to be added. This could pose a production problem, as well as questions about possible side effects. Studies will therefore have to be carried out to assess the benefit/risk ratio of mRNA therapies compared with conventional treatments.
What is certain, however, is that mRNA does not risk modifying our genes and, once its message is delivered to the cells, it is destroyed and disappears within a few days of the injection."
To learn more about the discovery of messenger RNA, visit the Institut Pasteur website.
Sources :
Source 1 : Messenger RNA: a safe and highly effective vaccine against Covid-19, press release from the French National Academy of Medicine, the French National Academy of Pharmacy and the French Academy of Sciences
Source 2 : mRNA vaccines that can modify our genome, Inserm
Source 3 : The wonderful story of messenger RNA and its vaccine power, The Conversation
Source 4 : GlobalData, January 2021
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