Un pharmacien prépare le vaccin à ARNm de Pfizer en vue de l’administrer au personnel et aux résidents d’un établissement pour personnes âgées, aux États-Unis, le 30 décembre 2020. Dans ce pays, plus de 2 millions de personnes ont déjà été vaccinées contre la Covid-19. Brendan Smialowski / AFP

Advantages, disadvantages, risks… What you need to know about RNA vaccines

Destinations

RNA used for vaccination belongs to the class of messenger RNAs (mRNA).
These small molecules have been known since the 1960s, when François Jacob and Jacques Monod, two French scientists, played a major role in their discovery.
Messenger RNAs are present in a fleeting way in our cells. In a way, they form the “assembly plan” of proteins: in the cell nucleus, the information corresponding to a given protein, carried by DNA, is “copied” in the form of an mRNA molecule.
This then passes into the cytoplasm (the space between the nucleus of the cell and its membrane). It will be read there by the ribosomes, the units responsible for the production of proteins, then destroyed.

This is the function of mRNA vaccines. The principle is to inject into cells the information allowing them to produce a protein of the infectious agent against which one wishes to obtain immunity. The cells of the vaccinated individual will make the viral component themselves, triggering an immune response.

It has long been difficult to work with RNA molecules due to their fragility. But thanks to scientific progress, things have changed, and today we can consider using mRNAs as a vaccine.

What are the advantages and disadvantages of RNA vaccines?

Use mRNA to vaccinate presents of numerous advantages.

First, it is a safer approach to vaccines in all stages, from conception to use, because no living thing is handled.
The manufacture of mRNA vaccines has also become “simpler” than that of other types of vaccines, whether they are live attenuated vaccines (based on the use of live infectious agents modified so that they lose their potency. infectious) or inactivated vaccines (which contain “killed” infectious agents or fragments of infectious agents).

The production of these two types of vaccines against viruses usually requires the use of cell cultures or embryonated eggs, under very controlled conditions.
MRNA vaccines avoid these expensive steps because they are produced by chemical synthesis. In addition, unlike live attenuated vaccines, there is no risk of a return to virulence, since they do not contain an infectious agent.

In addition to the fact that mRNA vaccines are easy to produce and inexpensive, their adaptation to changing pathogens can occur quickly. If a new mutated viral variant against which the vaccine would be less effective emerges, it suffices (theoretically!) To modify the sequence of the mRNA to match that of the new viral variant in order to regain the lost effectiveness.
Finally, a consequence of their original presentation to the immune system is that mRNA vaccines generate balanced immune responses between the cellular (lymphocytes) and humoral (antibody) components. However, these balanced responses are more effective in fighting viruses.

The disadvantages of these mRNA molecules are mainly related to their rather poor stability. Indeed, they are fragile molecules and their conservation is not always obvious even if progress has been made in recent years (lyophilization). Whether outside or in cells, mRNAs disappear quickly, due to their molecular structure …

Another disadvantage is that when mRNAs are foreign to our cells, they activate type 1 and 3 interferon responses (interferons are proteins produced in particular in reaction to viral infections). These responses result in their degradation and may reduce the induction of the desired immune response upon vaccination.

Can RNA Vaccines Modify Our Genomes?

The mRNAs of the vaccines developed against COVID-19 are not genetically modified organisms (GMOs) and do not constitute a gene therapy approach. Indeed, they are just pieces of nucleic acids inspired by viral genomes, which do not have the capacity to modify our genes.
Remember that mRNAs remain in the cytoplasm of cells and are not intended to reach the nucleus. In order to enter this part of the cell, the molecules present in the cytoplasm must carry a specific “labeling”. In addition, transport molecules should intervene to take them there.
And even if these vaccine mRNAs enter the nucleus, RNA cannot integrate into our genome without being transformed into DNA (we speak of reverse transcription), which requires very specific enzymes, called reverse transcriptases.
These are most often viral: they are found in viruses of the Retrovirus family (such as HIV, which causes AIDS) and Hepadnaviruses (such as the hepatitis B virus).
Somewhat specific proteins with reverse transcriptase activity, such as eta DNA polymerase, also have been identified in our cells.
However, these proteins are not located in the cell cytoplasm and are not intended to interact with mRNAs. A modification of our genomes by an mRNA is therefore more of (science) -fiction …
Furthermore, it is not enough for reverse transcription to take place: the integration of the DNA obtained into the genome would require the presence of other enzymes called integrases. And if we push the fiction to the point of considering integration despite everything, this would not necessarily lead to deleterious effects for the host cell.
This would require that this fragment fit into a region that contains a gene, but genes do not make up most of our genome. Finally, such a modification would not be transmitted to the offspring anyway.

For all these reasons, the “risks” of modifying our genomes by mRNAs are virtually statistically nil. We run infinitely higher risks when we take our car or board a plane …

Have mRNA vaccines been developed too quickly?

This remark comes up frequently in recent debates. Here too, it should be remembered that vaccination with nucleic acids, including mRNA, is a long history (the first attempts to use mRNA for vaccination date back to the early 1990s).

Very many preclinical publications relating to this approach in animals (rodents, pigs, cattle and macaques, etc.) have been published and have not shown any major side effects. In addition, the clinical tests in humans (from phases 1, 2 and 3) demonstrated excellent vaccine efficacy and no more side effects than with conventional vaccines.

It should be noted in passing that even in the placebos groups (that is to say in which no active ingredient has been injected), side effects are reported. This means that these side effects are partly related to the injection itself.

Finally, in veterinary medicine, DNA vaccines have been available for several years (West-Nile Innovator® against West-Nile disease in horses, Oncept Canine Melanoma® against oral melanoma in dogs and Clynav® against pancreatic disease in salmon ) and no major adverse effects have been reported.

What about the allergic phenomena observed in some patients in the United States and the United Kingdom?

Allergic reactions have been reported in some patients following vaccination. Post-vaccination allergic reactions, although rare, are well known. They are linked to certain components of the vaccines for which the vaccinated patients would have been sensitized previously (in their everyday life or during previous vaccinations including the same compound).

Faced with the risk of allergies, we are not all equal, and our genetic heritage plays a large part. Any allergic reaction (type 1 hypersensitivity) goes through a phase of sensitization to the antigen (the substance recognized as foreign by the immune system, which triggers the reaction) – the first time it is encountered – then through a phase of latency. Later, when confronted again with the same antigen, the body develops the allergic reaction.

Regarding allergies following vaccination against COVID-19, these have been compared to a substance, polyethylene glycol, present at low dose in a vaccine formulation. This substance, in common use, has been identified as an allergen in rare cases and would have posed a problem in people at known or unidentified allergic risk. In the United States, where more than 2.1 million people have already been vaccinated, allergic reactions have actually been noted, but they are rare.

Generally, people at risk know each other and for this it is advisable to be vigilant with mRNA vaccines, just like more conventional vaccines, but also with simple antibiotics or even the most classic foods (peanuts, fruits of sea…).

Benefit / risk ratio

Medical treatment is never a trivial act and vaccination is no exception. It must be the subject of a rigorous benefit / risk analysis, for ourselves and for the community, nationally and internationally. In the case of the current COVID-19 pandemic, it is clear that the risk associated with the use of mRNA vaccines is very low while the health, economic and social risks of the COVID-19 crisis are at the fore.

The use of these new weapons – closely monitored by those in charge of pharmacovigilance – could constitute an important step forward in the fight against infectious diseases. And the revolution might not end there: indeed, RNA could also be used for fight against cancer, orphan diseases, and even against allergies !

Francois Meurens, Professor Immuno-Virology (DMV-PhD) – Oniris (Nantes-Atlantique National Veterinary, Food and Food School), UMR 1300, Inrae

This article is republished from The Conversation under a Creative Commons license. Read theoriginal article.