Messenger RNA Vaccines: How Do They Work and Are They Safe?

Pfizer’s vaccine, which is believed to be 90% effective in preventing Covid-19, is an RNA vaccine that is based on a technology whose foundations were laid only two decades ago. How does it work? What are its advantages and disadvantages?

COVID-19 Vaccine

COVID-19 Vaccine

Types Of Vaccines

Vaccines are pharmaceutical products designed to stimulate the immune system to target and eliminate a pathogen. When we look at the ingredients of the different vaccines, we see that there are many ways to achieve this goal.

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Vaccines can be divided into two broad families: those that contain infectious agents and those that do not. The vaccines that contain the infectious agents are the historical vaccines, those of Pasteur and Jenner. These in turn fall into two categories: live attenuated vaccines, which contain the entire pathogen but are weakened by chemical or physical treatment, and inactivated vaccines, which contain a version of the pathogen that cannot replicate.

With the development of genetic engineering and molecular biology, vaccines without an infectious agent have emerged. They rely on the injection of a protein, toxin, or virus-like particle created from scratch.

Pfizer’s Covid-19 vaccine is an RNA vaccine that does not require an infectious agent. The immunogenic properties of RNA were not discovered until the 1990s. The first applications of this technique were in cancer, and the first clinical trial was conducted in 2002. However, the first preclinical trials with infectious agents did not take place until 2012.

This technology is still the subject of research. Currently, no messenger RNA (or mRNA) vaccine is on the market for use in humans. Several are in clinical trials, including Pfizer’s. However, they are already being used in animals, particularly in pigs.

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How messenger RNA vaccines work, their advantages, and disadvantages

Messenger RNA vaccines, as the name implies, are based on the injection of a synthetic messenger RNA. This comprises the sequence of the protein of interest as well as other non-structural proteins that facilitate its translation through the cellular machinery.

Not all mechanisms of action of mRNA vaccines have been elucidated yet, but it seems that many cell types are able to internalize these RNAs, which are then translated into proteins. This process mimics what happens in natural infection, where the cell “infected” with mRNA antigens presents them to immune cells via its MHC. Messenger RNA vaccines have been shown to stimulate both the cellular immune response (CD4+ and CD8+ T cells) and the humoral immune response (activation of B cells and the production of antigen-specific antibodies).

The mRNA can also trigger innate immunity. Dendritic cells, monocytes, and B lymphocytes strongly express TLR 7, a specific intracellular recognition system of non-pathogenic RNA (PAMPs-PRRR system). When TLR7 recognizes single-chain RNA, cells secrete IFN-alpha and other chemokines. These cells, which are all antigen-presenting cells, also activate T cells through their TLR7. Here, it is the RNA molecule itself that activates these mechanisms and not the translated protein antigen.

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mRNA vaccines are therefore capable of activating both sides of the immune response with sufficient intensity without the need for an adjuvant. To improve the stability of RNA, researchers encapsulate it in lipid bubbles called liposomes, in which the RNA is stabilized by cationic polymers (the RNA is charged – ). This protects it from ribonucleases present in tissues and blood and improves its penetration into cells.

Pfizer’s recent press release does not explain the nature, duration, and variations of the vaccine-induced immune response, based on the profile of clinical trial participants. It is expected that these data will be published in a scientific study soon.

Advantages and disadvantages of mRNA vaccines

Messenger RNA vaccines have been studied extensively because they have significant advantages. First, their large-scale and low-cost production is not a problem with current technology. Each dose of vaccine is extremely pure and contains only the RNA of interest encapsulated in its lipid bubble and nothing else. Therefore, they are safe.

As mentioned before, adjuvants do not seem to be necessary to get a satisfactory immune response, because a simple lipid capsule enhances the immunogenic properties of RNAs. mRNAs have a very short half-life and are easily degradable. They do not interact with the genome, and their absorption by cellular machinery occurs exclusively in the cytoplasm, unlike DNA vaccines.

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As it is a new technology, it has drawbacks, mainly related to the lack of scientific data on its use. As explained above, messenger RNA vaccination activates both adaptive and innate immune responses. However, the high production of interferons as a result of TLR7 activation would also increase the activity of ribonucleases, enzymes that degrade RNAs. Vaccine RNAs that lose their lipid bubble or are not encapsulated at the time of injection would therefore be more likely to be destroyed before they even enter the cells.

Adverse events of grade 3, i.e., total disability or risk of life, were reported in some clinical trials for two mRNA rabies vaccines and the H10N8 and H7N9 viruses during phase 1.

Finally, the fragility of messenger RNAs is also a disadvantage. Pfizer announced that the vaccine should be stored at -80°C. This poses obvious logistical problems. It is then not possible to buy the vaccine in advance and store it in the refrigerator before vaccination. One can imagine people having to go to vaccination centers capable of storing large amounts of liquid nitrogen vaccine units and administer the injection in a relatively short period of time.

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Reading the literature on the subject, it seems that mRNA vaccines are very promising in the treatment of infectious diseases for which there is not yet a vaccine, such as Covid-19, and cancer. Pfizer’s vaccine, if it receives all the necessary certification it will be the first to be approved for use in humans.

References

mRNA vaccines — a new era in vaccinology

Understanding mRNA COVID-19 Vaccines

Developing mRNA-vaccine technologies

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