Covid-19 mRNA vaccines: composition and perspectives

Since the beginning of the SARS-CoV-2 pandemic, the international scientific community has taken action in record time to prepare one or more safe and effective vaccines to prevent infection and the possible clinical evolution in the most serious forms of respiratory disease defined as "COVID-19 (Coronavirus disease 2019)".

Among the first vaccines approved by the WHO were the innovative messenger RNA (mRNA) vaccines, the result of years of studies and collaborations, insights and contributions by numerous researchers in research groups around the globe (as extensively reported in this in-depth article published in Nature).

In addition to the two main vaccines in use in Italy and other countries, discussed below, another experimental mRNA-based vaccine was developed by the German company CureVac. However, the company has withdrawn the application for approval forwarded to the regulatory bodies to focus on a second generation vaccine, as well as the GSK comany.

Composition of mRNA vaccines

These new vaccines are composed of a synthetic messenger RNA (mRNA) molecule of the spike gene in which a nitrogenous base (uridine) has been replaced by a pseudouridine (ψ, one of the rare bases found in the secondary structure of another type of RNA, transfer RNA, which acts downstream of mRNA in protein synthesis), which differs from uridine by a particular chemical bond.

This change has two consequences:

1. the such modified mRNA is not recognized by intracellular sensors which would promote the rapid degradation of a "normal" mRNA and simultaneously trigger the production of interferon (a set of antiviral molecules) and the inflammatory response;
2. pseudouridine stabilizes the mRNA thus allowing the production of high levels of protein, in this case of the SARS-CoV-2 spike protein for several days.

Illustrative diagram of the essential elements that make up mRNA vaccines. A lipid envelope encloses a messenger RNA molecule that carries the sequence of the SARS-CoV-2 virus Spike protein. In the mRNA molecule, the uridine nitrogen base (U) is replaced by a pseudouridine (ψ).

The mRNA molecule is protected by a lipidic envelope that protects the mRNA and allows better absorption of the vaccine by the cells in is injected into. The lipid envelope is also responsible for the symptoms that are frequently associated with the inoculation of the vaccine (which are called "reactogenicity") for 1-2 days.

These symptoms reflect the induction of a local inflammatory response that serves to enhance the specific immune response, that is, the production of anti-Spike antibodies. The manifestation of more or less annoying symptoms is subjective, so those who do not manifest them are equally protected by vaccination.

mRNA vaccines currently used in clinical field

At present, the two mRNA-based vaccines approved in Italy to prevent COVID-19 disease are produced by the Moderna biotechnology company, USA, with public support from the US government, and by the German BioNTech in collaboration with the multinational Pfizer.

These vaccines are currently approved for all citizens over 12 years of age, although studies are underway to use them also in children under 12 (Pfizer / BioNTech has already applied to the Food and Drug Administration, FDA, American to be able to administer in the 5-11 year range).

They are vaccines approved to protect against death and serious illness requiring hospitalization in intensive care, events against which they offer more than 90% protection, even when caused by viral variants that have emerged in recent months. They are also very effective in protecting against the transmission of the virus from individual to individual (approx. 75-80% in the case of the delta variant, the most contagious) and are therefore a fundamental tool for containing the spread of the virus in society.

Illustrative scheme of vaccination with RNA vaccines. Viral RNA is encapsulated in lipid nanoparticles (similar to the membranes of our cells) in order to protect it from degradation (which is why the vaccine must be stored at a very low temperature, -70 /-80 ° C). The lipid nanoparticles containing the RNA fragment encoding the SARS-CoV-2 Spike protein are delivered into the recipient’s cells by injection into the deltoid muscle. In the cells of the body, the virus RNA is translated into the Spike protein. This is recognized by the immune system, generating a protective response. The lipid envelope and viral RNA will be rapidly degraded, without causing side effects.

Vaccines based on mRNA against COVID-19 represent a big step forward also for the development of others against infections for which so far it has not been possible to discover, such as HIV infection, the cause of AIDS. Currently, immunization studies in mice and non-human primates have shown their efficacy against Zika virus infection which frequently causes microcephaly and other brain malformations during fetal life when a pregnant woman becomes infected, but also against influenza viruses. In the cases mentioned, it has not yet been possible to extend the studies to humans also due to the obvious priority of controlling the SARS-CoV-2 pandemic.

Predictions on the future "evolution" of these vaccines

A feature of these vaccines is their extreme versatility, as they are synthesized in vitro. In fact, they were initially conceived as personalized cancer therapies. The limiting factors for their modification and production are essentially the availability of the sequence of the gene of which the RNA is to be synthesized and, obviously, the availability of the "raw material", the nucleotides necessary to synthesize the mRNA molecules to be incorporated into the vaccine (largely produced in China and other Asian countries).

This technology is revolutionizing the entire vaccine design and production chain and, in view of future pandemics of viruses, bacteria, parasites, the possibility of using mRNA vaccines represents a huge step forward.

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Another important evolution associated with mRNA vaccines is the development of effective and safe platforms for making our cells produce therapeutic proteins.

For example, the discoverers of modified mRNA-based technology (the HungarianKatalin Karikò and the American Drew Weissman, recently awarded the prestigious Lasker Prize, often "antechamber" of the Nobel Prize) have shown that both mice and macaques inoculated with mRNA of erythropoietin produce elevated levels of the hormone just 6 hours after inoculation.

Finally, an important application remains the original engine of the search for these new vaccines, that is, the design of personalized vaccines against the neoplasm of a certain person in the general perspective of the so-called "precision medicine".