Are RNA vaccines a miracle of science?
Text updated on 2021-02-05
The speed with which an effective anti-COVID19 vaccine was obtained is unprecedented in the history of medical research. This success is the result of the combined efforts of basic, applied, and medical research.
RNA vaccines are the result of more than 30 years of research, including the following milestones:
The RNA in today's vaccines is synthesized in vitro from an enzyme called T7 phage RNA polymerase (from bacterial viruses). This enzyme was discovered in 1970.
In 1978, Giorgos J Dimitriadis succeeded in producing a protein, rabbit globin, in mouse cells by directly injecting them with RNA. This feat had already been achieved a few years earlier in 1971 by John B. Gurdon's team in frog eggs.
In 1990, Jon A. Wolff in the USA showed that the injection of an RNA directly into the muscle of a mouse induces the expression of the protein encoded by this RNA. The article concludes that: "Intracellular expression of genes (DNA or mRNA) encoding antigens could provide an alternative approach to vaccine development".
In 1993, Frédéric Martinon and his colleagues showed that a liposome containing an RNA encoding the nucleoprotein (NP) of the influenza virus induced in mice an immune response mediated by certain cells of the immune system, the cytotoxic T lymphocytes (CTL).
RNA vaccines can trigger an excessive innate immune response by activating the Toll-like receptor (TLR) pathway. Katalin Karikó and Drew Weissman successfully mitigated this risk in 1995 by introducing modified nucleosides such as pseudouridine into the RNA (ψ).
The Pfizer/BioNTech and Moderna vaccines are based on the injection of an RNA encoding the Spike (S) protein of the coronavirus SARS-CoV-2 in its stabilized pre-fusion form. This stabilized form was made possible by structural studies of the Spike protein from the MERS-CoV virus in 2017 and the introduction of two proline amino acid residues that are not present in the Spike protein of the natural SARS-CoV-2 virus.
The synergy and complementarity with applied and biomedical research thus made it possible to move from proof of concept to clinical trials and large-scale production of an available effective vaccine in just one year after the start of the epidemic.
Blog on RNA vaccine development.Gozlan, M. (2020) The scientific adventure of messenger RNA vaccines. Biomedical realities. Blog Le Monde.
Report of the High Authority of Health on the immunological and virological aspects of the infection by SARS-CoV-2.Report of the High Authority of Health (HAS) December 2020 - Immunological and virological aspects of the infection by SARS-CoV-2.
Discovery of RNA polymerase.Chamberlin, M., McGrath, J., & Waskell, L. (1970). New RNA polymerase from Escherichia coli infected with bacteriophage T7. Nature, 228(5268), 227-231.
Mouse cells produce a protein, globin, from rabbit RNA.Dimitriadis, G. J. (1978). Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Nature, 274(5674), 923-924.
Frog cells produce a protein, hemoglobin, from rabbit RNA.Lane, C. D., Marbaix, G., & Gurdon, J. B. (1971). Rabbit haemoglobin synthesis in frog cells: the translation of reticulocyte 9 s RNA in frog oocytes. Journal of molecular biology, 61(1), 73-91.
The injection of RNA into the muscle of a mouse induces the expression of the protein encoded by this RNA.Wolff, J. A., Malone, R. W., Williams, P., Chong, W., Acsadi, G., Jani, A., & Felgner, P. L. (1990). Direct gene transfer into mouse muscle in vivo. Science, 247(4949), 1465-1468.
RNA encoding the nucleoprotein (NP) of the influenza virus induces an immune response in mice.Martinon, F., Krishnan, S., Lenzen, G., Magné, R., Gomard, E., Guillet, J. G., ... & Meulien, P. (1993). Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. European journal of immunology, 23(7), 1719-1722.
Reduction of the immunogenicity of RNA by introducing modified nucleosides into the RNA.Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005). Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity, 23(2), 165-175.
Structural and immunogenicity studies of MERS-CoV Spike protein.Pallesen, J., Wang, N., Corbett, K. S., Wrapp, D., Kirchdoerfer, R. N., Turner, H. L., ... & McLellan, J. S. (2017). Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proceedings of the National Academy of Sciences, 114(35), E7348-E7357.