Ksenia Vlassova

Introduction. COVID-19 is an acute respiratory tract infection, triggered by SARS-CoV-2 virus, that has caused 171 million cases and 3.5 million deaths worldwide¹. The viral particles, containing RNA and ribonucleoproteins encapsulated in membrane, are transmitted through aerosols to animals and humans. Coronavirus uses S proteins to bind to the host cell ACE2 receptors and the S2-domain facilitates entrance of the virus into the cell via clathrin-mediated endocytosis². Methods. The initial steps of vaccine development include selection of the surface target protein, synthesis of the corresponding DNA, and in vitro transcription of mRNA³.  Next, exploration of the optimal chemical modifications and testing multiple delivery vehicles was performed to select those for efficient delivery into cells^3,4. The selected formulation candidates/mRNA complexes were tested in vivo with an objective to select the lead delivery vehicle^5,6. The clinical trials first explore safety of the vaccine candidates, and next short-term efficiency against the virus⁷. A number of the clinical studies involved individuals that were infected with COVID-19, ones who received the vaccine, and ones that had never been infected or vaccinated. Blood samples were taken from these groups to compare neutralizing antibody levels, as well as characterize the overall immune response^8,9. Ultimate goals in vaccine development is confirmation that vaccine enables long term protection of the individuals against the virus and emerging new strains, which was addressed by harvesting and analyzing blood samples up to 6 months post vaccination¹⁰. Results. The lead vaccine candidate identified was nucleoside-modified mRNA encoding SARS-CoV-2 spike protein^3-5. From many delivery formulations tested, lipid nanoparticles (composed of ionizable cationic lipid, phosphatidylcholine, cholesterol and polyethylene glycol-lipid) performed the best in cells, mice and monkeys^4-7. Clinical studies with human subjects demonstrated vaccine safety upon intramuscular administration, and robust and sustained neutralizing antibody responses^7,8. It was observed that mRNA-lipid complexes induce strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses^9,10. Conclusions. A number of COVID-19 vaccine candidates went through the entire pipeline – from fundamental basic research through clinical trials, mass production, and injection of millions of people world-wide – in one year. The early phase basic research on nucleic acid-based vaccine candidates, and various delivery formulations, performed in hundreds of laboratories worldwide was critical to success. Importantly, the current vaccines seem to enable long term protection against SARS-CoV-2 and the emerging variants of this virus.

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