The successful translation from the successfully modified messenger RNA (mRNA) to a high-efficacy mRNA vaccine against SARS-CoV-2 that saved the world also won Dr. Katilin Karikó and Dr. Drew Weissman their well-deserved Nobel Prize for Physiology or Medicine in 2023.
The idea of using mRNA to express desired proteins to solve medical issues has been around for decades.15 The process was met with three major challenges:
- Unprotected mRNA can be easily degraded by an enzyme called RNAse and is therefore highly unstable. The stability issue of mRNA was solved with nanoparticle technology called lipid nanoparticle (LNP).
- The mRNA is vulnerable to degradation by nucleases. As known, nucleic acids (DNA as well as RNA) are nucleotides connected by phosphodiester bonds. It was crucial to clear the hurdle of nuclear degradation of mRNA for a mRNA-based vaccine to work.
- A challenge concerning mRNA delivery to mammalian cells is immunogenicity against the introduced exogenous mRNA by the host immune system for the simple reason that exogenous mRNA is regarded by the host immune system as a “non-self” and, therefore, a “danger” signal. To present host integrity and protect host health, the immune system unleashes a plethora of immune cells together with cytokines to destroy the dangerous non-self entities.
The crucial step in mRNA modification by the joint effort of Dr. Kaitlin Kariko and Dr. Drew Weissman to solve both the nuclease problem and immunogenicity problem was the substitution of nucleotide uridine with the modified nucleotide of pseudouridine (Ψ, pronounced as “sai”). As Dr. Kariko described in her seminal paper published in 2008, the Ψ substitution served the dual purpose of enhancing the stability of RNA molecules as well as reducing destructive immune response against RNA.16 The full name of the pseudouridine is N1-methyl-pseudouridine.
Of note, Pfizer’s mRNA vaccine against SARS-CoV-2 was jointly developed with the German companies BioNTech (collaboration) as well as Moderna, the U.S. company based in Boston, MA, both used pseudouridine. Their products reached 95% efficacy.17 Both products received FDA emergency approval and later regular approval. (By contrast, a third biotech company opted to use the non-modified mRNA in the development of mRNA-based SARS-CoV-2 vaccine. Unfortunately, this other company’s product, not surprisingly, had an efficacy of merely 46%, which did not receive official approval as an anti-COVID-19 vaccine.)
15. Karikó K, Ni H, Capodici J, Lamphier M, Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem. 2004;279(13):12542-12550. doi:10.1074/jbc.M310175200
16. Karikó K, Muramatsu H, Welsh FA, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008;16(11):1833-1840. doi:10.1038/mt.2008.200
17. Patel R, Kaki M, Potluri VS, Kahar P, Khanna D. A comprehensive review of SARS-CoV-2 vaccines: Pfizer, Moderna & Johnson & Johnson. Hum Vaccin Immunother. 2022;18(1):2002083. doi:10.1080/21645515.2021.2002083
