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Using modified nucleotides to make mRNA vaccines

The key features of the Mrna vaccines are the use of Modified nucleotides in their synthesis and the use of lipid nanoparticles to deliver them to cells. The main difference between the Pfizer/BioNTech vaccine and the Moderna vaccine is in the delivery system. The lipid vescicules used by Moderna are somewhat more stable and the vaccine doesn't need to be kept constantly at ultra-low temperatures.

Both vaccines use modified RNAs. They synthesize the RNA using Modified Nucleotides based on variants of uridine; namely, pseudouridine, N1-methylpseudouridine and 5-methylcytidine. (The structures of the nucleosides are from Andries et al., 2015).) The best versions are those that use both 5-methylcytidine and N1-methylpseudouridine.

I'm not an expert on these mRNAs and their delivery systems but the way I understand it is that regular RNA is antigenic—it induces antibodies against it, presumably when it is accidently released from the lipid vesicles outside of the cell. The modified versions are much less antigenic. As an added bonus, the modified RNA is more stable and more efficiently translated.

Two of the key papers are ...

Andries, O., Mc Cafferty, S., De Smedt, S.C., Weiss, R., Sanders, N.N. and Kitada, T. (2015) "N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice." Journal of Controlled Release 217: 337-344. [doi: 10.1016/j.jconrel.2015.08.051]

Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B.L., Tam, Y.K., Madden, T.D., Hope, M.J. and Weissman, D. (2015) "Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes." Journal of Controlled Release 217: 345-351. [doi: 10.1016/j.jconrel.2015.08.007]




This post first appeared on Sandwalk, please read the originial post: here

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Using modified nucleotides to make mRNA vaccines

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