Reference:
Mulroney, T. E., Pöyry, T., Yam-Puc, J. C., Rust, M., Harvey, R. F., Kalmar, L., Horner, E., Booth, L., Ferreira, A. P., Stoneley, M., Sawarkar, R., Mentzer, A. J., Lilley, K. S., Smales, C. M., von der Haar, T., Turtle, L., Dunachie, S., Klenerman, P., Thaventhiran, J. E. D., & Willis, A. E. (2023). N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting. Nature. https://doi.org/10.1038/s41586-023-06800-3
Summary:
The article investigates the effects of N1-methylpseudouridine (1-methylΨ) on mRNA translation fidelity. Utilised in mRNA vaccines, this modified ribonucleotide reduces immunogenicity but increases +1 ribosomal frameshifting. Experiments showed that 1-methylΨ incorporation led to ribosome stalling and erroneous translation, eliciting cellular immune responses to these frameshifted products in both mice and humans vaccinated with the BNT162b2 vaccine. This raises concerns about potential off-target effects of mRNA therapies. Although current vaccines have shown no adverse effects linked to mistranslation, the findings highlight the necessity for careful optimisation of mRNA sequences to mitigate unintended immunogenic responses, particularly in future therapeutic applications.