Abstract:

To the Editor:

N1-methyl-pseudouridylated (m1Ψ) RNA enabled the mRNA Covid-19 vaccines to save lives during the pandemic, however, many questions exist on how the modified mRNA behaves in vivo. A recent study by Monroe and coworkers, shows slight, context dependent changes in translational fidelity.

The earliest study on translation of m1ΨRNA dates to 2015. One study on translational fidelity found no statistically significant difference between the protein products of m1ΨRNA and standard RNA (1). However, additional experiments published after the vaccination campaign show significant changes in translational output between normal RNA and m1ΨRNA (2,3).

The first result saw that m1ΨRNA increased rates of +1 ribosomal frameshifting, affecting approximately 8% of proteins produced (3). The most recent result found that m1ΨRNA translational fidelity is highly dependent on the sequence context (2), which explains why it was not observed in a previous study (1).

Taken together, these results suggest that we still do not know how chemical modifications impact translation. m1ΨRNA is rare, but not unprecedented in nature. It is found in archaea, first discovered in 1982, and later found in other extremophiles, at a specific position in their transfer RNA.

The recent discoveries by Monroe and associates of context-dependent fidelity underscores the need for greater basic science understanding of processes before widespread application. These potential issues with translational fidelity have fortunately manifested into safety problems with the mRNA vaccines, but this could depend on the specific antigen. Further testing should accompany any mRNA vaccine using this chemical modification.