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Therapeutic in vitro transcribed (IVT) mRNAs commonly incorporate modified ribonucleotides, with the aim of decreasing innate immunogenicity and increasing mRNA stability. For example, the clinically approved SARS-CoV-2 mRNA-based vaccines incorporate the modified ribonucleotide N1-methylpseudouridine (1-methylΨ). Despite their widespread use, whether such ribonucleotide modifications can interfere with the translation of mRNA has not been well-studied. Writing in Nature, Mulroney et al. now demonstrate that the incorporation of 1-methylΨ into mRNA can affect the fidelity of mRNA translation. It results in ribosomal frameshifting, producing frameshifted polypeptides that were found to elicit an off-target cellular immune response following vaccination of mice and humans with modified mRNA.