mRNA Vaccine Generating Off-Target Unintended Proteins

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mRNA Vaccine Generating Off-Target Unintended Proteins

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mRNA Vaccine Generating Off-Target Unintended Proteins

Breaking News! mRNA Vaccine’s m1Ψ Modification Causes Ribosomal Frameshifting, Generating Off-Target Unintended Proteins, Poses New Challenges for mRNA Vaccines.

In vitro transcription (IVT) mRNAs have emerged as a method to combat human diseases, including their use in SARS-CoV-2 vaccines. IVT mRNAs are transfected into target cells, where they are translated into recombinant proteins, exerting the expected therapeutic effects of encoding bioactive or immunogenic proteins. Modified ribonucleotides are often incorporated into therapeutic IVT mRNA to reduce its innate immunogenicity, but their impact on mRNA translation fidelity has not been fully explored.

Recently, a study led by James E. D. Thaventhiran and Anne E. Willis at the University of Cambridge, United Kingdom, published online in Nature under the title “N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting.” The research demonstrates that introducing N1-methylpseudouridine into mRNA in vitro can lead to +1 ribosomal frameshifting. Mice and humans, after receiving the BNT162b2 vaccine mRNA, produce cellular immune responses to the +1 frameshift products.

The observed +1 ribosomal frameshifting may result from N1-methylpseudouridine-induced ribosomal stalling during IVT mRNA translation, causing frameshifting on the smooth ribosome sequence.

However, the study proves that synonymous targeting of this sequence provides an effective strategy to reduce the generation of +1 frameshift products.

In summary, this data enhances our understanding of how modified ribonucleotides affect mRNA translation fidelity.

While there are no reports of adverse consequences of mistranslation in human mRNA-based SARS-CoV-2 vaccines, these findings highlight the potential off-target effects of future mRNA-based therapeutic approaches and emphasize the necessity for sequence optimization.

One key feature of therapeutic IVT mRNA is the inclusion of modified ribonucleotides, known to lower innate immunogenicity and enhance mRNA stability—both advantageous characteristics for mRNA therapy. For instance, clinically approved SARS-CoV-2 mRNA vaccines contain N1-methylpseudouridine (1-methylΨ), proven to reduce the innate immunogenicity of IVT mRNA. Some modified ribonucleotides, like 5-methylcytidine (5-methylC), occur naturally as post-transcriptional mRNA modifications in eukaryotes, while others, such as 1-methylΨ, do not.

The study investigates how 5-methoxyuridine (5-methoxyU), 5-methylC, and 1-methylΨ affect IVT mRNA translation. These modified ribonucleotides have been used in IVT mRNA to increase the synthesis of recombinant proteins in vitro and have been considered in preclinical concepts for IVT mRNA therapy. As mentioned earlier, 1-methylΨ is a ribonucleotide used in the licensed IVT mRNA-based SARS-CoV-2 vaccine and is also utilized in developing human vaccines and therapies based on mRNA.

Despite their widespread use, surprisingly little is known about how ribonucleotide modifications affect protein synthesis, especially the translation of therapeutic IVT mRNA. There is interest in understanding how modified ribonucleotides affect mRNA translation fidelity for several reasons. Some ribonucleotide modifications can recode mRNA sequences (e.g., inosine). In prokaryotes, 5-methylC increases misreading during mRNA translation, but its impact on eukaryotic mRNA translation fidelity remains unexplored. The effects of 5-methoxyadenine on translation fidelity have not been studied. Pseudouridine (Ψ) is known to increase misreading of stop codons in eukaryotic mRNA and may affect misreading during prokaryotic mRNA translation. While 1-methylΨ appears not to affect codon misreading, it has been shown to influence protein synthesis rates and ribosome density on mRNA, indicating a direct impact on mRNA translation.

1-methylΨ, a modified ribonucleotide, significantly increases +1 ribosomal frameshifting during mRNA translation and elicits cellular immune responses to +1 frameshift products after inoculation with mRNA containing 1-methylΨ. Besides impacting host T-cell immunity, the off-target effects of ribosomal frameshifting may include the increased production of new B-cell antigens. Other ribonucleotide modification strategies, such as the incorporation of 5-methoxyadenine, significantly reduce the translation efficiency of IVT mRNA, potentially limiting clinical translation. These findings are crucial for understanding the fundamental principles of how ribonucleotide modifications affect mRNA translation and are particularly important for designing and optimizing future mRNA-based therapeutic approaches to avoid potential decreases in efficacy or increased toxicity due to mistranslation events.

Original Article Link: Nature Article

mRNA Vaccine Generating Off-Target Unintended Proteins

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