The ever-growing field of mRNA-based vaccines and therapeutics underscores the promise that mRNA technology holds for the future. The current synthesis approach for mRNA products relies on IVT synthesis. In order to enhance stability and decrease the immunogenicity of mRNA products, chemically modified ribonucleotides have been employed in IVT synthesis and were even honored with the 2023 Nobel Prize in Physiology or Medicine.
While goal-oriented chemical modifications seem to reward scientists, a crucial question has been lingering for some time: How does N1-methylpseudouridine modification affect translation? This is a particularly important question as such chemical modification is an integral part of COVID vaccines. For example, 5-methoxyuridine leads to misreading of mRNA in prokaryotes, and pseudouridine increases the misreading of mRNA stop codons in eukaryotes.
To address this issue, the N1-methylpseudouridine-modified COVID-19 vaccine BNT162b2 was studied. It was clearly demonstrated that N1-methylpseudouridine modification led to +1 ribosomal frameshifting. Additionally, there is a high probability of an immune response to +1 ribosomal frameshifted products upon vaccination. In other words, such ribosomal shifting could lead to potential off-target effects in T cell immunity, along with the production of new B cell antigens. Furthermore, N1-methylpseudouridine modification led to slower translation elongation, which facilitated the ribosomal shifting due to altered aminoacyl-tRNA binding.
This study sheds light on a major issue, indicating that future designs of mRNA vaccines or therapeutics could mitigate such off-target products.
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