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Researchers identify vaccine mRNA sequences that cause ribosomal frameshifting and show how to prevent it
• Preventing ribosomes from “slippage”: Researchers have discovered how to prevent ribosomes from occasionally shifting by one “letter” while reading vaccine mRNA, an error that produces unintended proteins with unknown properties.
• Modify the modification: The team identified specific mRNA sequences containing a modified building block called N1-methylpseudouridine that make ribosomes prone to slipping out of the correct reading frame. Changing these sequences can almost completely prevent such frameshifting.
• Rules for mRNA vaccines and therapeutics: The findings provide simple rules for designing synthetic mRNAs and could help improve future vaccines against infectious diseases as well as cancer immunotherapies.
When the coronavirus SARS-CoV-2 turned our world upside down, mRNA vaccines against COVID-19 brought the breakthrough. Their success established modified mRNA as a powerful foundation for vaccines and opened the way for new mRNA-based technologies, with potential applications ranging from vaccines against other infectious diseases to cancer immunotherapy.
Researchers led by Marina Rodnina and Panagiotis Poulis from the Max Planck Institute for Multidisciplinary Sciences (Göttingen, Germany) have now uncovered an important aspect of how such modified mRNAs are translated into proteins. In a study published in Nature Communications, they show why ribosomes can occasionally shift into the wrong reading frame when translating modified mRNA, and how these errors can be largely avoided through mRNA sequence design.
Decoding three letters at a time
Our cells make proteins by reading messenger RNA (mRNA) three “letters” at a time. Each group of three “letters”, called a codon, specifies an amino acid in the protein. mRNA vaccines use the same machinery: they deliver synthetic mRNA that instructs our cells to produce a viral protein, which is then recognized by the immune system, and causes a protective immune response in the body.
A key feature of current mRNA vaccines is that the natural mRNA building block uridine (U) is replaced with a modified version, N1-methylpseudouridine. This modification reduces unwanted immune activation and promotes efficient protein production. However, it can also affect how the ribosome moves along the mRNA. At certain sequences, the ribosome can occasionally slip forward by one letter, shifting the way all subsequent codons are read and producing an unintended protein.
The Max Planck researchers have now unraveled why and how this frameshifting happens, and identified strategies to avoid it.
Getting to the bottom of frameshifting
To uncover the mechanism, the researchers combined experiments in human cells with a fully reconstituted in-vitro translation system, allowing them to pinpoint where and when the ribosome slips. Using single-molecule fluorescence microscopy, they could then follow individual ribosomes in real time and observe how transfer RNAs (tRNAs), that read codons and deliver the corresponding amino acids, move during frameshifting.
That revealed the exact trigger: N1-methylpseudouridine destabilizes the tRNA’s interaction with the mRNA on the ribosome, making it more likely to shift by one nucleotide into the wrong reading frame.
A codon-design fix
“Importantly, frameshifting occurs only at particular mRNA sequences – and these can be avoided,” Poulis says. For example, the researchers identified UUU C as a slippery sequence when U is replaced by N1-methylpseudouridine. Changing the sequence without changing the encoded protein, for example from UUU C to UUC C, almost completely abolished frameshifting.
“Our study provides a rule set for designing mRNA vaccines and therapeutics,” Poulis says. By avoiding sequences that promote frameshifting, developers can reduce unintended translation products while retaining the benefits of modified mRNA. The principle extends beyond COVID-19 vaccines to other mRNA-based applications, including vaccines against other infectious diseases and personalized cancer vaccines.
“When selecting modifications for therapeutic mRNAs, we need to consider two things: how effectively they reduce unwanted immune activation and how faithfully the mRNA is translated,” Rodnina explains. Understanding how modified mRNAs affect the ribosome thus provides a molecular basis for designing the next generation of mRNA vaccines and therapeutics.
Prof. Dr. Marina V. Rodnina
Director
Department of Physical Biochemistry
+49 551 201-2900
rodnina@mpinat.mpg.de
https://www.mpinat.mpg.de/rodnina
Dr. Panagiotis Poulis
Department of Physical Biochemistry
+49 551 201-2927
panagiotis.poulis@mpinat.mpg.de
Poulis, P.; Robecchi, G.; Kurochkina, A. O.; Felletti, M.; Rodnina, M. V. Recoding by N1-methylpseudouridine guides rational mRNA vaccine design. Nature Communications (2026). https://doi.org/10.1038/s41467-026-77796-3
https://www.mpinat.mpg.de/5341543/rn_2605 – original press release
https://www.mpinat.mpg.de/rodnina – website of the Department of Physical Biochemistry, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
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