Getting mRNA on-target

C&I Issue 1, 2024

Read time: 1-2 mins


The technology behind the mRNA vaccine for Covid-19 shows huge promise for other vaccines as well as therapeutics for cancer, cardiovascular disease and immunological diseases.

Now researchers have found that while the technology produces most proteins as intended, there are also some unintended immune responses. However, they also report a solution to enable the safer design of future mRNA vaccines.

Researchers at the University of Cambridge, UK, studied the mechanisms of the Pfizer–BioNTech mRNA vaccine. They found an off-target immune response in one third of those vaccinated, but with no ill effects (Nature, doi: 10.1038/s41586-023-06800-3).

mRNA is the genetic material that tells cells in the body how to make a specific protein. The team, led by Anne Willis and James Thaventhiran, discovered that the cellular machinery that reads mRNA ‘slips’ when confronted with repeats of a chemical modification commonly found in mRNA therapeutics. In addition to the target protein, this leads to the production of off-target proteins.

The team found that bases with a chemical modification called N1-methylpseudouridine, which are currently contained in mRNA therapies, are responsible for the slips along the mRNA sequence. However, removing these runs of N1-methylpseudouridine from the mRNAs prevents off-target protein production.

‘We can remove the error-prone code from the mRNA in vaccines so the body will make the proteins we want for an immune response without inadvertently making other proteins as well,’ explains Thaventhiran. ‘The safety concern for future mRNA medicines is that mis-directed immunity has huge potential to be harmful, so off-target immune responses should always be avoided.’

‘This is a landmark study impacting both upon our understanding of the fundamental molecular biology around how proteins are made, but also with real-world relevance because of the use of modified nucleotides,’ comments virologist Stephen Griffin, University of Leeds, UK.

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