Harmless off-target proteins produced by COVID-19 RNA vaccine

RNA-based vaccines for COVID-19 can be misread by the body, producing harmless off-target proteins, according to new research.

Researchers from University of Cambridge found that these nonsense proteins prompted unintended immune responses in one third of the Pfizer messenger RNA (mRNA) COVID-19 vaccine recipients, but that these were not harmful. They have now have now pinpointed why this occurs and developed an updated design for future mRNA therapeutics that avoids the problem. Their findings are published in Nature.

'Research has shown beyond doubt that mRNA vaccination against COVID-19 is safe. Billions of doses of the Moderna and Pfizer mRNA vaccines have been safely delivered, saving lives worldwide,' said joint senior author Dr James Thaventhiran from the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge. 'We need to ensure that mRNA vaccines of the future are as reliable.'

In cells, mRNA transports genetic instructions copied from the DNA and acts as a template for a protein to be made. In RNA vaccines, mRNA containing the instructions for a particular pathogenic protein (such as the spike protein of SARS-CoV-2) safely mimics an infection.

However, foreign mRNA is often attacked by the immune system, and to bypass this immune defence, one of the RNA bases, uridine, is chemically modified. This discovery led to a Nobel Prize (see BioNews 1210).

The researchers identified that bases with this chemical modification can cause 'slips' when being translated into protein: a letter in the genetic code can be skipped, resulting in a 'frameshift' where the sequence of amino acids in the protein is incorrect.

Using blood samples from patients who received COVID-19 vaccines, the team found one-third of the Pfizer recipients showed an immune reaction to the frameshifted proteins, compared to none in the control group who received a non RNA-based vaccine. None of the recipients reported any side-effects from their vaccine, consistent with the comprehensive safety information accessible for these COVID-19 vaccines.

The team then demonstrated that it is possible to redesign mRNA sequences to circumvent these 'off-target' effects, resulting in the desired protein. These design adjustments can be readily incorporated into future mRNA vaccines, ensuring the achievement of their intended effects while mitigating the risk of harmful and unintended immune responses.

'These new therapeutics hold much promise for the treatment of a wide range of diseases. As billions of pounds flow into the next set of mRNA treatments, it is essential that these therapeutics are designed to be free from unintended side-effects,' said joint senior author Professor Anne Willis, director of the MRC Toxicology Unit. 'These findings can be implemented rapidly to prevent any future safety problems arising and ensure that new mRNA therapies are as safe and effective as the COVID-19 vaccines'.