In a groundbreaking study, scientists from the University of Cambridge have uncovered a unique aspect of how the mRNA Covid vaccines are processed in our body, which may explain why some 25-30% of individuals inoculated with these vaccines experienced an unexpected immune reaction.
Their study, titled "N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting," was published yesterday in the world-leading journal, Nature.
These mRNA vaccines, which have revolutionized medical science, function by instructing the body to produce a specific protein. This protein mimics an infection, triggering antibody production without causing the disease.
The foundation of this technology lies in a Nobel Prize-winning innovation: the substitution of uridine, a natural RNA base, with a synthetic counterpart. This pivotal adjustment enables the creation of proteins in the body without triggering an immune response against the vaccine itself.
But this technology is not without its complexities. The Cambridge team discovered that the body's protein-producing machinery - called the ribosome - sometimes falters when processing the modified uridine. This misstep, akin to a bicycle gear slipping, leads to a phenomenon known as "frameshifting."
To illustrate, translating mRNA into protein is similar to reading a sentence of 3-letter words, such as: "The cat ate the fat rat." But the ribosome sometimes skips forward by a letter, called a frameshift, to read: "The cat a tet hef atr."
As a result, the entire genetic code becomes misinterpreted, producing a nonsensical protein. In 25-30% of cases, this process inadvertently activates the immune system, the Cambridge scientists found.
Despite this frameshifting, the vaccines still effectively protect against Covid-19. Yet, the Cambridge scientists caution that this off-target effect, although harmless in the context of Covid vaccines, could potentially lead to the creation of active, unintended proteins in future mRNA therapies for other diseases.
Dr. James Thaventhiran, the senior author of the study, reassures that mRNA vaccination against COVID-19 remains safe and has played a vital role in saving lives globally. But Dr. Thaventhiran stressed that this discovery presents an opportunity to enhance vaccine safety.
By adjusting the mRNA code to minimize the use of the problematic pseudo-uridine, the Cambridge study showed that the risk of frameshifting can be mitigated without compromising the vaccine's efficacy.
This research, already shared with the medicines regulator Medicines and Healthcare Products Regulatory Agency (MHRA), paves the way for improved mRNA vaccines, including those for cancer and other therapeutics.