Recently, new research suggests that scientists may have found ways to prevent the risk of potential negative immune responses before delivering mRNA to patients. The study was done by scientists from the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge and researchers from other institutions. The research team discovered a sequence in the mRNA that triggers an unexpected immune response if the cellular machine misinterprets it, and found a way to prevent this from happening.
Details of this work were published in Nature titled "N1-methylpseudouracil mRNA leads to +1 ribosome shifting". To sum up, they found that the cellular machine "slips" when it encounters a string of N1-methylpseudouracil bases, causing the ribosome to shift the frame about 10% of the time, causing the mRNA to be misinterpreted. This can lead to the production of unexpected proteins, which trigger an immune response.
Working with scientists from the University of Kent, the University of Oxford and the University of Liverpool, the MRC team looked for evidence of the presence of off-target proteins in people who received the Pfizer COVID-19 mRNA vaccine. In the study, about one-third of the 21 vaccinated people had unexpected immune activity, although it is important to note that these patients did not experience any adverse effects as a result. The researchers also confirmed that the observed off-target protein may not be caused by SARS-CoV-2 infection, but rather a response to the vaccine.
The research team noted that although there are other ribonucleotide modifications that can be used, such as 5-methoxyuracil, this option "significantly reduces the translational efficiency of IVT mRNA and may limit clinical application." To prevent slippage when using N1-methylpseudouracil, the research team designed so-called "anti-slip" mRNA sequences that eliminated the operation of these modified bases. This correction results in the production of the desired protein without the unintended protein.
Similar design modifications may be used to improve** and vaccines in the future. The research team believes that in order to ensure that future ** and vaccines are both safe and effective, "it is important to modify the mRNA sequence design for applications that require higher doses or more frequent administration, such as hormone production in the body."
They also point to other protein mistranslations that may not have been discovered or studied as causes. This type of research is critical to ensuring that future ** and vaccines are both safe and effective. Dr. Anne Willis, Director of the MRC Toxicology Unit and co-first author, said: "These new methods hold great promise in a wide range of diseases. With billions of pounds flowing into the next generation of mRNA, it is vital to ensure that these methods are designed without surprises. ”
Dr. James Th**Enthiran, investigator and co-first author of the MRC Toxicology Unit, expressed a similar view in his comments. "Studies have clearly shown that COVID-19 mRNA vaccines are safe. Billions of doses of Moderna and Pfizer's mRNA vaccines have been safely delivered, saving lives around the world," he noted. "We need to make sure that future mRNA vaccines are just as reliable. Our demonstration of 'anti-slip' mRNA is critical to the future safety of this drug platform. ”
Reference: "N1-methylpseudouridylation of mRNA causes +1ribosomal frameshifting."
Editor: Zhou Min.
Typesetting: Li Li.