Fears about the COVID-19 vaccine's side effects have left some folks hesitant to join the immunization party, inadvertently affecting broader disease prevention.
A recent study in Nature unveils a potential cause of unwanted mRNA vaccine reactions. A simple solution could mitigate the unintended side effects, scaring people away from the treatment. This research by Mulroney et al. at the University of Cambridge marks a significant step forward in enhancing the safety profile of mRNA vaccines, instilling hope for a future with fewer complications.
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The roots of this study trace back to the pioneering work of Dr. Katalin Kariko and Dr. Drew Weissman, whose innovative delivery system, packing mRNA in lipid nanoparticles, laid the foundation for the Pfizer-BioNTech and Moderna's vaccines combating COVID-19. mRNA, the molecular messengers at the heart of these vaccines, prompts recipients to produce a protein mimicking the SARS-CoV-2 virus, effectively presenting the immune system with a "Wanted Poster" for future encounters.
The vaccine's laboratory-engineered mRNA strands contain specialized nucleotides such as the modified nucleobase N1-methylpseudouridine (m1Ψ). A critical facet of COVID-19 mRNA vaccines, integrating m1Ψ within the mRNA code ensures a more robust immune response, key in the fight against the virus.
Mulroney et al. discovered that these high-tech nucleotides sometimes subvert the process of mRNA translation, which is crucial for protein synthesis.
When a ribosome manufactures proteins from mRNA, sometimes it slips and ignores a base during translation. Skipping the translation ahead by a single nucleotide can change all of the following amino acids on the protein strand on the strand. This mistake is called a +1 ribosomal frameshift.
The researchers propose that m1Ψ may cause the ribosomes to stall mid-decoding, leading to unintended mRNA vaccine side effects. The study posits that the use of m1Ψ, while it enhances the intended immune response, increases the risk of undesirable protein production through frameshifts. Evidence suggests that these mistaken proteins contribute to unintentional immune responses in vaccine recipients.
Mulroney et al. optimized new mRNA sequences with this potential pitfall in mind. Introducing stickier nucleotides around m1Ψ nucleotides proved to be a strategic move that resulted in virtually undetectable amounts of undesirable proteins.
Mulroney et al.'s research sheds light on the complex task of programming vaccines to provide the best instructions for our cells to decode. By discovering the limitations of modified ribonucleotides and mRNA translation, scientists can work to minimize adverse outcomes, offering a more straightforward path to safer and more effective mRNA vaccines.
Sources: Nature, Penn Medicine, Viral Zone, Dominican University of California
