The remarkable efficacy of mRNA vaccines against SARS-CoV-2 has generated much interest in synthetic mRNA therapeutics for disease treatment and prevention. But some fundamental scientific questions remain about whether the modified nucleotides used in vaccines faithfully produce the protein products for which they are designed.
Synthetic mRNAs used in COVID-19 vaccines incorporate the modified nucleotide N1-methylpseudouridine to improve stability and reduce unwanted immune responses. These two characteristics are necessary for the proper functioning of the vaccine. Yet the incorporation of this non-standard nucleotide introduces the possibility that the cellular machinery may misinterpret the genomic information encoded by the mRNA, leading to errors in protein translation that could have unexpected effects down the line. .
Don’t worry, as it turns out. A new study from Washington University in St. Louis finds that N1-methylpseudouridine used in COVID-19 mRNA vaccines is translated faithfully. The research, published in Cell Reports, was conducted by scientists in the lab of Hani Zaher, associate professor of biology in Arts & Sciences.
“Cellular mRNAs typically lack N1-methylpseudouridine,” said Kyusik Kim, a graduate student in the Molecular Cell Biology program, first author of the study. “We found that the presence of N1-methylpseudouridine in mRNAs does not seem to lead to an increase in the number of errors during translation.
“If that’s the case,” Kim said, “then we can continue to use them therapeutically and we won’t have to worry as much about them making the wrong protein.”
The translation of the genetic code into functional protein is a feat accomplished in all areas of life by the ribosome. The Zaher lab conducts research that expands our understanding of the mechanisms that govern translational fidelity on the ribosome and the impact of these mechanisms on cell shape.
In this particular study, researchers at the Zaher lab used several experimental systems to study the effects of N1-methylpseudouridine on translation. They discovered that N1-methylpseudouridine is accurately read by the ribosome. They also found that mRNAs containing N1-methylpseudouridine did not appear to produce miscoded proteins more frequently than mRNAs containing unmodified nucleotides.
“There has been a huge explosion of interest in using mRNA therapeutics for many different diseases,” Kim said. “This paper adds more confidence that mRNA therapeutics aren’t going to make proteins they weren’t meant to make.”
Kim et al., N1-methylpseudouridine found in COVID-19 mRNA vaccines produces faithful protein products, Cell Reports (2022), https://doi.org/10.1016/j.celrep.2022.111300
Funding: This work was supported by a grant from the National Institutes of Health (NIH) (R01GM141474).
The authors thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital and the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis for the use of the Genome Technology Access Center, who provided sequencing services for this study.