The antiviral drug molnupiravir appears to be causing a series of characteristic mutations in circulating SARS-CoV-2 viruses. In countries where the drug is widely used, scientists observe virus variants with many of these changes in the genome, while in countries where it is not used, there are far fewer of these mutations. Whether these mutations lead to resistance or dangerous new virus variants is not yet clear, but the authors urge in their publication in Nature to further investigate the drug’s impact on the virus’s evolution.
The virus inhibitor molnupiravir inhibits the growth of the coronavirus by introducing numerous mutations into the genetic code while it multiplies in the host cell. The substance resembles an RNA building block and is randomly incorporated into new virus RNA during replication. With all these errors, the virus becomes so crippled that it can no longer replicate.
Molnupiravir was greeted with high expectations in October 2021. It was the first drug in a year and a half of the pandemic that seemed to be effective in the fight against severe and fatal Covid-19. Another advantage was that it could be taken in pill form, as opposed to the earlier drug remdesivir, which required infusion. In a press release, the American manufacturer Merck/MSD stated that it prevented half of hospitalizations, and no patient who received it died in the initial study. However, later studies revealed slightly lower effectiveness, and it was subsequently found that the drug was no more effective than standard medical care in vaccinated individuals.
One concern was that potentially dangerous virus variants could emerge, but the expectation was that with such a high number of mutations, no virus would survive. The new study shows that this can still occur.
Scientists from the United Kingdom and South Africa used a global database containing 15 million genetic codes of SARS-CoV-2 variants. They examined how mutations changed over the course of the pandemic in different countries. While the virus always undergoes small mutations during replication, the researchers identified a specific sequence profile that was notably different from the usual mutations, and this profile could be traced back to individuals who had received molnupiravir.
In countries where molnupiravir has been widely used since late 2022, such as the United States, Australia, Japan, and the United Kingdom, these mutations were prevalent. In countries where the drug was not approved, like Canada, this profile was much less common. They also observed evidence of these variants being transmitted between individuals.
The major concern is that new, potentially more virulent variants may develop in patients receiving molnupiravir in this manner. In patients with weakened immune systems, the virus can persist after infection for an extended period, accumulating numerous mutations. This is one of the prevailing explanations for the emergence of Omicron, the coronavirus variant that has an unexpectedly high number of mutations compared to its predecessors.
“It is entirely expected that a small portion of mutated viruses will escape with a drug like this. Through natural selection, there will always be a few viruses that continue to multiply,” says Marc Bonten, a physician-microbiologist at UMC Utrecht, specializing in microorganism resistance.
“This was also the objection to this drug upon its introduction.” However, he considers the likelihood of a more pathogenic coronavirus variant emerging from the viruses that escaped to be small. “But in biology, nothing is ruled out. We do not yet fully understand how these more virulent strains arise.”