Since the emergence of SARS-CoV-2 in 2019, the virus has accrued a variety of mutations to infect its human hosts more effectively. Certain antiviral treatments work by increasing the rate of these random mutations, leading some to worry that these drugs could accelerate the evolution of an even more infectious super strain.
Now, scientists at Harvard University and the Weizmann Institute of Science in Israel have weighed in on this discussion. Focusing on the antiviral molnupiravir, the team used mathematical models to assess the risks posed by these treatments and whether they can be administered safely.
“[These antivirals] harm the virus by introducing lethal mutations,” Martin Nowak, a professor of mathematics at Harvard and one of the study’s co-authors, told Newsweek. “But in principle they could also help the virus to find advantageous mutations which make it grow faster or escape from vaccination. Therefore, concerns are valid.”
However, the question here is whether dangerous mutations are more likely to occur in the presence or absence of this drug. “Even without such drug treatment, concerning viral variants do emerge due to natural spontaneous mutations,” Yitzhak Pilpel, another of the study’s co-authors from the Weizmann Institute, told Newsweek.
“This is how strains such as delta and omicron emerged during the pandemic. The question that we formalize is whether this and other mutagenic drug treatments increase or decrease this evolutionary risk beyond the spontaneous basal level.”
In their paper, published in the journal PLoS Biology, the team, comprised of Nowak, Pilpel and Gabriela Lobinska, introduced this concept of evolutionary safety: “A treatment is evolutionarily safe if it reduces the number of mutants produced by a patient in the course of infection,” Nowak said.
Just like in natural selection, the mutations induced by drugs like molnupiravir are totally random. “Most mutations that are induced will either be lethal or neutral,” Nowak said. “Only a small subset of mutations will be advantageous for the virus.”
So, in the case of drugs like molnupiravir, the hope is that the increased rate of mutation will produce enough negative mutations to kill the virus before it can develop or benefit from any advantageous ones.
“If the dose is too low then the increase in the mutation rate could be too small,” Nowak said. “Our work suggests that increasing the mutation rate further would improve evolutionary safety.”
In other words, if taken correctly and at a sufficient dose, patients with severe disease who receive molnupiravir produce fewer surviving mutant viruses than those who do not receive this drug. However, increasing the induced mutation rate of this drug would make it even less likely to cause dangerous super strain mutations.
This concept of evolutionary safety is not only relevant to the treatment of COVID-19 and could be used to prevent the evolution of super strains in various forms of disease. “This notion of lethal mutagenesis may also apply to antibiotics treatment against bacteria,” Pilpel said. “The world faces a concerning shortage of such drugs. If we master and control evolutionary safety of mutagenic drugs then they might add to our ability to develop new antibiotics too.”
Going forward, the team hope that this concept will be used to assess the safety of future drugs. “We suggest that the evolutionary safety of mutagenic drugs needs to be carefully evaluated [before] FDA approval,” Nowak said.