Science: “New SARS-CoV-2 variants have changed the pandemic. What will the virus do next?”

A popular notion holds that viruses tend to evolve over time to become less dangerous, allowing the host to live longer and spread the virus more widely. But that idea is too simplistic, Holmes says. The evolution of virulence has proven to be quicksand for evolutionary biologists, he says. It’s not a simple thing.

Two of the best studied examples of viral evolution are myxoma virus and rabbit hemorrhagic disease virus, which were released in Australia in 1960 and 1996, respectively, to decimate populations of European rabbits that were destroying croplands and wreaking ecological havoc. Myxoma virus initially killed more than 99% of infected rabbits, but then less pathogenic strains evolved, likely because the virus was killing many animals before they had a chance to pass it on. (Rabbits also evolved to be less susceptible.) Rabbit hemorrhagic disease virus, by contrast, got more deadly over time, probably because the virus is spread by blow flies feeding on rabbit carcasses, and quicker death accelerated its spread.

Other factors loosen the constraints on deadliness. For example, a virus variant that can outgrow other variants within a host can end up dominating even if it makes the host sicker and reduces the likelihood of transmission. And an assumption about human respiratory diseases may not always hold: that a milder virus—one that doesn’t make you crawl into bed, say—might allow an infected person to spread the virus further. In SARS-CoV-2, most transmission happens early on, when the virus is replicating in the upper airways, whereas serious disease, if it develops, comes later, when the virus infects the lower airways. As a result, a variant that makes the host sicker might spread just as fast as before.

Kai Kupferschmidt

As with many other uncertainties surrounding this pandemic, the simplest answer to this question is “we just don’t know yet”. Evolution does not follow a predictable path, and even if it did, there are too many variables to consider, from local restrictions, to vaccinations levels, to complex interactions between the virus and the human immune system in vaccinated or unvaccinated people. As much as we all want this crisis to be over, the best approach remains proceeding with extra caution, vaccinating people and keeping restrictions in place to reduce transmission, because the only way to reduce viral mutation is to have as few infections as possible.

Each dot represents a virus isolated from a COVID-19 patient in this family tree of SARS-CoV-2, which shows a tiny subset of the more than 2 million viruses sequenced so far. (data) NEXTSTRAIN; GISAID

And the virus has tricks up its sleeve. Coronaviruses are good at recombining, for instance, which could allow new variants to emerge suddenly by combining the genomes—and the properties—of two different variants. In pigs, recombination of a coronavirus named porcine epidemic diarrhea virus with attenuated vaccine strains of another coronavirus has led to more virulent variants of PEDV. Given the biology of these viruses, recombination may well factor into the continuing evolution of SARS-CoV-2, Korber says.

Given all that uncertainty, it’s worrisome that humanity hasn’t done a great job of limiting the spread of SARS-CoV-2, says Eugene Koonin, a researcher at the U.S. National Center for Biotechnology Information. Some dangerous variants may only be possible if the virus hits on a very rare, winning combination of mutations, he says. It might have to replicate an astronomical number of times to get there. But with all these millions of infected people, it may very well find that combination.

Indeed, Katzourakis adds, the past 20 months are a warning to never underestimate viral evolution. Many still see Alpha and Delta as being as bad as things are ever going to get, he says. It would be wise to consider them as steps on a possible trajectory that may challenge our public health response further.