In the short history of the COVID-19 pandemic, 2021 was the year of the new variants. Alpha, Beta, Gamma and Delta each had a few months in the sun.
But this was the year of Omicron, which took over the globe in late 2021 and continues to dominate, with subvariants — with more prosaic names like BA.1, BA.2, and BA.2.12.1 — emerging in quick succession. Two closely related subvariants called BA.4 and BA.5 are now driving infections around the world, but new candidates, including one called BA.2.75, are knocking on the door.
Omicron’s continued dominance has evolutionary biologists wondering what comes next. Some think it’s a sign that SARS-CoV-2’s initial evolutionary frenzy is over and, like other coronaviruses that have been with humanity for much longer, it’s slipping into a pattern of gradual evolution. “I think a good guess is that either BA.2 or BA.5 will produce additional offspring with more mutations, and that one or more of these subvariants will spread and be the next,” says Jesse Bloom, an evolutionary biologist at Fred Hutchinson Cancer Research Center.
But others believe a new variant may already be evolving, different enough from Omicron and all other variants to merit the next Greek letter designation, pi, perhaps in a chronically infected patient. And even if Omicron isn’t replaced, its dominance is no reason for complacency, says Maria Van Kerkhove, technical lead for COVID-19 at the World Health Organization. “It’s bad enough as it is,” she says. “If we can’t get people to act [without] a new Greek name, that’s a problem.”
Even with Omicron, Van Kerkhove points out, the world could face sustained waves of disease as immunity wanes and new subvariants emerge. She is also concerned that the surveillance efforts that allowed researchers to detect Omicron and other new variants early on are being scaled back or weakened. “These systems are being dismantled, they’re being defunded, people are being fired,” she says.
The variants that reigned in 2021 did not emerge from the other. Instead, they evolved in parallel from SARS-CoV-2 viruses that were circulating at the beginning of the pandemic. In the viral family trees that researchers draw to visualize the evolutionary relationships of SARS-CoV-2 viruses, these variants appeared at the tips of long, bare branches. The pattern appears to reflect the virus, which lurks and evolves within a single person for a long time before reappearing and spreading in greatly altered form.
More and more studies seem to confirm that this occurs in immunocompromised people who cannot clear the virus and have long-standing infections. For example, on July 2, Yale University genomic epidemiologist Nathan Grubaugh and his team published a preprint on medRxiv of one such patient they found by accident. During the summer of 2021, their surveillance program at Yale New Haven Hospital kept finding a variant of SARS-CoV-2 called B.1.517, although that lineage should have disappeared from the community long ago. All of the samples turned out to be from the same individual, an immunocompromised patient in his 60s who was being treated for B-cell lymphoma. He was infected with B.1.517 in November 2020 and is positive to date.
By tracking its infection to see how the virus changed over time, the team found it was evolving at twice the normal rate of SARS-CoV-2. (Some of the viruses circulating in patients today could qualify as new variants if found in the community, says Grubaugh.) This supports the hypothesis that chronic infections may drive the “unpredictable emergence” of new variants, the researchers write in their form .
Other viruses that chronically infect patients also change faster within a host than when they spread from one person to the next, says Aris Katzourakis, an evolutionary biologist at the University of Oxford. It’s partly a numbers game: There are millions of viruses that replicate within an individual, but only a handful are passed through transmission. So much potential evolution is lost in a chain of infections, while chronic infection offers endless opportunities for evolution.
But since Omicron’s release in November 2021, no new variants have appeared out of nowhere. Instead, Omicron has accumulated small mutations, giving it a better ability to evade immune responses and—along with waning immunity—resulting in back-to-back waves. “I think it’s probably going to be harder and harder for these new things to pop up and take over because all the different Omicron lines are tough competition,” Grubaugh says, considering how transmissible and immune-avoiding they already are.
If that’s the case, the U.S. decision to update COVID-19 vaccines by adding an Omicron component is the right move, Bloom says. even if Omicron is constantly changing, a vaccine based on it will likely offer more protection than one based on previous variants.
But it’s still possible that an entirely new variant unrelated to Omicron will emerge. Or one of the previous variants like Alpha or Delta could make a comeback after causing chronic infection and going through a bout of accelerated evolution, says Tom Peacock, a virologist at Imperial College London: “That’s what we would call second-generation variants.” Given Of these possibilities, “the study of chronic infections is now more important than ever,” says Ravindra Gupta, a microbiologist at the University of Cambridge. “They could tell us what kind of mutational direction the virus will take in the population.”
BA.2.75, which has recently been picked up, has already worried some scientists. Nicknamed Centaurus, it evolved from Omicron, but seems to have quickly accumulated a whole host of major changes in its genome, more like an entirely new variant than a new subvariant of Omicron. “It looks the same as alpha or gamma or beta,” says Peacock.
BA.2.75 appears to be spreading in India, where it was first identified, and has been found in many other countries. Whether it really surpasses other subvariants is unclear, says Van Kerkhove: “The data situation is currently super limited.” “In any case, I think it’s worth paying close attention to,” says Emma Hodcroft, a virologist at the University of Bern.
However, keeping an eye on everything is becoming more difficult as surveillance decreases. Switzerland, for example, now sequences about 500 samples a week, compared to 2,000 at its peak, says Hodcroft; the United States fell to about 10,000 from more than 60,000 a week in January. “Some governments are looking to cut the money they’ve spent on sequencing,” says Hodcroft. Defending the cost is a “tough sell,” she says, “especially when you feel like the countries around you will keep sequencing even if you stop.”
Even if a variant emerges in a place with good surveillance, it can be more difficult than in the past to predict how big the threat is because differences in previous COVID-19 waves, vaccines and vaccination schedules have created a global immunity checkerboard. This means that a new variant can do well in one place, but hit a wall of immunity elsewhere. “The situation has become even less predictable,” says Katzourakis.
Given that Omicron appears to be milder than previous variants, surveillance efforts should aim to identify variants that cause serious illness in hospitalized patients, Gupta says. “I think that’s where we should focus our efforts because if we continue to focus on new genomic variants, we might get a little tired and then drop the ball if something happens.”
Many virologists admit that the development of SARS-CoV-2 has surprised them again and again. “It was really partly a failure of the imagination,” says Grubaugh. But whatever scenario researchers can envision, Bloom concedes that the virus will chart its own course: “I think in the end we’ll just have to wait and see what happens.”