As Omicron rages on, scientists have no idea what comes next

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 couple of months in the Sun.

But this was the year of Omicron, which swept the globe late in 2021 and has continued to dominate, with subvariants—given more prosaic names such as BA.1, BA.2, and BA.2.12.1—appearing in rapid succession. Two closely related subvariants named BA.4 and BA.5 are now driving infections around the world, but new candidates, including one named BA.2.75, are knocking on the door.

Omicron’s lasting dominance has evolutionary biologists wondering what comes next. Some think it’s a sign that SARS-CoV-2’s initial frenzy of evolution is over and it, like other coronaviruses that have been with humanity much longer, is settling into a pattern of gradual evolution. “I think a good guess is that either BA.2 or BA.5 will spawn additional descendants with more mutations and that one or more of those subvariants will spread and will be the next thing,” says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center.

But others believe a new variant different enough from Omicron and all other variants to deserve the next Greek letter designation, Pi, may already be developing, perhaps in a chronically infected patient. And even if Omicron is not replaced, its dominance is no cause 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 emphasizes, the world may face continuing waves of disease as immunity wanes and fresh subvariants arise. She is also alarmed that the surveillance efforts that allowed researchers to spot Omicron and other new variants early on are scaling back or winding down. “Those systems are being dismantled, they are being defunded, people are being fired,” she says.

The variants that ruled in 2021 did not arise one out of the other. Instead, they evolved in parallel from SARS-CoV-2 viruses circulating early in the pandemic. In the viral family trees researchers draw to visualize the evolutionary relationships of SARS-CoV-2 viruses, these variants appeared at the tips of long, bare branches. The pattern seems to reflect virus lurking in a single person for a long time and evolving before it emerges and spreads again, much changed.

More and more studies seem to confirm that this occurs in immunocompromised people who can’t clear the virus and have long-running infections. On 2 July, for example, Yale University genomic epidemiologist Nathan Grubaugh and his team posted a preprint on medRxiv about one such patient they found accidentally. In the summer of 2021, their surveillance program at the Yale New Haven Hospital kept finding a variant of SARS-CoV-2 called B.1.517 even though that lineage was supposed to have disappeared from the community long ago. All of the samples, it turned out, came from the same person, an immunocompromised patient in his 60s undergoing treatment for a B cell lymphoma. He was infected with B.1.517 in November 2020 and is still positive today.

Making waves

A series of Omicron subvariants has appeared in rapid succession around the world since the beginning of this year. Some scientists say that pattern will likely continue—but an entirely new variant could still arise.

Graphic of Omicron subvariant infections in 2022

(Graphic) C. Bickel/


; (Data) Nextstrain/GISAID

By following his infection to observe how the virus changed over time, the team found it evolved at twice the normal speed of SARS-CoV-2. (Some of the viruses circulating in the patient today might be qualified as new variants if they were found in the community, Grubaugh says.) That supports the hypothesis that chronic infections could drive the “unpredictable emergence” of new variants, the researchers write in their preprint.

Other viruses that chronically infect patients also change faster within one host than when they spread from one person to the next, says Aris Katzourakis, an evolutionary biologist at the University of Oxford. This is partly a numbers game: There are millions of viruses replicating in an individual, but only a handful are passed on during transmission. So a lot of potential evolution is lost in a chain of infections, whereas a chronic infection allows for endless opportunities to evolve.

But since Omicron emerged in November 2021, no new variants have appeared out of nowhere. Instead, Omicron has accumulated small changes, making it better at evading immune responses and—together with waning immunity—leading to successive waves. “I think it’s probably harder and harder for these new things to emerge and take over because all the different Omicron lineages are stiff competition,” Grubaugh says, given how transmissible and immune-evading they already are.

If so, the U.S. decision to update COVID-19 vaccines by adding an Omicron component is the right move, Bloom says; even if Omicron keeps changing, a vaccine based on it is likely to provide more protection than one based on earlier variants.

But it’s still possible that an entirely new variant unrelated to Omicron will emerge. Or one of the previous variants, such as Alpha or Delta, could make a comeback after causing a chronic infection and going through a bout of accelerated evolution, says Tom Peacock, a virologist at Imperial College London: “This is what we would call second-generation variants.” Given those possibilities, “Studying chronic infections is now more important than ever,” says Ravindra Gupta, a microbiologist at the University of Cambridge. “They might tell us the kind of mutational direction the virus will take in the population.”

BA.2.75, which was picked up recently, already has some scientists concerned. Nicknamed Centaurus, it evolved from Omicron but seems to have quickly accumulated a whole slew of important changes in its genome, more like an entirely new variant than a new Omicron subvariant. “This looks exactly like Alpha did, or Gamma or Beta,” Peacock says.

BA.2.75 appears to be spreading in India, where it was first identified, and has been found in many other countries. Whether it’s really outcompeting other subvariants is unclear, Van Kerkhove says: “The data is superlimited right now.” “I certainly think it’s something worth keeping a close eye on,” says Emma Hodcroft, a virologist at the University of Bern.

Keeping an eye on anything is getting harder, however, because surveillance is decreasing. Switzerland, for example, now sequences about 500 samples per week, down from 2000 at its peak, Hodcroft says; the United States went from more than 60,000 per week in January to about 10,000. “Some governments are anxious to cut back on the money they dedicated to sequencing,” Hodcroft says. Defending the expense is a “hard sell,” she says, “especially if there’s a feeling the countries around you will continue sequencing even if you stop.”

Even if a variant emerges in a place with good surveillance, it may be harder than in the past to predict how big a threat it poses, because differences in past COVID-19 waves, vaccines, and immunization schedules have created a global checkerboard of immunity. That means a new variant might do well in one place but run into a wall of immunity elsewhere. “The situation has become even less predictable,” Katzourakis says.

Given that Omicron appears to be milder than previous variants, surveillance efforts should aim to identify variants that cause severe disease in hospitalized patients, Gupta says. “I think that that’s where we should be focusing our efforts, because if we keep focusing on new variants genomically, we may get a bit fatigued, and then kind of drop the ball when things do happen.”

Many virologists acknowledge that SARS-CoV-2’s evolution has caught them by surprise again and again. “It was really in part a failure of imagination,” Grubaugh says. But whatever scenario researchers can imagine, Bloom acknowledges the virus will chart its own course: “I think in the end, we just kind of have to wait and see what happens.”

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