In the short history of the COVID-19 pandemic, 2021 was the year of new variants. Alpha, Beta, Gamma and Delta each had several months on the Sun.

But this was the year of the Omicron, which swept the globe in late 2021 and has continued to dominate, with sub-variants – with more prosaic names such as BA.1, BA.2 and BA.2.12.1 – appearing rapidly . Two closely related subvariants named BA.4 and BA.5 are now driving infections worldwide, but new candidates, including one called BA.2.75, are knocking on the door.

Omicron’s enduring 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 much longer, it’s settling into a pattern of gradual evolution. “I think a good guess is that either BA.2 or BA.5 will create other offspring with more mutations and that one or more of those subvariants will spread and be the next thing,” says Jesse Bloom, an evolutionary biologist in Fred Hutchinson Cancer Research Center.

But others believe that a new variant sufficiently different from Omicron and all other variants to merit the designation of the next Greek letter, 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 points out, the world could face constant waves of disease as immunity wanes and new subvariants arise. She is also alarmed that the surveillance efforts that allowed researchers to spot Omicron and other new variants early on are being scaled back or reduced. “Those systems are being dismantled, they’re being defunded, people are being laid off,” she says.

The variants that ruled in 2021 were not born from each other. Instead, they evolved in parallel from the SARS-CoV-2 viruses circulating at the start 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 hiding in a single person for a long time and evolving before emerging and spreading again, much altered.

More and more studies seem to confirm that this happens in immunocompromised people who cannot clear the virus and have long-term infections. On July 2, for example, Yale University genomic epidemiologist Nathan Grubaugh and his team posted a preprint on medRxiv about one such patient they found by accident. In the summer of 2021, their surveillance program at Yale New Haven Hospital continued to find a variant of SARS-CoV-2 called B.1.517 even though that lineage was supposed to have disappeared from the community long ago. It turned out that all the samples came from the same person, an immunocompromised patient in his 60s who was being treated 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 sub-variants have appeared in rapid succession around the world since the beginning of this year. Some scientists say this pattern is likely to continue — but an entirely new variant may yet emerge.

Chart of Omicron subvariant infections in 2022
(Graphics) C. Bickel and N. Desai/science; (Data) Nextstrain/GISAID

By following his infection to observe how the virus changed over time, the team found that it evolved at twice the normal rate of SARS-CoV-2. (Some of the viruses circulating in patients today might qualify as new variants if found in the community, Grubaugh says.) This supports the hypothesis that chronic infections can drive the “unpredictable emergence” of new variants, the researchers write in the preprint. theirs.

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

But since Omicron appeared in November 2021, no new variant has appeared out of nowhere. Instead, Omicron has accumulated small changes, making it better at evading immune responses and – along with declining 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 lines are fiercely competitive,” Grubaugh says, given how transmissible and immunological they are already. .

If so, the US decision to update the COVID-19 vaccines by adding an Omicron component is the right move, says Bloom; even if Omicron continues to change, 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 earlier variants, like Alpha or Delta, might come back after it causes a chronic infection and has gone through a period of accelerated evolution, says Tom Peacock, a virologist at Imperial College London: “That’s what we’ll call the second. -Variants of the generation.” Given these possibilities, “The study of chronic infections is now more important than ever,” says Ravindra Gupta, a microbiologist at the University of Cambridge. “They can tell us what kind of mutational direction the virus will take in the population.”

BA.2.75, which was received recently, already has some scientists worried. Nicknamed Centaurus, it evolved from Omicron, but seems to have quickly accumulated a host of significant changes to its genome, more like an entirely new variant than a new Omicron subvariant. “It looks just like 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. It’s unclear whether it’s actually outperforming other subvariants, Van Kerkhove says: “The data is limited right now.” “I certainly think it’s something worth keeping a close eye on,” says Emma Hodcroft, a virologist at the University of Bern.

However, keeping an eye on everything is becoming more difficult because surveillance is decreasing. Switzerland, for example, now sorts about 500 samples a week, from 2000 at its peak, says Hodcroft; The United States went from more than 60,000 a week in January to about 10,000. “Some governments are anxious to cut the money they put into the rankings,” says Hodcroft. Spend protection is a “tough sell,” she says, “especially if there’s a sense that the countries around you will continue to rank even if you stop.”

Even if a variant emerges in a country with good surveillance, it may be more difficult than in the past to predict how big a threat it poses because changes in past COVID-19 waves, vaccines, and immunization schedules have created a global immunity table. . This means that a new variant may work well in one country but run up against a wall of immunity elsewhere. “The situation has become even less predictable,” says Katzourakis.

Given that Omicron appears to be milder than earlier variants, surveillance efforts should aim to identify variants that cause severe disease in hospitalized patients, Gupta says. “I think that’s where we need to focus our efforts, because if we keep focusing on new genomic variants, we can get a little tired and then drop the ball when things happen.”

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

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