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 world in late 2021 and continued to dominate, with sub-variants — with more prosaic names like BA.1, BA.2 and BA.2.12.1 — appearing in quick succession. Two closely related subvariants, called BA.4 and BA.5, are now causing infections worldwide, but new candidates, including one called BA.2.75, are knocking on the door.
Omicron’s continued dominance has evolutionary biologists wondering what’s next. Some believe this is a sign that the initial frenzy of SARS-CoV-2 evolution is over and that it, like other coronaviruses that have been with humanity much longer, is settling into a pattern of gradual evolution. “I think it’s a good guess that either BA.2 or BA.5 will create additional 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 at Fred Hutchinson Cancer Research Center.
But others believe that a new variant, different enough from Omicron and all other variants to merit the next Greek letter designation, Pi, may already be developing, perhaps in a chronically infected patient. And even if Omicron isn’t replaced, its dominance is no cause for complacency, says Maria Van Kerkhove, technical lead for COVID-19 at the World Health Organization. “It’s already bad enough,” 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 continued waves of disease as immunity wanes and new sub-variants emerge. She is also concerned that the surveillance efforts that allowed researchers to detect Omicron and other new variants early are being reduced or reduced. “These systems are being dismantled, they are being defunded, people are being laid off,” she says.
The variants that prevailed in 2021 did not derive from each other. Instead, they evolved in parallel from the SARS-CoV-2 viruses 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 appear at the tips of long, bare branches. The pattern seems to reflect the virus hiding in a person for a long time and evolving before emerging and spreading again, much changed.
More and more studies seem to confirm that this happens in immunocompromised people who cannot clear the virus and have long-lasting infections. On July 2, for example, Yale University genomic epidemiologist Nathan Grubow and his team published a preprint on medRxiv about one such patient they discovered by chance. In the summer of 2021, their surveillance program at Yale New Haven Hospital continued to detect a variant of SARS-CoV-2 called B.1.517, even though this strain should 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 undergoing treatment for B-cell lymphoma. He was infected with B.1.517 in November 2020 and is still positive today.
By tracking his infection to see how the virus changed over time, the team found that it was evolving at twice the normal rate of SARS-CoV-2. (Some of the viruses circulating in a patient today could qualify as new variants if they were found in the community, Grubo says.) This supports the hypothesis that chronic infections can lead to the “unpredictable emergence” of new variants, the researchers wrote in their preprint.
Other viruses that chronically infect patients also change more quickly within a host than when they spread from one person to another, says Aris Katsourakis, 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 handful are transmitted during transmission. So much of the potential evolution is lost in a chain of infections, while chronic infection allows endless opportunities for development.
But since Omicron appeared in November 2021, no new variants have appeared out of nowhere. Instead, Omicron has accumulated small changes that make it better at evading immune responses and – along with waning immunity – resulting in successive waves. “I think it’s probably harder and harder for these new things to come in and take over because all the different Omicron lines are strong competition,” Grubo says, given how infectious and immune-evading they already are.
If so, the US decision to update the COVID-19 vaccines by adding the Omicron component is the right move, Bloom says; 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, such as Alpha or Delta, may return after having caused a chronic infection and gone through a bout of accelerated evolution, says Tom Peacock, a virologist at Imperial College London: “This is what we would call a second – generation variants.” 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 mutational direction the virus will take in the population.’
BA.2.75, which was taken recently, is already causing concern among some scientists. Nicknamed Centaurus, it evolved from Omicron, but seems to have quickly accumulated a whole host of important changes to its genome, more like an entirely new variant than a new sub-variant of Omicron. “It looks just like Alpha, 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. It’s not clear whether it really overtakes other subvariants, Van Kerchow says: “The data is extremely limited at the moment.” “I certainly think it’s something worth keeping a close eye on,” says Emma Hodcroft, a virologist at the University of Bern.
However, it’s increasingly difficult to keep track of everything as surveillance declines. Switzerland, for example, now sequences about 500 samples a week, down from 2,000 at its peak, Hodcroft says; The United States went from more than 60,000 a week in January to about 10,000. “Some governments are looking to cut the money they’ve put into sequencing,” Hodcroft says. Protecting spending is “a hard sell,” she says, “especially if there’s a sense that the countries around you will continue the sequence even if you stop.”
Even if a variant emerges in a place with good surveillance, it may be more difficult than in the past to predict how much of a threat it poses because differences in past waves of COVID-19, vaccines and immunization schedules have created a global chessboard. board of immunity. This means that a new variant may do well in one place but run into a wall of immunity elsewhere. “The situation has become even less predictable,” says Katsourakis.
Given that Omicron appears to be milder than previous variants, surveillance efforts should be aimed at identifying 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 variants genomically, we might get a little tired and then drop the ball when things happen.”
Many virologists admit that the evolution of SARS-CoV-2 has surprised them time and time again. “It was really partly a failure of imagination,” says Grubo. But whatever scenario researchers may envision, Bloom admits the virus will chart its own course: “I think ultimately we’ll just have to wait and see what happens.”