In the short history of the COVID-19 pandemic, 2021 has become a year of new options. Alpha, Beta, Gamma and Delta each spent several months on the Sun.
But this was the year of the Omicron, which took the world by storm in late 2021 and continues to dominate, with sub-variants with more prosaic names like the BA.1, BA.2 and BA.2.12.1 popping up one after the other. Two closely related subvariants, called BA.4 and BA.5, are currently causing infections around the world, but new candidates, including one called BA.2.75, are knocking on the door.
Omicron’s long dominance has left evolutionary biologists wondering what will happen next. Some believe that this is a sign that the initial crazy evolution of SARS-CoV-2 is over and that it, like other coronaviruses that have been with humanity much longer, is establishing a pattern of gradual evolution. “I think it’s a good guess that either BA.2 or BA.5 will produce additional offspring with more mutations, and that one or more of those subvariants will spread and become next,” says Jesse Bloom, an evolutionary biologist at the 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 patient with a chronic infection. And even if Omicron isn’t replaced, its dominance is no cause for complacency, says Maria Van Kerckhove, the World Health Organization’s technical lead on COVID-19. “It’s bad enough as it is,” she says. “If we can’t get people to act [without] the new Greek name is a problem.”
Even with Omicron, Van Kerchow points out, the world could face continued waves of disease as immunity wanes and new sub-variants emerge. She also worries that the surveillance efforts that allowed researchers to detect Omicron and other new variants early are being scaled back or curtailed. “These systems are being dismantled, they are being defunded, people are being laid off,” she says.
The options that prevailed in 2021 did not arise from each other. Instead, they evolved in parallel from the SARS-CoV-2 viruses circulating at the beginning of the pandemic. In the family trees of viruses that researchers draw to visualize the evolutionary relationships of SARS-CoV-2 viruses, these variants appear at the tips of long bare branches. The model appears to reflect a virus that hides in one person for a long time and evolves before emerging and spreading again, having changed significantly.
More and more studies are confirming that this happens in immunocompromised people who cannot clear the virus and have long-term infections. For example, on July 2, Yale University genomic epidemiologist Nathan Grabo and his team published a preprint on medRxiv about one such patient they found by chance. In the summer of 2021, their surveillance program at Yale University Hospital in New Haven continued to find a variant of SARS-CoV-2 called B.1.517, even though the lineage was thought to have long since disappeared from the community. It turned out that all the samples came from the same person, 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 still positive.
After following his infection to see how the virus changed over time, the team found that it evolved twice as fast as SARS-CoV-2. (Some of the viruses circulating in patients today would qualify as new variants if they were found in the community, Grubo says.) This supports the hypothesis that chronic infections can cause the “unpredictable emergence” of new variants, the researchers wrote in their preprint.
Other viruses that chronically infect patients also change more quickly within a single host than when they spread from one person to another, says Aris Katsourakis, an evolutionary biologist at the University of Oxford. Part of it is a numbers game: Millions of viruses multiply in the human body, but only a few are transmitted during transmission. Thus, much of the potential for evolution is lost in the chain of infections, whereas chronic infection provides unlimited opportunities for development.
But since Omicron appeared in November 2021, new options have not appeared out of thin air. Instead, the Omicron has accumulated small changes that make it better at evading immune responses and—along with weakened immunity—resulting in successive waves. “I think it’s probably harder and harder for these new things to come out and gain ground because all the different lines of Omicron are so competitive,” Grubo says, given how infectious and immune-evasive they already are.
If so, the U.S. decision to update its 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 greater protection than a vaccine 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 causing a chronic infection and going through a period of accelerated evolution, says Tom Peacock, a virologist at Imperial College London: “That’s what we’d call the second. – options of generations”. 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 the direction of virus mutations in the population.”
BA.2.75, which was recently picked up, is already causing concern among some scientists. It was nicknamed Centaur and evolved from Omicron, but seems to have quickly accumulated a number of important changes in its genome, looking more like an entirely new variant than a new sub-variant of Omicron. “It looks exactly like Alpha or Gamma or Beta,” Peacock says.
BA.2.75 appears to be spreading in India, where it was first detected, and has been detected in many other countries. Whether it actually outperforms the other subvariants is unclear, Van Kerchow says: “The data is extremely limited at this point.” “I think it’s worth keeping a close eye on,” says Emma Hodcroft, a virologist at the University of Bern.
However, it becomes harder to keep track of anything as the follow-up diminishes. Switzerland, for example, now sequences about 500 samples a week, compared to 2,000 at its peak, Hodcroft says; The United States has gone from more than 60,000 a week in January to about 10,000. “Some governments are looking to cut the money they spend on sequencing,” Hodcroft says. Defending spending is “a tough sell,” she says, “especially if there’s a sense that countries around you will continue sequencing even if you stop.”
Even if a variant emerges in a well-surveillance setting, it may be more difficult than in the past to predict how much of a threat it poses, as differences in past COVID-19 waves, vaccines, and immunization schedules have created a global immunity checkerboard. . This means that a new variant may work well in one location, but hit 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 focus on 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 continue to focus on new genomic variants, we can get a little tired and then kind of drop the ball when something happens.”
Many virologists admit that the evolution of SARS-CoV-2 has repeatedly caught them by surprise. “It was really partly a mistake of the imagination,” says Grubo. But whatever scenario researchers might envision, Bloom admits the virus will chart its own course: “I think ultimately we’ll just have to wait and see what happens.”