Where did ‘weird’ Omicron come from? | Science

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Since South African scientists announced last week that they had identified an unsettling new variant of SARS-CoV-2, the world has anxiously awaited clues about how it might change the trajectory of the pandemic. But as big a mystery—if less urgent—is where and how Omicron evolved, and what lessons its emergence holds for avoiding future dangerous variants.

Omicron clearly did not develop out of one of the earlier variants of concern, such as Alpha or Delta. Instead it appears to have evolved in parallel – and in the dark. Omicron is so different from the millions of SARS-CoV-2 genomes that have been shared publicly that pinpointing its closest relative is difficult, says Emma Hodcroft, a virologist at the University of Bern. It likely diverged early from other strains, she says. “I would say it goes back to mid-2020.”

That raises the question of where Omicron’s predecessors lurked for more than a year. Scientists see essentially three possible explanations: The virus could have circulated and evolved in a population with little surveillance and sequencing. It could have gestated in a chronically infected COVID-19 patient. Or it might have evolved in a non-human species, from which it recently spilled back into people.

Christian Drosten, a virologist at Charité University Hospital Berlin, favors the first possibility. “I assume this evolved not in South Africa, where a lot of sequencing is going on, but somewhere else in southern Africa during the winter wave,” he says. “There were a lot of infections going on for a long time and for this kind of virus to evolve you really need a huge evolutionary pressure.”

But Andrew Rambaut of the University of Edinburgh can’t see how the virus could have stayed hidden in a group of people for so long. “I’m not sure there’s really anywhere in the world that is isolated enough for this sort of virus to transmit for that length of time without it emerging in various places,” he says.

Instead, Rambaut and others propose the virus most likely developed in a chronically infected COVID-19 patient, likely someone whose immune response was impaired by another illness or a drug. When Alpha was first discovered in late 2020, that variant also appeared to have acquired numerous mutations all at once, leading researchers to postulate a chronic infection. The idea is bolstered by sequencing of SARS-CoV-2 samples from some chronically infected patients.

“I think the evidence supporting it is becoming stronger,” says Richard Lessells, an infectious disease researcher at the University of Kwa-Zulu-Natal. In one case Lessells and his colleagues described in a preprint, a young woman in South Africa with an uncontrolled HIV infection carried SARS-CoV-2 for more than 6 months. The virus accumulated many of the same changes seen in variants of concern, a pattern also seen in another patient whose SARS-Cov-2 infection persisted even longer.

To head off one possible source of future variants, Lessells says, “What we need to do is, is close the gaps in the HIV treatment cascade. So we need to get everybody diagnosed, we need to get everybody on to treatment, and we need to get those that are currently on ineffective treatment on to effective treatment regimens.”

But Drosten says experience with chronic infections of influenza and other viruses in immunosuppressed patients argues against this hypothesis for Omicron. Variants that elude the immune system do develop in such people, but they come with a host of other changes that make them less able to transmit from person to person. “These viruses have very low fitness out in the real world.” That’s because the mutations allowing a virus to survive in one individual over time may be very different from those needed to best spread from one person to the next.

Jessica Metcalf, an evolutionary biologist at the Institute of Advanced Study in Berlin, isn’t so sure that is true for SARS-CoV-2. “I think one reason that this virus has done so well is that better binding to ACE2 [its receptor on human cells] helps for both within-host spread and between-host spread.” Still, for the moment, she agrees with Drosten that Omicron most likely circulated and evolved in a hidden population.

Some think the virus might have hidden in rodents or other animals, rather than people, and therefore experienced different evolutionary pressures that selected for novel mutations. “The genome is just so weird,” says Kristian Andersen, pointing to its medley of mutations, many of which have not been seen before in other variants.

“It is interesting, just how crazily different it is,” says evolutionary biologist Mike Worobey of the University of Arizona. Although he favors an immunosuppressed person as the source of Omicron, Worobey notes that 80 percent of white-tailed deer sampled in Iowa between late November 2020 and early January 2021 carried SARS-CoV-2, according to a recent preprint. “It does make me wonder if other species out there can become chronically infected, which would potentially provide this sort of selective pressure over time.”

It’s too early to rule out any theory about Omicron’s origin, says Aris Katzourakis, an evolutionary biologist at the University of Oxford, but he is skeptical of the animal scenario, given the sheer number of human infections. “I’d start worrying about animal reservoirs more if we were succeeding in suppressing the virus, and then I could see it as somewhere it might hide.”

Many global health leaders have used the emergence of Omicron to focus the world’s attention on the huge gap between COVID-19 vaccinations in richer and poorer countries. Richard Hatchett, head of the Coalition for Epidemic Preparedness Innovations, opened his remarks at the World Health Assembly on Monday by saying low vaccine coverage in South Africa and Botswana had “provided a fertile environment” for the variant’s evolution. “The global inequity that has characterized the global response has now come home to roost,” he said.

Yet there is little evidence to support that statement, say some scientists. “The idea that if we had vaccinated more in Africa, we wouldn’t have this: I’d like that to be true, but we have literally no way of knowing,” says Katzourakis. For now, the lessons to be drawn from Omicron remain as unknown as its origin.


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