Little more than two months after it was first spotted in South Africa, the Omicron variant of the coronavirus SARS-CoV-2 has spread around the world faster than any previous versions. Scientists have tracked it in more than 120 countries, but remain puzzled by a key question: where did Omicron come from?

There’s no transparent path of transmission linking Omicron to its predecessors. Instead, the variant has an unusual array of mutations, which it evolved entirely outside the view of researchers. Omicron is so different from earlier variants, such as Alpha and Delta, that evolutionary virologists estimate its closest-known genetic ancestor probably dates back to more than a year ago, some time after mid-2020 (ref. ¹). “It just came out of nowhere,” says Darren Martin, a computational biologist at the University of Cape Town, South Africa.

The question of Omicron’s origins is of more than academic importance. Working out under what conditions this highly transmissible variant arose might help scientists to understand the risk of new variants emerging, and suggest steps to minimize it, says Angela Rasmussen, a virologist at the University of Saskatchewan Vaccine and Infectious Disease Organization in Saskatoon, Canada. “It’s very difficult to try to mitigate a risk that you can’t even remotely wrap your head around,” she says.

The World Health Organization’s recently formed Scientific Advisory Group for the Origins of Novel Pathogens (SAGO) met in January to discuss Omicron’s origins. The group is expected to release a report in early February, according to Marietjie Venter, a medical virologist at the University of Pretoria in South Africa, who chairs SAGO.

Ahead of that report, scientists are investigating three theories. Although researchers have sequenced millions of SARS-CoV-2 genomes, they might simply have missed a series of mutations that eventually led to Omicron. Alternatively, the variant might have evolved mutations in one person, as part of a long-term infection. Or it could have emerged unseen in other animal hosts, such as mice or rats.

For now, whichever idea a researcher favours “often comes down to gut feeling rather than any sort of principled argument”, says Richard Neher, a computational biologist at the University of Basel in Switzerland. “They are all fair game,” says Jinal Bhiman, a medical scientist at the National Institute for Communicable Diseases in Johannesburg, South Africa. “Everyone has their favourite hypothesis.”

Craziest genome

Researchers agree that Omicron is a recent arrival. It was first detected in South Africa and Botswana in early November 2021 (see ‘Omicron takeover’); retrospective testing has since found earlier samples from individuals in England on 1 and 3 November, and in South Africa, Nigeria and the United States on 2 November. An analysis of the mutation rate in hundreds of sequenced genomes, and of how quickly the virus had spread through populations by December, dates its emergence to not long before that — around the end of September or early October last year². In southern Africa, Omicron probably spread from the dense urban province of Gauteng, between Johannesburg and Pretoria, to other provinces and to neighbouring Botswana.

But because Johannesburg is home to the largest airport on the African continent, the variant could have emerged anywhere in the world — merely being picked up in South Africa because of the country’s sophisticated genetic surveillance, says Tulio de Oliveira, a bioinformatician at the University of KwaZulu-Natal in Durban and at Stellenbosch University’s Centre for Epidemic Response and Innovation, who has led South Africa’s efforts to track viral variants, including Omicron.

What stands out about Omicron is its remarkable number of mutations. Martin heard about it when he took a phone call from de Oliveira, who asked him to look at the craziest SARS-CoV-2 genome he had ever seen.

The variant has more than 50 mutations when compared with the original SARS-CoV-2 virus isolated in Wuhan, China (see go.nature.com/32utxva). Some 30 of these contribute to changes in amino acids in the spike protein¹, which the coronavirus uses to attach to and fuse with cells. Previous variants of concern have had no more than ten such spike mutations. “That is a hell of a lot of changes,” says Neher (see ‘Most mutated’).

Researchers have seen many of these mutations before. Some were previously known to give the virus an increased ability to bind to the ACE2 receptor protein — which adorns host cells and is the docking point for SARS-CoV-2 — or to help it evade the body’s immune system. Omicron forms a stronger grip on ACE2 than do previously seen variants³. It is also better at evading the virus-blocking ‘neutralizing’ antibodies⁴ produced by people who have been vaccinated, or who have been infected with earlier variants. Other changes in the spike protein seem to have modified how Omicron enters cells: it appears to be less adept at fusing directly with the cell’s membrane, and instead tends to gain entry after being engulfed in an endosome (a lipid-surrounded bubble)³.

But more than a dozen of Omicron’s mutations are extremely rare: some have not been seen at all before, and others have popped up but disappeared again quickly, presumably because they gave the virus a disadvantage¹.

Another curious feature of Omicron is that, from a genomic viewpoint, it consists of three distinct sublineages (called BA.1, BA.2 and BA.3) that all seem to have emerged at around the same time — two of which have taken off globally. That means Omicron had time to diversify before scientists noticed it. Any theory about its origins has to take this feature into account, as well as the number of mutations, notes Joel Wertheim, a molecular epidemiologist at the University of California, San Diego.

Silent spread

Researchers have explained the emergence of previous variants of concern through a simple process of gradual evolution. As SARS-CoV-2 replicates and transmits from person to person, random changes crop up in its RNA sequence, some of which persist. Scientists have observed that, in a given lineage, about one or two single-letter mutations a month make it into the general viral circulation — a mutation rate about half that of influenza. It is also possible for chunks of coronavirus genomes to shuffle and recombine wholesale, adds Kristian Andersen, an infectious-disease researcher at Scripps Research in La Jolla, California. And viruses can evolve faster when there is selection pressure, he says, because mutations are more likely to stick around if they give the virus an increased ability to propagate under certain environmental conditions.

Some scientists think that person-to-person spread would not be conducive to accumulating as many changes as Omicron has since mid-2020. “It does seem like a year and a half is a really short period of time for that many mutations to emerge and to apparently be selected for,” says Rasmussen.

But Bhiman argues that enough time has elapsed. She thinks the mutation process could have occurred unseen, in a region of the world that has limited genomic sequencing and among people who don’t typically get tested, perhaps because they didn’t have symptoms. At some point in the past few months, she says, something happened to help Omicron explode, maybe because the progress of other variants — such as Delta — was gradually impeded by the immunity built up from vaccination and previous infection, whereas Omicron was able to evade this barrier.

Although researchers have submitted almost 7.5 million SARS-CoV-2 sequences to the GISAID genome database, hundreds of millions of viral genomes from people with COVID-19 worldwide have not been sequenced. South Africa, with some 28,000 genomes, has sequenced less than 1% of its known COVID-19 cases, and many nearby countries, from Tanzania to Zimbabwe and Mozambique, have submitted fewer than 1,000 sequences to GISAID (see ‘Missing genomes’).

Martin says that researchers need to sequence SARS-CoV-2 genomes from these countries to get a better sense of the likelihood of unobserved evolution. It is possible that the three sublineages of Omicron each separately arrived in South Africa from a region with limited sequencing capacity, he says.

But de Oliveira says the scenario that Omicron evolved unseen through person-to-person transmission is “extremely implausible”. Intermediate steps in Omicron’s evolution should have been picked up in viral genomes from people travelling from countries that do little sequencing to those that do a lot.

“This is not the nineteenth century, where you take six months to go from point to point by sailboat,” says Sergei Pond, a computational evolutionary biologist at Temple University in Philadelphia, Pennsylvania.

And Andersen adds that, because some of Omicron’s mutations haven’t been seen before, the variant might have evolved in an environment not involving person-to-person chains of transmission. Some of the changes in Omicron don’t match any seen even in the broader viral group of sarbecoviruses, which includes the virus that causes severe acute respiratory syndrome (SARS). For example, one particular site on the genomes of all known sarbecoviruses encodes a serine amino acid, but a mutation in Omicron means the variant has a lysine at that position¹, which changes the biochemistry of that region, Andersen says.

However, says Jesse Bloom, a viral evolutionary geneticist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, SARS-CoV-2 has not yet explored all of its possibilities in people. “The virus is still expanding in the evolutionary space.”

Chronic infection

An alternative incubator for fast-paced evolution is a person with a chronic infection. There, the virus can multiply for weeks or months, and different types of mutation can emerge to dodge the body’s immune system. Chronic infections give the virus “the opportunity to play cat and mouse with the immune system”, says Pond, who thinks it is a plausible hypothesis for Omicron’s emergence.

Such chronic infections have been observed in people with compromised immune systems who cannot easily get rid of SARS-CoV-2. For example, a December 2020 case report described a 45-year-old man with a persistent infection⁵. During almost five months in its host, SARS-CoV-2 accumulated close to a dozen amino-acid changes in its spike protein. Some researchers suggest Alpha emerged in someone with a chronic infection, because, like Omicron, it seems to have accumulated changes at an accelerated rate (see go.nature.com/3yj6kmh).

“The virus has to change to stick around,” says Ben Murrell, an interdisciplinary virologist at the Karolinska Institute in Stockholm. The receptor-binding domain, where many of Omicron’s mutations are concentrated, is an easy target for antibodies, and probably comes under pressure to change in a long-term infection.

But none of the viruses from individuals with chronic infections studied so far has had the scale of mutations observed in Omicron. Achieving that would require high rates of viral replication for a long time, which would presumably make that person very unwell, says Rasmussen. “It seems like a lot of mutations for just one person.”

Further complicating the picture, Omicron’s properties could stem from combinations of mutations working together. For example, two mutations found in Omicron — N501Y together with Q498R — increase a variant’s ability to bind to the ACE2 protein by almost 20 times, according to cell studies⁶. Preliminary research by Martin and his colleagues suggests that the dozen or so rare mutations in Omicron form three separate clusters, in which they seem to work together to compensate for the negative effects of any single one¹.

If this is the case, it means that the virus would have to replicate sufficiently in a person’s body to explore the effects of combinations of mutations — which would take longer to achieve than if it were sampling the space of possible mutations one by one.

One possibility is that multiple individuals with chronic infections were involved, or that Omicron’s ancestor came from someone with a long-term infection and then spent some time in the general population before being detected. “There are a lot of open questions,” says Rasmussen.

Proving this theory is close to impossible, because researchers would need to be lucky enough to find the particular person or group that could have sparked Omicron’s emergence. Still, more comprehensive studies of SARS-CoV-2’s evolution in chronic infections would help to map out the range of possibilities, says Neher.

Mouse or rat

Omicron might not have emerged in a person at all. SARS-CoV-2 is a promiscuous virus: it has spread to a wild leopard, to hyenas and hippopotamuses at zoos, and into pet ferrets and hamsters. It has caused havoc in mink farms across Europe, and has infiltrated populations of white-tailed deer throughout North America. And Omicron might be able to enter a broader selection of animals. Cell-based studies have found that, unlike earlier variants, Omicron’s spike protein can bind to the ACE2 protein of turkeys, chickens and mice^3,7.

One study found that the N501Y–Q498R combination of mutations allows variants to bind tightly to rat ACE2 (ref. ⁶). And Robert Garry, a virologist at Tulane University in New Orleans, Louisiana, notes that several other mutations in Omicron have been seen in SARS-CoV-2 viruses adapting to rodents in laboratory experiments.

The types of single-nucleotide substitution observed in Omicron’s genome also seem to reflect those typically observed when coronaviruses evolve in mice, and do not match as well with the switches that are observed in coronaviruses adapting to people, according to a study of 45 mutations in Omicron⁸. The study noted that, in human hosts, G to U substitutions tend to occur in RNA viruses at a higher rate than C to A switches do, but that Omicron does not show this pattern.

It is possible, then, that SARS-CoV-2 could have acquired mutations that gave it access to rats — jumping from an ill person to a rat, possibly through contaminated sewage — and then spread and evolved into Omicron in that animal population. An infected rat could later have come into contact with a person, sparking the emergence of Omicron. The three sublineages of Omicron are sufficiently distinct that, according to this theory, each would represent a separate jump from animal to human.

A large population of animals with infections lasting longer than in humans could give SARS-CoV-2 room to explore a wide diversity of mutations and “build up a large ghost population of viruses that no one knows about”, says Martin, who says he finds this ‘reverse zoonosis’ theory convincing. Changes that make the virus better at spreading in its animal host won’t necessarily affect its ability to infect people, he says.

An animal reservoir could also explain why some of the mutations in Omicron have been rarely seen before in people, says Andersen.

In the dark

But others say that even a single viral jump from an animal to a person is a rare event — let alone three. Meanwhile, the virus has had plenty of opportunities to slip between people. And although some of Omicron’s mutations have been seen in rodents, that doesn’t mean they can’t happen or haven’t occurred in people, too, and have simply been missed.

Murrell also points out that SARS-CoV-2 didn’t immediately go through a period of accelerated evolution after jumping to people for the first time. When it spread to mink and deer, it did pick up changes, but not as many mutations as Omicron has accumulated, says Spyros Lytras, an evolutionary virologist at the University of Glasgow, UK. This means that the evidence isn’t sufficient to suggest Omicron’s predecessor would have undergone rapid selection after finding a new home in the wild.

To confirm this theory, researchers would need to find close relatives of Omicron in another animal, but they haven’t been looking — “something that has been horribly neglected”, says Martin. Since the pandemic began, researchers have sequenced fewer than 2,000 SARS-CoV-2 genomes isolated from other animals, mostly from mink, cats and deer.

Now that Omicron has taken off, how it evolves in people could offer more clues about its origins. It might, for instance, shed mutations that, in retrospect, are found to have helped it adapt to a different animal host, or in a person with a chronic infection. But it could also not change by much, leaving researchers in the dark.

The answer to Omicron’s emergence will probably be one or a combination of the three scenarios, says Bloom. But, he adds, researchers are far from explaining the processes that brought Omicron here, let alone predicting what the next variant will look like.

And many scientists say they might never find out where Omicron came from. “Omicron really shows us the need for humility in thinking about our ability to understand the processes that are shaping the evolution of viruses like SARS-CoV-2,” says Bloom.

• NEWS FEATURE
• 15 June 2022

Virologist Sissy Sonnleitner tracks nearly every COVID-19 case in Austria’s rugged eastern Tyrol region. So, when one woman there kept testing positive for months on end, Sonnleitner was determined to work out what was going on.

Before becoming infected with SARS-CoV-2 in late 2020, the woman, who was in her 60s, had been taking immune-suppressing drugs to treat a lymphoma relapse. The COVID-19 infection lingered for more than seven months, causing relatively mild symptoms, including fatigue and a cough.

Sonnleitner, who is based at a microbiology facility in Außervillgraten, Austria, and her colleagues collected more than two dozen viral samples from the woman over time and found through genetic sequencing that it had picked up about 22 mutations (see ‘Tracking spike’s evolution’). Roughly half of them would be seen again in the heavily mutated Omicron variants of SARS-CoV-2 that surged around the globe months later¹. “When Omicron was found, we had a great moment of surprise,” Sonnleitner says. “We already had those mutations in our variant.”

Omicron did not arise from the woman’s infection, which doesn’t seem to have spread to anyone. And although no definitive links have been made to individual cases, chronic infections such as hers are a leading candidate for the origins of Omicron and other variants that have driven COVID-19 surges globally. “I don’t think there can be any doubt in anyone’s mind that these are a source of new variants,” says Ravindra Gupta, a virologist at the University of Cambridge, UK.

Researchers want to understand how the virus might evolve the ability to spread from person to person more easily, to evade the immune response, or to become more or less severe. Some or all of these qualities might be forged during the course of a chronic infection. “We don’t quite understand what can evolve in a single individual — and what cannot,” says Alex Sigal, a virologist at the Africa Health Research Institute in Durban, South Africa.

The odds are remote that this knowledge could help to predict the next deadly strain or even to trace variants such as Omicron to their origin. Still, virologists hope that by improving their understanding of viral evolution, they will be able to anticipate what future variants might look like — and potentially find better ways to treat chronic infections. “It’s such an important problem, given that we don’t want another variant that we can’t handle,” says Sigal.

Deadly competition

Since late 2019, scientists have sequenced the genomes of more than 11 million samples of SARS-CoV-2 taken from people. These efforts have drawn an evolutionary tree that is remarkable in its breadth, showing how the virus has changed during its march around the planet, gaining just a couple of stable mutations per month as it moves from person to person.

“But that’s only one part of the evolutionary story,” says Sarah Otto, an evolutionary biologist at the University of British Columbia in Vancouver, Canada. Each person’s infection is its own universe, where new mutations arise as the infection spreads from cell to cell. Most of these changes won’t matter to the virus, and many will do it harm. But some might give it a slight advantage over other versions of the virus in that person’s body, enhancing its ability to spread or providing some resistance to immune defences. These two traits — infectivity and immune evasion — are the main ways in which SARS-CoV-2 has evolved since it first emerged in 2019.

In acute SARS-CoV-2 infections, which generally last a week or two before being cleared by the immune system, versions of the virus with advantageous mutations have little time to outcompete those that lack them. The odds of a virus with such an advantage being transmitted to another individual are therefore small. Studies suggest that only a few virus particles — maybe even just one — are needed to seed a new infection². “Which of those viruses happens to be in the aerosol droplet you sneeze out at the time someone walks by and breathes in is largely a matter of luck,” says Jesse Bloom, a evolutionary biologist at the Fred Hutchinson Cancer Center in Seattle, Washington. “So, most of the beneficial mutations that have arisen in a patient are lost, and then evolution has to start up all over again.”

This ‘transmission bottleneck’ is the reason SARS-CoV-2 picks up around two mutations per month globally, on average. But in chronic infections, which last for weeks to months, viruses with advantageous mutations have time to outcompete others.

Compared with acute cases, these long-term infections also allow time for much more viral diversity to develop. And through a process called recombination, which can shuffle the genomes of SARS-CoV-2 particles together, mutations that are beneficial in one part of the body, such as the upper airways, might show up in viruses bearing other useful properties, says Andrew Rambaut, an evolutionary biologist at the University of Edinburgh, UK. “If the result is a fitter virus, it can suddenly take off.”

As a result of chronic infections, globally, “this virus has opportunities not just to evolve in one way, in one direction, but literally thousands, maybe tens of thousands of directions over months”, Otto says.

Targeting spike

No two chronic infections are identical. But in dozens of case reports, researchers have begun to identify common signatures of long-term infection. One of the most striking, says Otto, is the large number of amino-acid changes that accrue in the virus’s spike protein, which helps it to infect cells and is a primary target for the body’s immune response.

Many of these mutations map to regions of the spike that are targeted by antibodies, such as its receptor binding domain (RBD) and the N-terminal domain, which are involved in recognizing and infecting host cells. This makes sense, says Darren Martin, an evolutionary virologist at the University of Cape Town in South Africa. If a person’s immune system fails to clear an infection fully, the surviving viruses are likely to bear immunity-evading mutations that helped them to survive the attack. One study³, which has not been peer reviewed, found that the most common mutation in chronic infections is at a position in the spike protein’s RBD called E484. Changes at this site can prevent some potent infection-blocking antibodies from attaching to the virus.

Some mutations don’t work particularly well on their own. Last year, Gupta and his team described a 102-day infection in a man in his 70s who had a compromised immune system, and who ultimately died from the infection⁴. After doctors had treated him with convalescent plasma — the antibody-containing portion of blood donated by people who had recovered from COVID-19 — Gupta’s team found that viruses with a pair of spike-protein mutations were thriving in the man’s airways.

One of the mutations, called D796H, conferred resistance to antibodies — but this benefit came at a cost to the virus. When the researchers engineered a non-replicating ‘pseudotype virus’ to carry the D796H mutation and measured how well it could infect cells in the lab, they found that this mutation alone made the pseudotype virus significantly less infectious. But when the pseudotype virus also contained a second mutation found in the same person — a two-amino-acid deletion at sites 69 and 70 — infectivity was restored almost completely⁴. Such compensatory mutations, which have more time to emerge in chronic infections, allow the virus to make evolutionary leaps, says Gupta. “Viruses struggle to do that when they’re jumping between hosts very quickly.”

In some cases, mutations have made sense only with hindsight. In late 2020, Jonathan Li, a physician-scientist at Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues released the first detailed report of a chronic SARS-CoV-2 infection: an ultimately fatal case in a 45-year-old man who had a rare autoimmune disease⁵. The virus developed mutations linked to antibody resistance, including E484K, and another spike mutation called N501Y, which lab studies had suggested improves the virus’s ability to bind to host-cell receptors, potentially boosting infectivity⁶.

The significance of the N501Y change became apparent when it was detected in a trio of fast-growing lineages later named the Alpha, Beta and Gamma variants of concern (VOCs). Omicron bears this mutation, as well as several others identified in the man’s infection. “He really was the harbinger of what was to come,” Li says.

Seeking variant origins

Alpha, identified in the United Kingdom in late 2020, was the first SARS-CoV-2 variant suspected to have emerged from a chronic infection. But that wasn’t the only possible explanation, says Rambaut. The variant might have arisen in a region — probably outside the United Kingdom — that had little capability to conduct genomic surveillance of SARS-CoV-2. Alternatively, Alpha could have evolved in an animal reservoir (the variant’s N501Y mutation enables it to infect mice, rats and mink).

A chance discovery nevertheless suggests that a chronic infection was the most likely source of Alpha. Rambaut and Verity Hill, an evolutionary biologist at the University of Edinburgh, reported in a March preprint the discovery of an intermediate version of Alpha in UK sequencing data⁷. The sequence was collected from a person in southeast England in July 2020, two months before Alpha was first detected in the same region.

The virus had acquired the N501Y mutation, as well as several other hallmarks of Alpha, but it lacked the full suite of changes. “It’s accumulating these mutations. It was probably a bit rubbish at spreading,” Hill says. Only once the Alpha intermediate gained further mutations did it have the capacity to take off, she suggests.

Combinations of mutations are seen in Omicron, too. That variant — which includes several sub-lineages with many overlapping mutations — is brimming with genetic changes linked to both immune escape and infectivity that had been spotted before. But what stood out to Martin was that the BA.1 subvariant that set off most countries’ Omicron waves has a collection of 13 spike mutations that scientists had rarely seen individually, let alone all together in a single virus.

Martin and his colleagues hypothesize⁸ that, among this unique set of mutations, are some that helped to offset the evolutionary costs associated with the mutations that hastened Omicron’s spread. “Those trade-offs take a long time to resolve and those require, in my opinion, chronic infections,” says Martin. These could be in humans or in animals, he adds.

Another characteristic of Omicron — the reduced severity of disease — could also be a product of chronic infection. Lab studies have suggested that Omicron’s relative mildness could be a result of its preference for infecting cells in the upper airways, as opposed to those in the lung⁹. The variant probably evolved from a strain that adeptly infected both upper and lower airways. Gupta suspects that Omicron’s shift probably depended on the kind of coordinated evolution that occurs when a virus spends months in a single person’s body. But what’s not clear are the evolutionary forces that propelled such a shift, he adds.

On the lookout

Chronic infections could be the best explanation for how variants such as Omicron and Alpha evolved. But it’s not obvious how one of the defining characteristics of most variants — their ability to spread like wildfire between people — might evolve in a single individual. “That’s a real mystery,” says Bloom. “When something’s not under selection, you often lose it. During a chronic infection there’s no longer selection for transmissibility.”

One possible explanation is that the same molecular mechanisms that help SARS-CoV-2 to infect a person’s airways, lungs and other organs are also important for enabling the virus to spread to others. “The same transmission dynamics are required when it’s inside you as when it’s going from one person to another,” says Martin.

But there is a difference between a virus that merely retains the ability to transmit, and one such as Omicron or Alpha that can cause a global surge in cases. A massive boost in transmissibility or the capacity to infect previously immune people might be what sets a dangerous VOC apart, says Rambaut. “It’s not that all chronic infections are going to produce VOCs. It’s going to be one in a million.”

That means that surveillance is unlikely to detect a variant at its point of emergence. In a May preprint, researchers spotted an Omicron strain that had picked up other spike mutations during chronic infection in an immunocompromised individual, and showed that it had spread to several people in the same hospital, as well as in the local community¹⁰. But wider spread of such infections seems exceedingly rare. A February preprint documenting 27 people with chronic infections reports no evidence that any had spread the virus to other individuals¹¹. If VOCs so rarely emerge from chronic infections, it will be difficult to prevent them without reducing overall rates of infection around the world, says Adi Stern, an evolutionary virologist at Tel Aviv University in Israel, who led the study.

Nevertheless, there is an urgent need to understand the viral factors that contribute to chronic infections. “We need to go beyond the case reports and understand what the virus is actually evolving during this time,” says Sigal.

Sigal and his team are tracking people with advanced HIV, whose immune systems can be severely compromised, to identify factors associated with chronic SARS-CoV-2 infection. HIV infects immune cells called CD4⁺ T cells, which also support the production of antibodies against viruses such as SARS-CoV-2. In unpublished work, Sigal and his colleagues have found that low levels of CD4⁺ T cells are associated with a risk of chronic SARS-CoV-2 infection, and that many of the cases are mild, with few or no respiratory symptoms.

On the basis of the sheer number of people living with HIV — nearly 40 million globally — and the likelihood that most people have already been infected with SARS-CoV-2, it seems likely that some cases of persistent infection are contributing to the emergence of new variants, says Otto. “From an Occam’s razor point of view, we know that should be a source.”

People with compromised immune systems aren’t the only potential source of variants. Researchers have documented SARS-CoV-2 infections lasting multiple weeks in people with healthy immune systems. From the perspective of natural selection, even a relatively short three-week infection provides exponentially more opportunities for the virus to evolve, compared with an acute infection lasting a week, says Martin.

People with relatively healthy immune systems might also provide the virus with more selection pressure than individuals who have impaired immune responses, says Hill. But how to identify people who are susceptible to such infections or what their symptoms might look like is an open question. “I would suspect they’re a lot more common than we realize,” says Hill.

Last year, Gonzalo Bello, a virologist at the Oswaldo Cruz Institute in Rio de Janeiro, Brazil, and his colleagues identified several strains of SARS-CoV-2 circulating in Amazonas state in Brazil¹². These carried some — but not all — of the mutations found in the Gamma variant that drove the region’s ferocious second wave in 2021. But each of the Gamma-like strains also had their own unique mutations: evidence, Bello says, that Gamma might have evolved not from a single chronic infection, but from transmission chains of medium-length infections involving relatively healthy people.

Such transmission chains could have contributed to the diversity of Omicron lineages, Bello suggests. “Maybe these individuals are where some of the steps in the origin of VOCs are happening,” he says. And if chronic infections in healthy people are a likely source of VOCs, improving global vaccination rates could help to prevent new ones emerging, Hill adds. “When you’ve got these huge uncontrolled waves of infection, you’re sowing the seeds for the next.”

Antiviral drugs and other treatments taken during a chronic infection could also be playing a part in the virus’s evolution. One trait scientists are looking out for is resistance to COVID-19 drugs such as Paxlovid (nirmatrelvir–ritonavir) and molnupiravir. (Resistance to the antiviral remdesivir has already been documented in chronic infections¹³.) The drugs affect highly conserved viral proteins — for which the barrier to drug resistance is high — but evolutionary leaps that characterize chronic infections could buy the virus time to come up with a way around that, says Gupta.

In unpublished laboratory experiments, a team led by virologist David Ho at Columbia University in New York City has found that SARS-CoV-2 can take numerous paths to Paxlovid resistance. Some involve gaining compensatory mutations that allow the virus to overcome the costs of Paxlovid resistance, allowing them to thrive, at least in the lab. Such mutations are unlikely to be behind anecdotal reports of recurring SARS-CoV-2 symptoms after Paxlovid treatment, says Ho (who himself experienced such a rebound). But if the treatment, which is normally taken for five days, is administered for a longer period to treat a chronic infection, there is a good chance resistance will emerge.

There is also an urgent need to identify effective treatments for chronic infections — particularly in people with immune-system impairments, who don’t always mount a strong response to vaccines. Most approved monoclonal antibody drugs are not effective against Omicron and its offshoots, and researchers have shown in a preprint that resistance to these therapies can emerge when they’re used to treat chronic infections¹⁴.

Convalescent plasma should create a higher evolutionary barrier than monoclonal antibody therapies, says Arturo Casadevall, a microbiologist at John Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Plasma that contains high levels of diverse antibodies has been shown to be effective at treating COVID-19, and some physicians are now giving it to people with compromised immune systems¹⁵.

Antiretroviral drugs that target HIV can also help people living with that virus to clear chronic SARS-CoV-2 infections, but adherence to the drugs can be a challenge, Sigal notes.

Last October, UK clinicians reported a case in which a person’s chronic infection was cleared after they received a COVID-19 vaccine¹⁶. For the Austrian woman whom Sonnleitner and her colleagues studied, the end of her seven-month infection also followed vaccination. But it’s impossible to know if the vaccine is what helped her to recover.

That outcome is rare for people with chronic infections, however; many reports end in death. “They really are heartbreaking cases,” Stern says. As many parts of the world attempt to move on from the pandemic, with some healthy people shrugging their shoulders at ‘mild’ Omicron infections, Stern says we must do more to protect those who are most at risk of a chronic SARS-CoV-2 infection. “It’s dangerous for them — and it’s dangerous for us as a society.”

All three variants have been detected in India, but BA.2 – which along with BA.1 caused the January wave in India – continues to be dominant, accounting for 32 per cent of all the genomic sequences submitted to the global database GISAID over the last 30 days.

Can a person who has had a previous omicron infection get it again?

“Yes, people who have had an Omicron infection in January may get another infection once other sub-variants such as BA.4 and BA.5 start circulating in the community. We have seen these variants take over from BA.2 to become the dominant variant in other countries. They are about 13 per cent to 15 per cent more transmissible than BA.2 which in itself was several-fold more transmissible than the wild type of the virus,” said Dr Lalit Kant, former head of the department of epidemiology and infectious diseases at the Indian Council of Medical Research.

Similarly, BA.2.12.1 that was first detected in New York is thought to be about 27 per cent more transmissible.

He added, “Not only that, the immunity from Omicron infections in January – which did not cause severe disease and hence would have led to fewer antibodies developing – must have started going down. Immunity from vaccination also starts waning after five to six months. So, there can be an increase in infections.”

Are these new variants likely to become dominant in India?

The first cases of BA.4 and BA.5 were detected in January and February in South Africa and became the dominant variants by May, suggesting a clear transmission advantage over the previous BA.2. Similarly, BA.5 has already become the dominant variant in Portugal.

Although proportions of the two variants are less in other European countries, the European Centres for Disease Control and Prevetion says, “The growth advantage reported for BA.4 and BA.5 suggests that these variants will become dominant throughout the EU/EEA, probably resulting in an increase in Covid-19 cases in coming weeks.”

Explained |A prosthetic leg suited for the way Indians sit and walk, adjustable and affordable

Other than its transmission edge, these variants can also circumvent some of the immunity gained from previous omicron infection or vaccination.

Data from lab studies has shown that BA.4 and BA.5 are more distant from their cousins BA.1 and BA.2 that led to the January surge in India. What this means is that vaccines that use spikes from the ancestral virus would be less effective.

“BA.4 and BA.5 are less efficiently neutralised by sera from individuals vaccinated with three doses of Covid-19 vaccine (AstraZeneca or Pfizer) or by sera from BA.1 vaccine breakthrough infections. In addition, there has been an increased rate of re-infection in Portugal,” the European CDC said.

So, could there be a wave with these new variants?

Dr Kant explained, “If we go by the example of other countries – and anything about Covid-19 has been notoriously hard to predict – it is likely that there will be some increase in infections but the cases are likely to be milder, leading to fewer hospitalisations and deaths.”