How the Omicron variant got so many mutations so quickly

On November 25, South African scientists announced the discovery of a new, “heavily mutated” variant of the coronavirus, triggering global panic. Countries quickly imposed travel bans and closed their borders, but the variant has already been detected in at least 23 countries, including the US

One reason for the knee-jerk reactions is the new variant’s high number of mutations: Omicron, as it has been dubbed by the World Health Organization, has more than 30 changes to its spike protein. This protein allows the virus to infect and take over human cells, and is also the target of most vaccines. Spike protein changes in previous variants, such as Delta and Alpha, are thought to have made the virus more infectious or more likely to evade the immune system and vaccines. It is not yet clear whether Omicron is more transmissible, or causes more severe disease than previous variants, or whether it will render the vaccines less effective. But a new pre-print study released by South African scientists on Thursday, which has been not yet been published in a scientific journal, suggests that Omicron is three times more likely to reinfect people.

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Mutations develop spontaneously as a virus replicates and spreads, but scientists are now trying to understand how so many mutations arose in Omicron in such a seemingly short space of time.

“The question is how this [rapid evolution] occurred, where it occurred, and which were the conditions that fueled [it],” says Gonzalo Bello, a virologist at the Oswaldo Cruz Institute in Rio de Janeiro. Bello was part of the team that tracked the rise of the Gamma variant in Brazil in November 2020, which fueled outbreaks in that country. With Gamma, “we realized that mutations did not appear in a single step in a single individual,” Bello explains. Instead, some mutations occurred in certain individuals but not in others. The rise of Gamma “was a process that occurred in a population of individuals, not in a single [person],” he says.

One possibility for how a heavily mutated variant, such as Omicron, could have arisen is that the virus began circulating and mutating in an isolated group of people, where it would have had an opportunity to change dramatically compared with variants outside of that bubble. It could then have gotten introduced, with its numerous mutations, into the larger population, where it was able to travel into different groups and countries, Bello says.

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Alternatively, the virus may have mutated significantly in a single individual before finding a new host. “This could happen in an immune-suppressed person,” such as someone with HIV, Anna-Lise Williamson, chair in vaccinology at the University of Cape Town, and Ed Rybicki, director of the university’s biopharming research unit, wrote in response to e-mailed questions. South Africa has the world’s largest HIV epidemic, with more than seven million people infected with the virus. Neighboring countries also have widespread HIV infections. This has led some scientists to hypothesize that Omicron arose in Southern Africa because it was first identified there, but older cases have since been identified in European countries and the US

Healthy people have many immune cells called CD4+ T cells, which stimulate another type called killer T cells, Williamson and Rybicki explain. In healthy people who get Covid, these killer T cells destroy the virus-infected cells. But in immunocompromised people, who have low numbers of CD4+ T cells, “the virus establishes a persistent infection” because of a lack of killer-T-cell responses. Their immune systems do, however, produce some immune cells called B cells that trigger an antibody response, and this “results in an arms race between the virus and antibodies,” according to Williamson and Rybicki. The weak B-cell response does not create enough antibodies to clear the virus completely, and consequently, the genetic sequence for the virus’s spike protein undergoes pressure to mutate to escape the antibodies.

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There is some evidence to support this idea. In a preprint study released in June, South African researchers described an HIV-positive woman who had a SARS-CoV-2 infection for more than six months. During that time, the virus in her evolved and developed a number of mutations, some of them on the spike protein.

Another possible hypothesis for how the virus rapidly gained so many mutations is that it spilt back into an animal reservoir before reinfecting humans, Bello says. Persuasive evidence suggests that the original SARS-CoV-2 likely arose in a bat, and there have been numerous cases of other wild and domesticated mammals contracting the virus. Last year, there were reports of coronavirus outbreaks on mink farms in North America and Europe, and in the Netherlands, there was a confirmed case of the mink infecting a farmworker.

Omicron may have jumped from animals to humans in this way, Bello says. “In another species, the virus will face a different kind of immune pressure, and so it could accumulate some mutations quite fast,” he says. The idea is mainly conjectured at this point, however.

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To fully understand where Omicron arose, it helps to determine the earliest human patient or community in which it spread. But it is difficult to identify the patient zero for a variant, says Akiko Iwasaki, a professor of immunobiology and molecular, cellular and developmental biology at Yale University. “That is because [virus] surveillance efforts only capture a fraction of infected people,” she says. As more people are tested, and their viral genomes are sequenced, it may be possible to pinpoint a general geographic area and an approximate time when the virus mutated into Omicron, Iwasaki says.

For Michael Head, a senior research fellow in global health at the University of Southampton in the U.K., Omicron is a wake-up call about vaccine inequity and the need for greater access. According to Oxford University’s Our World in Data platform, as of November 30, about eight billion vaccinations had been administered globally, and only 6 per cent of people in low-income countries had received at least one dose. African countries have administered more than 235 million vaccines, according to the African Centers for Disease Control and Prevention, but the continent’s population exceeds 1.2 billion people.

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“The main variants that have caused concern so far—in terms of Alpha to Delta, basically—have emerged from uncontrolled outbreaks in unvaccinated populations,” Head says. “That’s where Covid thrives best and that’s where the virus has the greater chance to mutate. If [the vaccine] can keep outbreaks under control, you reduce those opportunities.”

The World Health Organization’s Director-General Tedros Adhanom Ghebreyesus echoed these sentiments on November 28: “The Omicron variant reflects the threat of prolonged vaccine injustice,” he wrote in a tweet. “The longer we take to deliver #VaccinEquity, the more we allow the #COVID19 virus to circulate, mutate and become potentially more dangerous.”