three key questions about what’s after Omicron
three key questions about what’s after Omicron

three key questions about what’s after Omicron

Particles (orange; artificially colored) of the SARS-CoV-2 Omicron variant bud from a cell.Credit: Steve Gschmeissner / SPL

What now?

After Omicron variant brought a new wave of SARS-CoV-2 infections and anxiety in early 2022, some nations are starting to register a decrease in the number of cases. But after two years of fluctuations between pandemic rises and retreats, even the people of these countries can not help but wonder when the next blow comes – and what form it will take.

“I think it’s inevitable that we’ll see new variants with varying degrees of immune evasion,” says Andrew Rambaut, who studies viral evolution at the University of Edinburgh, UK. “They can emerge from where transmission is widespread.”

While waiting for the next variant to enter the scene, researchers are studying the currently dominant Omicron variant to better predict the future; this research is described in a separate Feature. Here are three key questions that researchers would like research to answer.

When does the next variant of worry emerge?

There is no way of knowing with certainty when a variant will become dominant or whether it will rise to the status of a ‘variant of concern’ – which means that there are signs that it has taken up worrying new properties, such as .ex. spread fastercauses more serious illness or avoids immune responses.

The public is most familiar with the first dominant sub-variants of Omicron and Delta. But researchers have tracked down a host of related sub-variants that jockey for dominance. In the UK, for example, a Delta variant called AY.4 was rapidly being supplanted by another, called AY.4.2, in late 2021. “And then Omicron came and just blew up,” says bioinformatics Andrew Page at the Quadram Institute in Norwich, UK.

The story of this viral dynamic suggests that a new variant will sweep through every few months, Page says. “They seem to happen pretty regularly,” he says. “It’s probably just going to tick on.”

But whether that variant will rise to the level of a variant of concern is still an open question. At present, the original BA.1 Omicron family is being replaced by another, called BA.2. This genus, though probably more transferable than BA.1, does not appear to be a major change from the original that swept through many countries earlier this year.

Such dynamics are likely to be common in viral pathogens. But the world has not followed a viral infection so closely before, Page says, and as a result, scientists had missed it little by little. However, this close examination is already declining: Covid-19 testing frequency in the UK has dropped, he notes, in part because Omicron tends to produce relatively mild disease. With a mild illness, people are less likely to seek testing and governments become less proactive in encouraging testing.

Eventually this will weaken SARS-CoV-2 genomic monitoring effort. When Omicron was discovered, the alarm went off very quickly, Page says, but in the future it may take weeks longer to realize that a new variant of concern is on the way. “There’s no way we can keep up the pace we’ve had so far,” he says. “But if it does not cause serious illness, then should you have such intense surveillance?”

Will the next variant cause serious illness?

Omicron is less likely to cause serious illness than previous variants of concern – a feature that has helped curb the effects of the variant’s violent spread.

Although this has given rise to speculation that the virus could develop into a strain that induces a milder disease, the evolutionary pathway of SARS-CoV-2 is still unclear, Rambaut says. So far, new variants of concern have not evolved from the dominant previous one. Instead, they are descended from separate genera. There is no guarantee that the next dominant variety will germinate from the ‘mild’ Omicron branch of the SARS-CoV-2 family tree. “It is possible that a later variant may be back to a Delta or Alpha genus, with sufficient immune evasion to sweep Omicron away,” Rambaut says.

Researchers still do not know to what extent Omicron’s relative mildness is due to the presence of immunity to SARS-CoV-2, rather than inherent properties of the virus itself. As more of the world’s population is vaccinated, infected, or both, immunity is likely to grow, as will resistance to severe COVID-19.

But there were some differences in how Omicron behaved compared to previous variants, notes immunologist Wendy Burgers at the University of Cape Town in South Africa. It has several animal experiments e.g. found Omicron is less likely to affect the lungsthan previous variants1. “Will the next mutated variant have different properties?” she says. “I do not think there is any guarantee that these inherent differences may not be worse.”

“We know a lot about humans, but it’s the virus that is unpredictable,” she says. “And I’m a little scared of that.”

Will vaccines protect against new varieties?

The 54 mutations in Omicron’s genome – and in particular the 34 that are collected in a key virus protein called spike – severely impair the ability of COVID-19 vaccines to prevent SARS-CoV-2 infection. However, the protection against serious illness seems to have been high and probably contributed to the perceived mild illness caused by Omicron.

It bodes well for the resistance of vaccine-mediated immunity to future variants of concern, Burgers says. Although Omicron’s peak mutations appear to weaken antibody defenses, scientists have discovered only small drops in the ability of immune cells, called T cells, to recognize the virus. These cells are thought to be particularly important in limiting the extent of a viral infection, killing infected cells, and limiting the spread of the virus. “I was really relieved after Omicron,” says Burgers. “I’m optimistic that the T cell response will be quite resistant even if a new variant emerges.”

But Burgers notes that as antibodies become less relevant to SARS-CoV-2 immunity, T cells become more important, and a viral variant that can evade T cell surveillance will have a significant survival benefit. “The T cell response makes a lot more out of the heavy lifting,” she says. “So one thing we might start to see is T cell flight.”

In other viruses, such as influenza, the ability to escape T cell immunity develops gradually over the years. But it’s hard to predict how fast it will progress in the midst of a raging pandemic, Burgers says.

It is also becoming more difficult for immunologists to predict how the population’s immunity will shape the course of the pandemic as the drivers behind this immunity become more and more complex. People may have received one of a number of vaccines, or a combination of vaccines, or experienced one infection from one or more variants, with or without vaccination.

In general this accumulation of exposures to SARS-CoV-2 variants should boost immunity, says infectious disease specialist Santiago Ávila Ríos at the Mexico National Institute of Respiratory Diseases in Mexico City. In a pre-print, Ríos and his team reported that multiple exposures to SARS-CoV-2, either through vaccination or infectionamplified antibody responses as well as responses from immune cells called B cells2. “So as more people are exposed to the virus through different mechanisms, the emergence of new variants of concern may impose a lower disease burden,” he says.

However, some types of exposure may be better than others to prepare the body to fight new varieties. A study3, who has not yet been peer reviewed, found that people who had been vaccinated and then infected with Omicron experienced “forthcoming increases in antibodies,” says virologist Penny Moore at the University of the Witwatersrand in Johannesburg, South Africa. These antibodies could bind to and disarm several SARS-CoV-2 variants in addition to Omicron, a property called cross-reactivity.

However, antibodies produced by humans that have been infected with Omicron but have not previously been exposed to SARS-CoV-2 – either by vaccination or infection – were not as robust to block other variants. “We can not assume that these people would be particularly well protected from incoming variants of concern,” Moore says.

Ultimately, the data continue to point to the importance of vaccination, Burgers says. “We know that vaccines strengthen our immunity and that immunity will be cross-reactive when it comes to T cells, with a different variant,” she says. “There’s a lot we do not know, but there is a lot that is in our control.”

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