How COVID-19 variants emerge — and how we can prepare for the next one

It’s wishful thinking to imagine SARS-CoV-2’s evolution is somehow done, ‘because we are so culturally and politically, and economically done with it’

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“We are not adequately humbled by what we don’t know about it,” Winnipeg internal medicine doctor Jillian Horton recently tweeted about COVID-19. First BA.1, then BA.2, now, a new Omicron offshoot, BA.2.12.1, is making its presence known in the U.S. where it’s driving a spike in cases in New York State. How do COVID-19 variants emerge, why do some take hold while others disappear and what could be coming next? Here’s some of what scientists do — and don’t — know.

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How does a coronavirus mutate to generate new variants?

SARS-CoV-2 enters the body through the respiratory system. It finds a healthy target cell that has receptors on its surface, in this case, the ACE2 receptor, that it uses to dock onto, and slip inside the cell. Once inside, the virus starts replicating, copying its genetic code over and over again.

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The replication process is prone to errors, to typos. Coronaviruses have a proof-reading enzyme that corrects mistakes. “It actually mutates slower than a lot of other viruses, but still at a rate that is enough to produce plenty of new mutations that occur randomly,” said Jesse Shapiro, an assistant professor in McGill University’s department of microbiology and immunology. Many mutations are harmless. Others give the virus a competitive edge by increasing transmission. Alpha, then Delta and now Omicron rapidly displaced each other on their way to supremacy. Compared to the original strain, they have been more infectious, more virulent, more resistant to natural or vaccine elicited immunity, or some combination of all three.

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The main variants so far have mutations in their spike protein gene that studs the surface of SARS-CoV-2, which the virus uses to glob on to cells. Some mutations are unique to each one, others shared by all.

“We talk a lot about the spike, but there are 23 other proteins in that virus and each have a role in how virulent the variants are, how transmissible they are, how stable they are,”  University of Ottawa virologist Marc-André Langlois said during a recent panel discussion hosted by Canada’s COVID-19 Immunity Task Force and featuring experts from the Coronavirus Variants Rapid Response Network, or CoVaRR-Net.

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The more we let the variants replicate and spread in humans, the higher the probability of generating new variants with new mutations in new parts of its genome, he said.

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Where are the COVID variants coming from?

In regions with high levels of infection. They can also emerge from people who are immunocompromised — organ transplant recipients, people undergoing treatment for cancer, people living with HIV or immune disorders — who don’t respond as well to vaccines and who have a hard time shaking COVID if they do get infected. The longer a virus lingers in the body, the more time to pile on mutations. Doctors have described cases where immunocompromised people with persistent COVID-infections of 100 days or more generated highly mutated variants that seemed a form of “saltational” evolution, where an organism makes sudden large leaps between generations. “It’s as if you all-of-a-sudden go from walking to flying, with nothing in between,” virologist Dr. Larry Corey of Seattle’s Fred Hutchinson Cancer Research Center told Fred Hutch News Service. Writing in the New England Journal of Medicine, Corey and four colleagues warn “heightened precautions” ought to be taken to prevent transmission of COVID to the immunocompromised.

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How many more mutations can SARS-CoV-2 undergo?

It’s wishful thinking to imagine SARS-CoV-2 is running out of steam, that its evolution is somehow done, “because we are so culturally and politically, and economically done with it,” COVID-19 modeller Caroline Colijn, of Simon Fraser University, said in an earlier interview. “I think evolution will continue to act. The way to stop evolution from giving us more variants is to reduce the size of the virus populations, and that’s infections. That’s not just hospitalizations.”

“There is no organism that stands still,” said McGill’s Shapiro, a CoVaRR-Net member. “Everything continues to mutate and adapt. It will continue to do so. That’s what flu does. That’s to be expected. That shouldn’t be alarming.” The question, said Shapiro, is: Is there a limit to its intrinsic transmissibility, “which is already really, really high. Will it go even higher? That’s what selection will always be promoting — every time there is a variant that can replicate faster, it will be selected, it will take off. It’s hard to know what the limit will be.”

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What could come next?

A virus can change two ways: antigenic “drift,” meaning small, subtle changes or mutations, like we’re seeing with the BA-2’s. The other change is a shift, an abrupt, major change. Omicron was a shift, not a drift. “Omicron is not related to any of the Deltas,” Shapiro said. “It branched off way, way earlier, probably in mid-2020, and had been simmering in an unsampled population, or an animal reservoir, or an immunocompromised person, or some combination of those things, and then emerged and really began to take off in late 2021.”

The next big variant could come directly descended from Omicron, or be wildly divergent, from another deep branch, and people shouldn’t hang their hats on Omicron’s lower severity, three researchers write in Nature Reviews. It’s “nothing but a lucky coincidence” that Omicron causes milder disease. As the world gets exposed and vaccinated, the pressure will be on SARS-CoV-2 to keep honing its ability to reinfect. “Once Omicron infects the majority of individuals, the next variant will need to be as antigenically different from Omicron and previous (variants of concern, or VOCs) as possible to overcome immunity against them,” they wrote. “The prospect of future VOCs featuring the potentially disastrous combination of the ability to reinfect due to immune escape along with high virulence is unfortunately very real.”

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It’s all very unpredictable, Shapiro said. There’s no pressure on the virus to become more severe, or less severe. “The virus doesn’t really care if it’s more or less virulent or the same.” If it’s so virulent that it kills people before they’re able to transmit, “that’s a dead end, from the perspective of the virus.”

We need to keep monitoring the virus, to keep testing and sequencing and continuing with global efforts of vaccination and getting infections down, the scientists said. “We need to try to stay away from the ‘let it rip’ mentality, to reduce the total number of infections,” Shapiro said. “The more infections there are every day, every month, the more opportunities for mutations to arise.”

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