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Tracking the Evolution of SARS-CoV-2

— What do scientists know about its behavior, and how does that help predict what comes next?

MedpageToday
Computer rendering of the COVID-19 virus with two different colored strands of DNA

Researchers have had an unprecedented front-row seat to real-time with SARS-CoV-2, which has achieved significant genetic diversity in the year that it's been circulating widely. What have they learned about how closely it's following traditional patterns of viral evolution, and what does that imply about its future?

SARS-CoV-2 variants have emerged rapidly during the pandemic because of high transmission rates, said Robert Cyril Bollinger, MD, MPH, a professor of infectious diseases at Johns Hopkins University.

"When you have millions of viruses transmitted in the world, and when they're replicating millions or billions of times within each person, there's just lots of random mutation. You can hardly even calculate how much," he said.

Fortunately, its evolution hasn't been as rapid as that of another RNA virus, influenza.

RNA viruses are traditionally sloppy replicators that are particularly prone to mutation. To replicate, they use an error-prone enzyme called .

But SARS-CoV-2 has a proofreading capability that makes it less error-prone than other RNA viruses. Errors still happen at a much faster rate than in cells of higher organisms, like humans, though.

Scientists worry about related to the rapid mutation rate of SARS-CoV-2: increased transmissibility, changes in virulence, and the ability to escape natural or vaccine-induced immunity.

In theory, viruses tend to evolve mutations that make them more transmissible and less virulent. That's because a virus that's easily passed around has obvious fitness advantages in terms of opportunities to reproduce and pass along its genes. On the flip side, highly virulent viruses, such as Ebola, are not so successful because they kill their hosts too fast and limit their spread, Bollinger said.

So far, transmissibility seems to be the major selective force driving SARS-CoV-2 evolution, while changes in virulence have been difficult to predict, he said. Either it's just too early to know how virulence could be changing, or the high proportion of mild or asymptomatic cases places little pressure on selecting for less virulent genes, according to Francois Balloux, PhD, director of the Genetics Institute at University College London.

"We have more evidence on transmissibility than virulence. The selective pressure is really for transmission," Balloux said. "To be fair, SARS-CoV-2 is not that virulent. Most transmission happens before severe symptoms develop, and then it kills a very small proportion of its hosts. If a strain emerged that was less virulent, it probably wouldn't have a big advantage."

Key Mutations and Key Variants

Several key mutations have emerged during the pandemic. First was , a spike protein mutation that increased binding to human ACE2 receptors. Many scientists consider the variant with this mutation "close to wild type," according to Malaya Kumar Sahoo, PhD, a research scientist at Stanford University.

Other key spike mutations include ,, and . All three have been linked to improved ACE2 receptor binding and increased transmissibility. is also considered an escape mutation because it may allow the virus to evade the human immune response and could be associated with decreased protection by vaccines.

The major variants making headlines these days contain some or all of these mutations. The B.1.1.7 or "U.K." variant contains the N501Y mutation, as well as another spike mutation called . This mutation has been increasing very rapidly worldwide, although its effect on transmissibility is unclear.

Both the B.1.351 or "South African" variant and the P.1 or "Brazilian" variant contain mutations (N501Y, K417N/T, and E484K).

Two other variants, B.1.429 and B.1.427, emerged in California and contain another mutation that affects the spike protein, , which may be associated with increased replication and infectivity, and possibly the ability to the human immune response.

What's interesting is that these key mutations (or similar versions of them) seem to crop up in similar ways in variants that look like they're becoming successful, researchers say.

"A lot of these mutations are being reported in very similar locations," Bollinger said. "So there may be something specific about virus variants that mutate in a particular way that gives them a fitness advantage."

Evolutionary Guesstimates on B.1.617

The new B.1.617 variant in India contains some of these key mutations. Along with D614G and L452R, it contains a mutation called E484Q, which is similar to the E484K mutation found in the variants from South Africa and Brazil. And, it contains a mutation called P681R, similar to the P681H mutation in the U.K. variant.

Like other variants that have emerged during the pandemic, B.1.617 actually has many other mutations, about 20-30 total mutations depending on the subtype. The of this variant in the GISAID occurred way back in October 2020.

Why did it take so long to increase in frequency? And what's special about B.1.617 that may make it more worthy of attention than other variants with lots of mutations?

Balloux thinks that the "jury is still out" on whether B.1.617 is more transmissible or more virulent. It could just be that it was in the right place at the right time: a lot of other variants are also circulating in India, cases have increased dramatically, and this variant could just be hitchhiking along.

"It's intriguing that B.1.617 took so long to really take off properly. Sure, it's going up in frequency because there's lots of transmission in India, but I don't have the impression it's going up faster," he said. "If you have an outbreak, cases go up. If by chance there's a viral lineage in the local area, it becomes more frequent, not always because it has an intrinsic advantage."

Based on the fact that the B.1.617.2 (a subtype that has spread most often in the U.K. and seems to be frequent in India) has lost the E484Q mutation, Balloux anticipates that this variant will "not become particularly widespread globally."

"I don't think that it will take over the world. I'm actually not even convinced that it will be considered a variant of interest in the future," he said.

But preliminary by the World Health Organization (WHO) suggests that B.1.617 may have higher growth rates than other variants that are circulating in India, suggesting increased transmissibility. The WHO adds that other circulating variants as well as human factors, such as lack of adherence to public health measures and mass gatherings during celebrations and elections, may have contributed to the epidemic.

While Sahoo thinks that B.1.617 could be "one of the drivers" of the epidemic in India, the other important cause is the "false presumption that the exponential phase was over, and returning to normalcy sooner, particularly in the megacities." Based on key mutations that could increase infectivity, Sahoo anticipates that B.1.617 could "potentially outcompete the U.K. strain," but that's less likely if India gets its cases under control in the next 2 months.

Getting those cases down in that timeframe would be a benefit to the entire world, Bollinger said.

"What I worry most about is letting this virus continue to mutate at this rate, so that eventually it escapes immune responses to vaccines," he said. "We haven't seen evidence of that just yet. But who's to say if we let this rage around the world."