Molecular Medicine Israel

A Guide to Emerging SARS-CoV-2 Variants

Scientists across the world are closely tracking the spread of mutations in the coronavirus and investigating whether they could render current vaccines less effective.

SARS-CoV-2 is no Ferrari among viruses when it comes to mutations. Scientists reckon that its 30,000-base RNA genome acquires around two single-letter mutations a month, a rate around half as fast as influenza and one-quarter the rate of HIV. But allowed to multiply and jump from body to body for more than a year, SARS-CoV-2 has inevitably flourished into a genetically diverse tree branching into countless different variants.

Many variants—defined by a specific assortment of mutations—are relatively unremarkable. But scientists have been keeping a close watch on three rapidly spreading variants—first identified in the UK, South Africa, and Brazil—which harbor an unusual constellation of mutations. They all share a mutation called N501Y that affects the receptor binding domain (RBD) of the spike protein, which the virus uses to clasp onto human cells’ receptors and enter them. That mutation replaces SARS-CoV-2’s 501st amino acid, asparagine, with tyrosine, potentially allowing it to bind more tightly to ACE2 receptors, studies in cells and animal models suggest.

By itself, that mutation isn’t unusual, but the variants possess an exceptionally large number of other mutations, some also on the spike protein. Substantive changes to a virus’ behavior, such as heightened transmissibility, are likely the result of multiple mutations rather than individual ones, molecular epidemiologist Emma Hodcroft of the University of Bern tells The Atlantic.

The observation that similar mutations have appeared in three independent variants, and the fact that they are spreading, makes scientists suspect that they may have an evolutionary edge.

“They have multiple, eight to ten, mutations in the spike protein all stacked up at once—that suggests that there [is] a lot of evolution and adaption of the protein happening,” Daniel Jones, a molecular pathologist at the Ohio State University, tells The Scientist. “The concern being that since that’s the target of vaccinations and . . . the target for antibody [therapies] like the Regeneron cocktail, for instance, that it might be the beginning of a virus that could evade antibody therapy and/or vaccine coverage.”

SARS-CoV-2 mutations’ effects on transmissibility

It’s often in a virus’ interest to become more transmissible so it can spread and replicate more quickly. Earlier in the pandemic, a spike protein mutation known as D614G—which is widely believed to have made the virus more transmissible—surged to dominance around the world, notes virologist John Moore of Weill Cornell Medical College.

Epidemiological data suggest that the B.1.1.7 variant, a descendant of the D614G lineage first identified in the UK that has spread to other parts of the world, also has heightened transmissibility. Eight of the 17 mutations it has recently accumulated are in the spike protein, which could feasibly have an effect on ACE2 binding and virus replication. Hypothetically, if a virus can bind more tightly to the body’s ACE2 receptors, it could be more capable of establishing an infection once it gets into the body and/or of generating more viral particles in the upper respiratory tract, making it easier to transmit to other people, particularly during the presymptomatic stage, explains Theodora Hatziioannou, a virologist at the Rockefeller University in New York.

She adds that in her view, it’s hard to definitively ascribe case surges, including the current one in the UK, to single factors such as increased transmissibility, over other driving factors, such as what she sees as ineffective lockdown policies. “I’m not saying that [increased] transmissibility is out of the question. I’m just saying it’s extremely hard to prove.”

In South Africa, epidemiologists have estimated that the new variant there, B.1.351 (also known as 501Y.V2), is around 50 percent more contagious compared with dominant lineages, based on its rapid spread, according to The Wall Street Journal.

In Brazil, it’s too early to conclude whether a variant now circulating there, called P.1, is inherently more transmissible. First reported on January 12 in the state of Amazonas, it’s been associated with a devastating surge in cases in Manaus, a city where researchers had previously estimated that 75 percent of residents had already been infected with SARS-CoV-2. But it’s still unclear whether properties of the virus itself are contributing to the surge, says virologist Paola Resende of the Oswaldo Cruz Institute in Rio de Janeiro. “In Brazil, we can see a lot of parties, we can see the pubs crowded, and people are on the streets not wearing masks. I think this behavior of the population is the main reason [for] the increase.”

Evading the immune system

Our immune system—and, in particular, antibodies—is a powerful evolutionary force on viruses. Some pathogens such as influenza, and maybe also common cold-causing coronaviruses, mutate their proteins toward new shapes to avoid being targeted by antibodies that would normally prevent them from infecting cells, a process known as antigenic drift. A study recently posted as a preprint to bioRxivby Hatziioannou and her colleagues suggests that the RBD mutations present in the B.1.351 variant are due to antigenic drift. The team passaged a model virus bearing the dominant SARS-CoV-2 spike protein in the presence of individual neutralizing antibodies extracted from people who had received either the Moderna or Pfizer/BioNTech vaccine. Depending on which antibody they were cultured with, the viruses would gradually adopt a single mutation—either E484K, K417N, and N501Y—which are present in B.1.351. That suggests that “the virus is mutating in these positions to avoid antibodies,” Hatziioannou says.

Such antibody-escape mutations don’t necessarily mean that the virus will cause more severe disease or entirely outwit the immune response, she cautions. There are other parts of the immune system to help clear the virus. There’s no evidence so far to suggest that the variants identified in South Africa or Brazil are more lethal. Based on an analysis of several datasets, scientists in the UK suggested last week there’s a “realistic possibility” that B.1.1.7 is deadlier than previous strains, but experts say it’s still too early to draw that conclusion. Another concern is about whether people who have overcome mild infections with older variants could become reinfected with a new one.

n a yet-to-be-peer-reviewed study, scientists in South Africa investigated that possibility by testing the potency of antibodies from 44 COVID-19 survivors against the B.1.351 variant. Remarkably, serum samples from 21 patients were not capable of neutralizing the virus in vitro. Antibodies from hospitalized patients with more severe disease were more effective against the virus compared to those who had only mild symptoms. “These data highlight the prospect of reinfection with antigenically distinct variants,” the authors reported.

There’s less information on the P.1 variant, which health officials in Minnesota reported January 25 has been detected there, marking the first observation in the US. Because its mutation pattern is similar to B.1.351—namely, it shares the E484K and K417N RBD mutations—“there would be reasons to believe that what applies for one would likely apply to the other,” Moore notes.

Resende and her colleagues have recently documented two cases when people became reinfected with a new variant. In one, the reinfection was caused by P.1. The other incident of reinfection was caused by P.2, a closely watched emergent sister variant that carries fewer changes overall but harbors the N501Y and E484K mutations. Given that reinfections are known to occur with SARS-CoV-2, albeit rarely, such anecdotal observations don’t tell researchers if it’s more likely to happen with the new variants. Nevertheless, “all mutations located in the receptor binding domain, we need to pay attention to,” Resende says.

Implications for vaccine efficacy

Such escape mutations in the RBD—a site most vaccines are targeting—don’t bode well for vaccinated individuals, who could theoretically be vulnerable to infection by a new variant. While mRNA vaccines, such as the ones developed by Pfizer/BioNTech and Moderna, are relatively straightforward to update, the processes of seeking regulatory approvals and producing a new vaccine aren’t trivial, Moore notes.

See “The Promise of mRNA Vaccines

Antigenic escape is not much of a concern with B.1.1.7, “because the location of the mutation suggested that it wouldn’t be an escape mutation,” Moore says. “Nobody that I know has been losing a moment of sleep over the UK variant from a vaccine-efficacy perspective.” Indeed, Pfizer and BioNTech recently reported preliminary data suggesting that their mRNA vaccine is just as effective against B.1.1.7 as it is against the variant that originated in Wuhan.

Researchers are still investigating the effect of the P.1 variant’s vulnerability to vaccines in Brazil, Resende says. As for the B.1.351 variant, a second experiment in Hatziioannou’s study provides some insights. She and her colleagues examined antibody-containing plasma from 20 people who had either received the Moderna or the Pfizer/BioNTech vaccine. The team tested the plasma against the dominant SARS-CoV-2 spike protein and pseudoviruses engineered to have the variant’s RBD mutations, either individually or in combination. The antibodies proved significantly less effective in neutralizing the pseudoviruses compared to pseudoviruses with the original spike protein, with a one- to threefold decrease in antibody potency. “It’s a really small difference,” she says, adding that it’s not entirely clear why the South African team—testing antibodies from survivors of natural infections against the actual RBD protein—observed a more dramatic drop in antibody potency.

This week, Moderna reported preliminary results from a separate in vitro examination of sera from eight people who had received two doses of the company’s vaccine. According to a press release, company scientists observed a reduction in antibody potency with the B.1.351 variant compared to prior variants, but the level of neutralizing antibodies “remain above levels that are expected to be protective.” The B.1.1.7 variant had no impact on antibody potency.

“There are grounds for concern [with vaccines], but the sky isn’t falling,” Moore says. Some researchers have pointed out that in addition to antibodies, there are other components of immune memory, which could prevent severe reinfections with novel variants. And because the vaccines—at least the ones examined in the study—are so effective, “even if antibody effectiveness were reduced tenfold, the vaccines would still be quite effective against the virus,” evolutionary biologist Jesse Bloom of the Fred Hutchinson Cancer Research Center in Seattle tells The New York Times.

Hatziioannou anticipates that if variants are left to spread for longer and accumulate many more mutations, vaccine manufacturers may have to update their vaccines at some point, as is done with annual flu shots. For now, “I think the vaccine will still work,” she says. “But this is the first step: it’s a little bit of resistance, and then [with] the next set of mutations a little bit more, and the next set of mutations a little bit more, until eventually we get to something that’s significantly more resistant.”

Meanwhile, new variants are on the horizon. This month, Jones and his colleagues discovered a novel variant in Columbus, Ohio, that lacks the complexity of mutations of the major three variants, but possesses the N501Y sequence. “It’s really this November, December timeframe, where we’ve seen all of these alternate viruses with the N501Y mutation go from low levels in the population to a very significant percentage,” he says. The COH.20G/501Y variant from Ohio has since also been found elsewhere in the US, but its rate of spread is hard to determine.

A second mutation that has popped up frequently in Jones’s recent samples and in other Midwestern states is located outside the spike (S) RBD. “It’s in a conserved area that regulates the cleavage of the S protein, [which] has also raised the possibility that this could be a functional change in the virus.”

L452R, a different mutation that appears to be spreading, was recently associated with large outbreaks in California, but experts say it’s not clear if it’s more infectious.

Variants are a numbers game, Moore says: give a virus more bodies and more time to spread, and novel variants are certain to emerge. The good news, Resende points out, is that all variants—be they existing or future ones—can in principle be controlled with the same measures: “washing our hands, wearing masks, avoiding crowded places.”

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