Toward the end of last year, doctors in Nelson Mandela Bay, a city of about 1 million people in the Eastern Cape of South Africa, started to see something alarming. The city had been hit by a tsunami of Covid-19 cases in June and July, swamping hospitals and leading to thousands of deaths. That wave began to subside as winter turned to spring in the southern hemisphere. But starting in November, hospitals in the city and its surrounding province began to fill up with Covid-19 patients again—this time twice as fast they had during the first surge.
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To figure out what was going on with the steep uptick in new cases, doctors at those hospitals enlisted the help of Tulio de Oliveira, a geneticist and bioinformatician at the University of KwaZulu-Natal in Durban who leads a national network of sequencing labs. His team began piecing together the genomes of the coronavirus that had caused each person’s infection. For months, these researchers had been periodically doing similar genomic surveillance work to keep tabs on the dozens of strains of SARS-CoV-2 that were circulating around the country, looking for any problematic mutations in the virus’s spike protein. Eight months into the pandemic, in 99 percent of the more than 1,500 genomes they’d sequenced, they’d only found one such mutation. De Oliveira was in the process of submitting those findings to a journal.
Then, on December 1, the first results came back from Nelson Mandela Bay.
In each of the 16 samples gathered from 15 clinics around the city, the viruses all possessed a near identical constellation of mutations unlike any that had ever before been seen in South Africa. And eight of those mutations were in the spike protein. “Literally the day before I had written, ‘The spike genome in South Africa is very stable,’” de Oliveira told WIRED in an interview. “Then I saw this new cluster and I thought, ‘Wow, that has changed.’”
He walked upstairs, to the office of South Africa’s corollary to Anthony Fauci, an epidemiologist named Salim Abdool Karim, to tell him the news. Days later, they alerted the World Health Organization. Now on the lookout, scientists in the United Kingdom soon discovered one of those mutations spreading in the southeast part of Britain. A few weeks later, an eerily similar cluster of genetic changes surfaced among travelers from Brazil. But neither was a case of jet-setters seeding a single new strain around the world. Analyses of global coronavirus genome databases showed that these were in fact three distinct versions of the virus—three distantly related branches of the SARS-CoV-2 family tree that had independently acquired some of the same mutations despite emerging on three different continents.
That pattern is what scientists refer to as “convergent evolution,” and it’s a sign of trouble ahead.
All viruses mutate. They are, after all, just autonomous bits of protein-encased, self-replicating strings of code equipped with imperfect internal spell-checkers. Make enough copies and there are bound to be mistakes. Coronaviruses actually make fewer mistakes than most. This one, SARS-CoV-2, evolves at a rate of about 1,100 changes per location in the genome annually—or about one substitution every 11 days.
The predictable pace at which the coronavirus’s genetic building blocks shift around can be detected by genomic sequencing, which allows scientists to identify new strains and follow them as they spread through a population or fade away. For most of 2020, those random changes didn’t have much of an effect on the way the virus behaves. But recently, three notable mutations have begun to show up alone or in combination with each other. And everywhere they do, these versions of the virus tend to quickly outcompete other circulating strains.
“That suggests there’s an advantage to these mutations,” says Stephen Golstein, an evolutionary virologist who studies coronaviruses at the University of Utah. “Every SARS-CoV-2 variant ‘wants to be more transmissible,’ in a sense. So the fact that so many of them are landing on these mutations suggest there could be a real benefit for doing so. These different lineages are essentially arriving at the same solution for how to interact more efficiently with the human receptor, ACE2.”
Like any virologist, Goldstein is hesitant to anthropomorphize his subjects. Viruses don’t have dreams and desires. They’re intelligent micromachines programmed to make as many copies of themselves as possible. But one way to do that is to increase their odds of invading new hosts. SARS-CoV-2 does that by guiding the array of spike proteins that coat its exterior toward a protein called ACE2 that sits on the outside of some human cells. The spike is encrusted in sugars which camouflage the virus from the human immune system, except for the very tip, known as the receptor binding domain, or RBD for short. This exposed section is the part that latches onto ACE2, changing the receptor’s shape—like a key rearranging the tumblers inside a lock—and allowing the virus to enter the cell and start replicating.
The mutations that have scientists so worried all occur in that little exposed bit of spike. And now researchers are racing to figure out how each of them might be giving SARS-CoV-2 some new tricks.
There’s N501Y, a mutation that occurs in all three variants, which replaces the coronavirus’s 501st amino acid, asparagine, with tyrosine. Studies in cells and animal models suggest that the change makes it easier for SARS-CoV-2 to grab onto ACE2, which is one hypothesis for why the variant has been, at this point, pretty convincingly associated with increased transmission. The best evidence for that so far has come out of the UK, which is doing more genomic sequencing than any other country in the world. Scientists there estimate that the UK variant, alternatively known as B.1.1.7, is between 30 and 50 percent more infectious than other circulating strains.
In Ireland, it became the dominant version of the virus in just a few weeks, and it has since spread to more than 60 countries, including the US. As of Tuesday, the US had detected 293 cases of the UK variant, according to data from the US Centers for Disease Control and Prevention. The agency estimates it will become dominant in the US by March.
A Brazilian variant, also called P1, and the South African one, sometimes called B.1.351, also have a second and third mutation in common: K417T and E484K. At this moment, scientists know more about the latter. It changes an amino acid that was negatively charged to one that’s positively charged. In variants without this mutation, that section of the RBD sits across from a negatively charged stretch of ACE2, so they repel away from each other. But the E484K mutation reverses that charge, making them snap tightly together instead.
On Monday, Minnesota reported the US’ first case of the Brazil variant, but so far no cases of the South African variant have yet been confirmed in the US.
Scientists at the Fred Hutchinson Cancer Research Center found that E484K might be the most important alteration when it comes to enhancing the virus’s ability to evade immune defenses. In lab experiments, they observed that antibodies in the blood of recovered Covid-19 patients were 10 times less effective at neutralizing variants possessing the E484K mutation. In a separate study, some of De Oliveira’s colleagues tested the blood from Covid-19 patients who fell ill in South Africa’s first wave, and they found that 90 percent of them had some reduced immunity to the new E484K-containing variant. In nearly half of the samples, the new variant escaped the preexisting antibodies completely. Another study by another South African colleague, this time using live virus, found similar results. (All are being shared as preprints—neither has yet been peer-reviewed, as has become common in the age of Covid.)
“All the evidence is starting to point in the same direction,” says de Oliveira. “We have a virus that is much less neutralized by convalescent plasma.” It’s still too soon to tell what that means in the real world. True reinfections are notoriously difficult to pin down. Scientists have to sequence samples taken from the first bout of illness and the second, and then compare the genetic signatures to determine if a different viral variant is responsible for each infection. De Oliveira says his group is in the process of doing that right now, and they’re finding many instances of what appear to be real reinfections with the South African variant. That data is not yet published. And until they sequence more samples, they can’t say whether B.1.351 is causing more reinfections than previous versions of the virus, which would be a sign that herd immunity might be much farther off than previously thought.
Researchers in Brazil have also found evidence of at least one reinfection with the new P1 lineage, but data there is even sparser. Some reinfections are to be expected, says William Hanage, an infectious disease epidemiologist at the Harvard T. H. Chan School of Public Health. The important thing is whether there are more reinfections with the new variant than the models would expect.
Still, that these worrying mutations are all cropping up in the same region of the spike protein is not a coincidence, says Goldstein. Of all the places in the coronavirus’s genome, the RBD is the least stable. “That’s because, historically, it’s been under the most evolutionary pressure to change,” he says. It may feel like the Covid-19 pandemic has been happening forever. But in evolutionary terms, it’s been but a blink.
Before SARS-CoV-2 crossed into humans, it had been circulating inside bats for millions of years. And when scientists began taking a closer look at the bat version of ACE2, they found a staggering diversity of the gene that codes for that protein. What they were seeing were the genetic scars of an evolutionary arms race. Bat populations had lived with SARS-CoV-2 for long enough that their ACE2 receptors had started changing—morphing in shape so that they became harder for the virus to grab onto. And in turn, SARS-CoV-2 had evolved to try to fit into those new shapes. Eventually, one of those descendants looked enough like the human ACE2 receptor that it could make the cross-species leap (with perhaps an intermediary host in there somewhere).
There are two major evolutionary forces driving diversification of the spike protein: interacting with ACE2, and getting clobbered by neutralizing antibodies. In the human population, a year isn’t long enough for new versions of ACE2 to crop up and be passed on to a new generation of people. And ACE2 plays a key role in regulating blood pressure, wound healing, and other essential functions, so any genetic changes that impair its ability to do those things would likely not get very far, even if they made it more difficult for the coronavirus to start an infection.
So if the evolution of the ACE2 receptor can’t rescue us in the short term, that leaves the body’s immune system, and the armies of cells that orchestrate ejecting any unwanted visitors from it. Many pathogens mutate their proteins toward new shapes to avoid being recognized by the antibodies that would normally adhere to them, blocking their entry into cells. That’s called antigenic drift. And that’s what some scientists think drove the emergence of the Brazil and South African variants.
In a study recently posted as a preprint and not yet formally reviewed, Theodora Hatziioannou, a virologist at Rockefeller University in New York, and her colleagues described creating a pseudo-coronavirus carrying a nonvariant version of the spike protein. They grew it in the presence of individual antibodies they had extracted from the blood of people who had received one of the two FDA-authorized Covid-19 vaccines, one from Pfizer/BioNTech and one from Moderna. Some antibodies spurred the pseudo-SARS-CoV-2 to acquire the E484K mutation. Others nudged it toward K17T or N501Y.
They tried the experiment again with no antibodies present, and none of these three mutations—the ones in the triple-variant threat—evolved the same evasive maneuvers. “This data shows that these mutations accumulating in the spike protein are antibody escape mutations,” says Hatziioannou. “As soon as you add a specific antibody, you see specific mutations.”
Her group used blood donated by immunized people. But the vaccines have not been rolled out widely enough to be exerting significant evolutionary pressure on the general population. So the obvious question is: Where did the virus encounter these antibodies?
Hatziioannou and others think there are clues to be found in the genomes of viruses that took up long-term residence in the bodies of immunocompromised Covid patients. Up until a few weeks ago, the prevailing theory was that escape mutations could have emerged in people with chronic infections, who might be receiving monoclonal antibody treatments or convalescent plasma, and therefore supercharging the selective pressures the virus has to contend with.
Goldstein has a simpler explanation, one that’s beginning to get more traction in the scientific community. The convergent evolution of wilier versions of the virus might just be a consequence of so many poorly managed government pandemic responses, which didn’t marshal sufficient resources or inspire the kind of collective action required to not just crush the initial curve, but keep it crushed. “The fact that we lost control in so many places in the fall allowed for the ballooning of this incredibly huge viral population size,” says Goldstein. That created the opportunity for that many more mutations to happen, and in some places, the right circumstances for some particularly insidious ones to get selected.
Hanage put it this way to reporters last week: “The strategy here and elsewhere has been to try and control the level of transmission that doesn’t require very severe restrictions, but also doesn’t allow the virus to go exponential and overload health care systems.” But the problem with that approach is that it still gives the virus plenty of opportunities to mutate, and in so doing, change its behavior. If those changes make it spread faster or give it an edge against treatments and vaccines, that balancing act falls apart. “It tips you from a point where you’re capable of dealing with it to a point where you’re not,” he continued.
Hannage pointed to what’s going on right now in Manaus, a city in the Brazilian Amazon where a devastating surge in May left up to 70 percent of its residents infected with SARS-CoV-2, according to an analysis published this month in Science. Doctors and researchers there assumed the city was safe for a while—that herd immunity, or close to it, had been reached. But this month, the Manaus public health system collapsed again under a new Covid crush, leaving hospitals scrambling to get enough oxygen for its mass of patients. “I’m not yet aware of any evidence to suggest that the P1 variant is more likely to infect or reinfect people,” said Hanage. “But the fact that this is happening in a place that had previously been exposed to such high amounts of transmission is extremely worrying, very worrying indeed.”
Scientists may never get a clear answer to exactly where and under what conditions these new variants emerged. But de Oliveira isn’t so sure it matters. “The one thing we know for sure is that if you keep the virus circulating long enough, it will develop escape mutations,” he says.
The much more pressing question, then, is to what degree will such mutations affect efforts to vaccinate our way out of the pandemic?
A spate of recent studies, released as preprints have mostly good—and some mixed—news on that front. Lab tests conducted by scientists at BioNTech showed that their vaccine should still work just as well against B.1.1.7, the UK variant.
In their recent preprint, Hatziioannou’s group also took a closer look at B.1.351, the South African variant. They found that antibodies taken from people vaccinated with either Pfizer/BioNTech or Moderna’s shots were up to three times less effective at neutralizing the pseudoviruses carrying the mutations found in B.1.351, compared to ones without those genetic changes in the spike protein. But since those vaccines have such a high starting efficacy—over 90 percent—there’s still a lot of wiggle room.
On Monday, Moderna scientists and their partners at the National Institutes of Health released the not-yet-peer-reviewed results of their own lab experiments using blood from people who had received the company’s vaccine. Although antibodies from immunized people fended off the UK variant just fine, they found, the South African variant caused some issues. Against that strain, the neutralizing power of the antibodies induced by Moderna’s vaccine was reduced six-fold, though they still functioned at levels believed to be effective.
In a statement, Moderna CEO Stéphane Bancel said that he is confident the company’s vaccine should still be protective against the newly detected variants, but that “it is imperative to be proactive as the virus evolves.” To that end, Moderna’s scientists are retooling the company’s mRNA sequence to more closely mimic the most significant mutations and plan to test it as an additional booster shot in clinical studies later this year.
“We shouldn’t panic yet, but we should be careful. This is a warning,” says Hatziioannou. “If the virus continues to accumulate mutations in its spike protein, we run the risk of the efficacy of vaccines diminishing further.”
Vaccines target the whole spike protein, and they have been shown to make lots of different antibodies that bind to different parts of it. So losing the ones that block the RBD isn’t game over. There are plenty of built-in redundancies. But it leaves more work for the rest of the immune system. It’s like trying to kick out a home invader after you’ve left the front door unlocked. It gives the virus a little leg up. “The most important antibody targets do happen to be the most variable parts of the spike protein,” says Goldstein. “That’s why we’re locked in this evolutionary battle with the virus.”
With these new variants showing signs of being better at spreading and eluding both natural immune defenses and treatments like monoclonal antibodies and convalescent serum, the race is on to vaccinate as many people as possible in the shortest time frame. At least in the US, the last mile challenges with getting ultra-cold, two-shot vaccines into people’s arms are proving so problematic that the Biden administration has proposed creating 100 new mass vaccination sites across the country.
That’s good. But scientists like Hanage are still worried that if governments and societies don’t do enough to slow the speed of infections soon, more dangerous mutations will almost certainly emerge. “The fact that it’s happened three times already means we can expect it to continue happening,” he said during last week’s press briefing.
If you ask de Oliveira, he’ll tell you that it is already happening, and much faster than anyone realizes. “I am quite convinced that there are dozens, if not hundreds, of variants with similar mutations emerging around the world right now,” he says. He believes that the only reason that South Africa and the UK picked them up first is because their governments invested in comprehensive surveillance networks. That’s why he thinks nations need to stop useless travel bans and start ramping up testing, sequencing, contact tracing, and vaccination efforts. It may take years to inoculate enough people to curb the coronavirus’s evolution. Buying time until then means doing everything that has so far proven effective at limiting its chances of finding new hosts, and new opportunities to mutate: social distancing, mask-wearing, avoiding crowds, and increasing ventilation. “The important thing,” says de Oliveira, “is to realize we have to drive transmission to almost zero if we are to avoid new variants emerging in the future.”
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