A Blog by Jonathan Low


Mar 16, 2021

How Scientists Continue To Underestimate Covid

Based on previous knowledge and experience, scientists and doctors have repeatedly underestimated the capacity of the virus to evolve in unexpected ways. 

That propensity continues to confound medical personnel. JL

Carolyn Johnson reports in the Washington Post:

Even before the variants emerged, there were hints that scientists had been underestimating the virus’s capacity to change. The past few months have been a wake-up call: “Don’t think twe are cleverer than evolution. There is an evolutionary jump from some hidden source of viral evolution. We have a blind spot in the community where the evolution is happening, and we can’t see it until we see it’s spread far enough. We’ve been underestimating the capacity of the virus to evolve since the beginning of the pandemic.”

Evolutionary biologist Jesse Bloom knew it was only a matter of time: The coronavirus would turn into an even more formidable foe, able to dodge the disease-fighting antibodies that protect people after being infected or vaccinated.

He even knew which mutation was likely to give it that superpower.

He just didn’t know it would happen quite this fast.

For much of 2020, most people — including most experts — weren’t particularly worried about the virus’s ability to evolve. SARS-CoV-2 was changing, but so far that hadn’t amounted to anything especially concerning. Then, in late fall, it jumped. Distinctive new versions of the virus sparked alarming surges in Brazil, South Africa and the United Kingdom.

In a few short months, variants have become a global preoccupation. Nearly every time public health experts talk about the trajectory of the health crisis, they dwell on the variants, the loose cannon that could wreck hard-won progress.

These variants carry not one but a slew of mutations. They appear to have worrisome new abilities, better at spreading or slipping by aspects of immunity.

Their sudden emergence caught scientists off guard and set the stage for the next chapter of the pandemic. The mass vaccination campaign that could have felt like a wave of relief is instead an ominous, urgent race against a changing virus. The path to herd immunity, the powerful milestone when the virus won’t be able to spark new outbreaks, is looking longer and more complex. Vaccines may not totally vanquish but simply chase a continually changing virus.

As scientists work to get a handle on the variants, the situation gives the public a rare front-row seat and real-time view of the unpredictability of viral evolution. The virus is changing, and scientists are preparing for a wide range of possible futures.

“We do have to come to terms with the fact that I’m pretty confident that SARS-CoV-2 is going to be more like influenza, which is with us all the time because the virus is changing, and we have to worry about keeping our vaccines updated,” Bloom said. “On the other hand, I think that a year from now, it’s going to be much less of a problem.”

Already, researchers are increasing genomic surveillance to track changes to the virus.

People like Bloom are building maps of the genetic escape routes the virus could take, so that when mutations inevitably arise, scientists can quickly interpret whether they’re likely to pose a threat.

That doesn’t necessarily mean a world where the pandemic never ends. The outlook is improving as vaccines are rolled out. If vaccines become outdated, they will be updated.

“There will be new variants and new ways in which the virus might be escaping our immune responses a little bit, but that’s the key — it’s probably not going to be that much” of an escape, said Sarah Cobey, who studies viral evolution at the University of Chicago.

In laboratories, scientists are testing whether the current variants remain susceptible to antibodies conjured by natural infection and vaccines. Companies are preparing new versions of vaccines and testing extra booster shots, just in case.

The stealthy, speedy arrival of variants has put scientists in the familiar position of being unable to predict where the virus is headed.

“If you really push virologists, and get them to be honest and not revisionist, the majority, if not all the individuals, in the community were saying, ‘It’ll probably be all right, it’ll probably be fine,’ ” said Paul Duprex, director of the Center for Vaccine Research at the University of Pittsburgh.

The past few months have been a wake-up call: “Don’t think that we are cleverer than evolution.”

Even before the variants emerged, there were hints that scientists had been underestimating the virus’s capacity to change.

Starting last spring, a 45-year-old man with a severe autoimmune disease was in and out of a Boston hospital for five months, with what turned out to be an astonishingly long chronic coronavirus infection. By sequencing the virus over different time points, doctors found that the virus was changing rapidly — highlighting the potential for what his team of doctors called “accelerated viral evolution.”

Instead of just one or two genetic tweaks, the virus accumulated 21 mutations, and they were concentrated in the spike protein — the spot where the immune system trains much of its firepower to block infections. After the man was given an antibody drug, new mutations emerged that may have helped the virus thwart the treatment.

Thousands of miles away in the United Kingdom, the virus took hold in a 70-year-old cancer survivor with a compromised immune system. After the patient received rounds of antibody-rich plasma treatment aimed at beating back his disease, the researchers saw different variants gaining and losing ground within him. One version of the virus increased when he was treated with plasma, then receded as the antibodies diminished, then dominated again when a last course of plasma was given.

Researchers created a lab version of that variant. One of its genetic changes reduced the virus’s susceptibility to antibodies, they found, but also carried a potential Achilles’ heel, making it less efficient at infecting cells. A second change — a missing portion of the genome — seemed to compensate, increasing the virus’s ability to infect cells. That change was also found in the fast-spreading variant that triggered a lockdown in the United Kingdom this winter.

In Pittsburgh, a man in his 70s who had received a cutting-edge cancer treatment that knocked out part of his immune system was admitted to a hospital with covid-19 pneumonia. He was sick for more than two months, and over the course of his illness, researchers were able to sequence the virus infecting him, uncovering a clue as to why the virus could change so flexibly.

Many scientists had assumed that because the virus had a proofreading mechanism to correct errors when it multiplied, it wouldn’t mutate rapidly. But the changes in the virus weren’t typos in the genetic code — they were missing swaths called deletions. The virus couldn’t proofread what wasn’t there.

“We’ve been underestimating the capacity of the virus to evolve since the beginning of the pandemic,” said Kevin McCarthy, a microbiologist at the University of Pittsburgh’s Vaccine Research Center.

These patients, who all died, provided clues about the virus’s evolutionary capacity before the variants caught the world’s attention.

Scientists know that viruses make copies of themselves in people’s cells — and they make occasional errors in the process. When infections resolve quickly and mutations accumulate slowly, that doesn’t give the virus much chance to cultivate a huge reservoir of genetic diversity.

But in immunocompromised people, the virus has far more chances to change its genetic couture. When well-meaning physicians apply a little pressure — such as a round of antibody-rich plasma to try to save a patient’s life — there might be a version of the virus that gains an advantage, able to dodge the treatment.

No one knows whether any particular variant arose in an immunocompromised person, but the cases have so far proven to be an eerie crystal ball, foreshadowing what plays out in the population. With the virus infecting more than 100 million people across the planet, it was given maximal opportunities to change disguise.

“It suggests to me there is an evolutionary jump from some hidden source of viral evolution,” said Jonathan Z. Li, who studies HIV drug resistance at Brigham and Women’s Hospital in Boston. “We have a blind spot in the community where the evolution is happening, and we can’t see it until we see it’s spread far enough.”

Not every mutation turns a virus into a supervillain. Most have little effect or might actually hobble the virus. And even mutations that seemingly work to the benefit of the virus can come with trade-offs.

A genetic tweak that allows the spike protein to fly under the immune system’s radar a bit more stealthily, for example, might seem unequivocally helpful to a virus. But a change like that could also backfire, making it less efficient at breaking into the body’s cells. A virus that is invisible to the immune system sounds fearsome, but it could be inept in critical ways.

One of the open questions about the evolutionary capacity of the coronavirus is whether there is a limit to its ability to change. The spike latches onto cells, like a key fitting into a lock. Many scientists had assumed that if that key changed too much, it wouldn’t be able to open the door anymore.

“The spike protein seems remarkably tolerant of change. … That, I don’t think most people would have expected,” said Francis S. Collins, director of the National Institutes of Health.

But there were warnings about the spike’s propensity for shape-shifting before the variants.

At Rockefeller University in New York last summer, virologist Paul Bieniasz and colleagues put the coronavirus’s distinctive spike protein under pressure in the laboratory.

In test tubes, they put the spike through an immunity trial, exposing it to successive rounds of antibodies designed to sift out versions of the spike capable of avoiding neutralization. Such experiments have limits in what they can predict about how a virus will behave as it spreads through people, but what Bieniasz saw emerge was a mutation at a site called E484.

One prominent virologist told the team, “I am not worried about this,” Bieniasz recalled. Yet months later, changes to E484 emerged in real life — on the variants found in South Africa and Brazil.

Bloom, at the Fred Hutchinson Cancer Research Center in Seattle, felt a similar shock of recognition late last year. His laboratory had been testing every possible mutation in the region of the spike protein that binds to cells, to see which ones posed the greatest threat to immunity, and E484 had become a focal point of their work.

“I think everyone in the community was surprised by how rapidly these experiments became relevant,” Bloom said.

What scientists are debating now is where the virus could be headed next.

It could be in a period of rapid evolution, in which the virus is adapting to get better at infecting people. After some amount of time — how much is another matter for debate — that rate could slow down. Or the virus, like influenza, could simply be in a constant back-and-forth with the immune system.

“Is the spike infinitely malleable? Is it plastic enough to let anything happen? There isn’t a simple answer,” said John Moore, a professor of microbiology and immunology at Weill Cornell Medicine.

The immediate implications for ordinary people are not dire. It remains important to bring down transmission to give the virus fewer chances to change — and for people to get vaccinated. But for scientists, there’s a long path ahead.

Kizzmekia Corbett, the scientific lead of the coronavirus vaccine program at NIH’s Vaccine Research Center, recently said the emergence of the variants feels like “a second pandemic.” Companies and scientists are already beginning tests of revamped vaccines, so that they will be ready if they are needed.

“I do think this virus shows more, let’s say, genetic flexibility than maybe was anticipated by some,” said Vincent Munster, chief of the virus ecology section at NIH’s Rocky Mountain Laboratories. “Even though we cannot really look into the future, it would be good to at least anticipate this might be a future scenario, so that we’re actually prepared.”


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