When Bette Korber, a biologist at the Los Alamos National Laboratory, spotted the first significant mutation in the Covid-19 virus last spring, some scientists were skeptical. They didn’t think it would make the virus more contagious and said its rapid rise may just be a coincidence.
Now, 11 months later, the D614G mutation she helped discover is ubiquitous around the world, presented in the genomes of rapidly spreading variants from the UK, South Africa and Brazil. Meanwhile, new mutations are appearing in increasingly complicated patterns, prompting top biologists to devise new ways to follow a fire hose of incoming genomic data.
The goal: to quickly detect variants that can decrease the effectiveness of vaccines against a pathogen that is unlikely to be eradicated anytime soon. The SARS-CoV-2 virus could set in and become a simple nuisance like the common cold. Or just like the flu, it might retain its ability to cause serious illness in certain segments of the population, a scenario that might require regular booster shots.
“By monitoring it carefully, we can stay one step ahead of the virus and that’s what everyone is working hard to do right now,” said Korber, who is working to create new math tools to detect medically significant variants.
The flood of new genomic data is so great that the Los Alamos lab has had to upgrade its servers to handle the incoming data. Meanwhile, Korber participates in four Zoom calls per week with experts around the world to define criteria for deciding when mutations are of sufficient concern to merit detailed laboratory monitoring of their impact on vaccines.
A key mystery discovered early on by top scientists was what type of virus the coronavirus will turn out to be. So far, it looks more like the flu, which changes shape all the time and requires annual revaccination, than measles, a virus so intolerant to the mutation that a vaccination schedule lasts a lifetime.
“Does that mean we have to make a new vaccine every year?” said Paul Duprex, who heads the Center for Vaccine Research at the University of Pittsburgh. “We do not know.
On the one hand, mRNA vaccines for Covid-19 have efficacy rates above 90%, much higher than the 60% rate for influenza vaccines in a good year. But vaccine makers Moderna Inc and Pfizer Inc, as well as its partner BioNTech SE, are taking no chances. Just in case, they’re already starting booster trials targeting B.1.351, the antibody-avoidant strain first spotted in South Africa.
When viruses replicate and copy their genomes, errors can erupt the long chain of RNA or TBEN “letters” that determine the development of viral proteins. Many mistakes have no effect, or they can even make the virus less apt. But a tiny percentage of these changes can give the virus an advantage, making it more infectious or giving it the ability to evade the immune system.
The HIV virus is known for its rapid rate of mutation. In comparison, SARS-CoV-2 mutates at a much slower rate, in part due to a replay enzyme that limits changes. But with over 125 million infections worldwide, some mistakes are sure to pass.
At the same time, the virus has found devious ways that can bypass its replay mechanism, researchers at the University of Pittsburgh have found. Rather than making changes to individual RNA letters, it drops groups of several letters at once, apparently reducing the ability of the virus’s natural spell-checking systems to see the change.
After 74 days
Some of the first deletions were seen in an immunocompromised cancer patient treated at the University of Pittsburgh Medical Center, who died after a 74-day battle with Covid-19. During that time, multiple immune-escaping deletions developed, according to Duprex of the University of Pittsburgh, who reported on the cancer patient’s deletions in November.
“If that damn thing is gone, you can’t fix it,” Duprex said.
What makes the future of SARS-CoV-2 so hard to predict is that the viral evolution is like a three-dimensional game of chess. It’s not just individual mutations that matter, but also the order and combinations in which they occur. According to Mark Zeller, a scientist at the Scripps Research Institute in San Diego, a single mutation can alter the virus in subtle ways, which changes the impact of others down the line.
The B.1.351 strain common in South Africa and the P.1 strain that beats Brazil share several mutations in the spike protein that the virus uses to enter cells. This includes the D614G mutation discovered by Korber, which makes the peak more stable, and the E484K mutation, which is believed to reduce the ability of some antibodies to bind to the peak.
Yet, so far, for reasons that are not well understood, it is B.1.351 that appears to have the most impact on vaccines from Pfizer and Moderna, at least in laboratory tests.
Overall, the history of virus elimination has been poor, with smallpox being the prime example. Even pockets of polio still exist in some countries, despite efforts to eliminate it. This does not bode well for the current virus, according to Jesse Bloom, a researcher at the Fred Hutchinson Cancer Research Center who studies viral evolution.
“The vaccination will drastically reduce this pandemic,” Bloom said. “But I don’t think we’re going to eradicate SARS-CoV-2.”
Bloom predicts that it will take “several years” for the virus to acquire enough mutations to completely escape existing vaccines. Of the estimated 100,000 possible single-letter mutations for the virus, less than 1% are likely to help the virus escape antibodies, he said.
A hopeful scenario
As the virus continues to evolve in the short term, one of the most encouraging scenarios is that it could miss big moves to escape the antibodies that make current vaccines work. In this scenario, there may be a practical limit to how much the virus can mutate and remain able to invade our cells.
The spike protein must maintain a shape that allows it to effectively attach to its human receptor, according to Shane Crotty, a researcher at the La Jolla Institute of Immunology.
“There aren’t an endless number of possibilities,” he said. “It’s like putting your foot in a shoe. It should always be basically the right shape and size and it should always be recognizable as a shoe. “
Yet evidence from other common cold coronaviruses indicates that they can mutate to evade the immune system over time.
In a recent study, Bloom and his colleagues compared the 1984 version of a common cold coronavirus called 229E to a version of the same strain that circulated in 2016, three decades later. At least 17% of the RNA letters in a key part of the spike protein that binds the virus to cells had been exchanged due to mutations.
To test what this meant for human immunity, they obtained blood samples from patients from the 1980s who could neutralize the 1984 virus strain. These people had likely been exposed to the 1984 virus and had developed protective antibodies against it. him.
When the researchers tested the samples against strains of the 229E virus that appeared in the 1990s or later, the protection wore off: only 2 of 8 blood samples were able to neutralize the 2016 strain, and both of these showed dramatically reduced activity against newer virus.
This gives some clues as to what changes might be made in the future, given enough time. “It’s pretty clear that human coronaviruses undergo substantial antigenic evolution,” Bloom said in an interview.
However, it remains unclear whether the virus can retain its ability to cause serious illness as it mutates and more people gain immunity from infections or vaccines.
In research published in January in the journal Science, disease modellers at Emory University found that a key factor will be whether protection against serious illness lasts much longer than protection against mild or asymptomatic re-infections. , which is typical of coronaviruses that cause colds.
Although the study was carried out before the emergence of the current variants, its fundamental conclusions hold good, according to Jennie S. Lavine, postdoctoral researcher at Emory University.
“What we are seeing with Covid-19 at the molecular and cellular level is not inconsistent with what we are seeing with endemic coronaviruses,” said Lavine, lead author of the article. “Immunity is waning, but not everything is waning quickly.”
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