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When Bette Korber, a biologist from Los Alamos National Laboratory detected the first significant mutation in the Covid-19 virus last spring, some scientists were skeptical. They did not believe it would make the virus more contagious and said its rapid rise could be just a coincidence.
Now, 11 months later, the D614G mutation he helped uncover is ubiquitous around the world. It appears in the genomes of fast-spreading variants of the United Kingdom, South Africa, and Brazil. Meanwhile, new mutations are popping up in increasingly complicated patterns, prompting top biologists to come up with new ways to trace a fire hose of incoming genomic data.
The goal: to quickly detect variants that can decrease the effectiveness of vaccines for a pathogen that is unlikely to be eradicated soon. The SARS-CoV-2 virus could settle down and become a simple nuisance like the common cold. Or like influenza, it could retain its ability to cause serious illness in some segments of the population, a scenario that might require regular booster injections.
“If we observe it carefully, we can anticipate the virus and that is what everyone is Fight do right now, ”said Korber, who is working to create new mathematical tools to detect medically significant variants.
The flood of new genome data is so great that the Los Alamos lab had to upgrade its servers to handle the incoming data. Meanwhile, Korber is on four Zoom calls a week with experts from around the world to devise criteria for deciding when mutations are of sufficient concern to warrant detailed lab monitoring of how they may affect vaccines.
A key mystery probed all along by leading scientists has been what kind of virus the coronavirus will turn out to be. So far, it’s more like influenza, which changes shape all the time and requires annual revaccination, than measles, a virus so mutation-intolerant that a vaccine regimen lasts a lifetime.
“Does it mean that we have to make a new vaccine every year?” saying Paul Duprex, who directs the University of Pittsburgh Vaccine Research Center. “We do not know”.
For one thing, mRNA vaccines for Covid-19 have efficacy rates in excess of 90%, much higher than the 60% rate for flu vaccines in a good year. But the vaccine manufacturers Moderna Inc. and Pfizer Inc., together with its partner BioNTech SE, take no chances. Just in case, they are already beginning trials of booster injections targeting B.1.351, the antibody-avoiding strain first detected in South Africa.
When viruses replicate and copy their genomes, errors can arise in the long string of RNA or DNA “letters” that determine how viral proteins develop. Many of the errors have no effect, or may even make the virus less suitable. But a small 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. By comparison, SARS-CoV-2 mutates at a much slower rate, in part due to a correcting enzyme that limits changes. But with more than 125 million infections worldwide, some bugs are likely to leak out.
At the same time, the virus has found devious ways that can bypass its proofreading mechanism, researchers at the University of Pittsburgh discovered. Instead of making changes to individual RNA letters, it removes groups of multiple letters at once, seemingly undermining the ability of the virus’s natural spell-checking systems to see the change.
Some of the first deletions were seen in an immunosuppressed cancer patient treated at the University of Pittsburgh Medical Center who died after a 74-day bout with Covid-19. In that time, multiple deletions developed that were leaking from the immune system, according to Duprex of the University of Pittsburgh, who reported on the deletions in the cancer patient in November.
“If the damn thing is gone, you can’t fix it,” Duprex said.
What makes the future of SARS-CoV-2 so difficult to predict is that viral evolution is like a three-dimensional chess game. Not only individual mutations matter, but also the order and combinations in which they occur. A single mutation can alter the virus in subtle ways that change the impact of others in the future, according to Mark Zeller, a scientist at the Scripps Research Institute in San Diego.
Both the B.1.351 strain common in South Africa and the P.1 strain that is hitting 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.
However, so far, for reasons that are not fully understood, it is B.1.351 that appears to have the most impact on the Pfizer and Moderna vaccines, at least in laboratory testing.
In general, the history of virus elimination has been poor, with smallpox being the main example. There are even pockets of polio in some countries, despite efforts to eliminate it. That doesn’t bode well for the current virus, according to Jesse Bloom, researcher at the Fred Hutchinson Cancer Research Center that studies viral evolution.
“Vaccination is going to alleviate this pandemic in a very substantial way,” said Bloom. “But I don’t think we are 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 roughly 100,000 possible single-letter mutations for the virus, less than 1% are likely to help the virus evade antibodies, he said.
A hopeful scenario
While the virus continues to evolve in the short term, one of the more hopeful scenarios is that it may run out of big moves it can make to evade the antibodies that make current vaccines work. Under this scenario, there may be a practical limit to how much the virus can mutate and remain fit to invade our cells.
The spike protein must retain a shape that allows it to efficiently latch onto its human receptor, according to Shane Crotty, a researcher at the La Jolla Institute of Immunology.
“There are not an infinite number of possibilities,” he said. “It’s like putting your foot in a shoe. It still has to be basically the correct shape and size and it still has to be recognizable as a shoe. “
Still, 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. 17% of the RNA letters in a key part of the spike protein that binds the virus to cells had been swapped due to mutations.
To test what this meant for human immunity, they obtained blood samples from patients in the 1980s that could neutralize the 1984 viral strain. These people likely have been exposed to the 1984 virus and developed protective antibodies against it. .
When the researchers tested the samples against strains of the 229E virus that appeared in the 1990s or later, the protection had faded: only 2 out of 8 blood samples were able to neutralize the 2016 strain, and those two showed greatly reduced activity. against the most recent ones. virus.
That provides some indication of how much could change in the future, given enough time. “It is quite clear that human coronaviruses undergo substantial antigenic evolution,” Bloom said in an interview.
However, it is unknown whether the virus can retain its ability to cause serious disease as it mutates and more people gain immunity through infections or vaccines.
In research published in January in the journal Science, disease modelers from A key factor, Emory University found, will be whether protection against serious illness lasts significantly longer than protection against mild or asymptomatic reinfections, something that is typical of coronaviruses that cause common colds.
While the study was conducted before current variants emerged, its basic conclusions hold, according to Jennie S. Lavine, a postdoctoral researcher at Emory University.
“What we see with Covid-19 at the molecular and cellular level is not incompatible with what we see with endemic coronaviruses,” said Lavine, who was the lead author on the paper. “Immunity wears off, but not everything wears off quickly.”