Transmission electron microscope image of SARS-CoV-2, the virus that causes Covid-19.
Source: BSIP / Universal Images Group / Getty Images
Source: BSIP / Universal Images Group / Getty Images
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When Bette Korber, a biologist at The 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 that its rapid increase may just be a coincidence.
Now, 11 months later, the D614G mutation that she helped to discover is ubiquitous worldwide, presented in the genomes of rapidly spreading variants in the United Kingdom, South Africa and Brazil. Meanwhile, new mutations are emerging in increasingly complicated patterns, encouraging leading biologists to develop new ways to track a fire hose with genomic data received.
The goal: to quickly detect variants that can decrease the effectiveness of vaccines for a pathogen that is unlikely to be eradicated anytime soon. The SARS-CoV-2 virus can settle and become a nuisance just like a common cold. Or, like the flu, it may maintain its ability to cause serious illness in some segments of the population, a scenario that may require regular booster doses.
Source: Los Alamos National Laboratory
“By watching it carefully, we can stay ahead of the virus and that’s what everyone is struggling to do now, ”said Korber, who is working to create new mathematical tools to detect clinically significant variants.
The flood of new genome data is so great that the Los Alamos laboratory had to update its servers to handle the data received. Meanwhile, Korber is on four weekly Zoom calls with experts around the world to define criteria for deciding when the mutations are worrying enough to warrant detailed laboratory follow-up on how they can affect vaccines.
An important mystery discovered from the beginning by leading scientists is what type of virus the coronavirus will prove to be. So far, it looks more like flu, which changes shape all the time and requires annual revaccination, than measles, a virus so intolerant of the mutation that a vaccine regimen lasts a lifetime.
“Does this mean that we need to get a new vaccine every year?” said Paul Duprex, who runs the Vaccine Research Center at the University of Pittsburgh. “We do not know.”
On the one hand, Covid-19 mRNA vaccines have efficacy rates above 90%, much higher than the 60% rate for flu vaccines in a good year. But vaccine manufacturers Moderna Inc. and Pfizer Inc., together with its partner BioNTech SE, don’t take any chances. As a precaution, they are already starting testing booster vaccines for B.1.351, the strain that avoids antibodies first detected in South Africa.
When viruses replicate and copy their genomes, errors can erode the long string of RNA or DNA “letters” that determine how viral proteins are developed. 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 escape 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 proof reading enzyme that limits changes. But with more than 125 million infections worldwide, some errors are bound to escape.
At the same time, the virus has found tortuous ways that can prevent its review mechanism, researchers at the University of Pittsburgh found. Instead of making changes to individual letters of RNA, it excludes groups of several letters at once, apparently diminishing the ability of the virus’s natural spell-checking systems to see the change.
74 day fight
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 attack with Covid-19. At that time, multiple deletions of immune escape developed, according to Duprex of the University of Pittsburgh, who reported the deletions of cancer patients in November.
“If the damn thing is gone, you won’t be able to fix it,” said Duprex.
What makes the future of SARS-CoV-2 so difficult to predict is that viral evolution is like a three-dimensional game of chess. It is not just individual mutations that 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.
Shared mutations
Both the B.1.351 strain common in South Africa and the P.1 strain that is affecting 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 reduces the ability of some antibodies to bind to the peak.
However, until now, for reasons not fully understood, it is B.1.351 that appears to have the greatest impact on Pfizer and Moderna vaccines, at least in laboratory tests.
Overall, the virus elimination history has been low, 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, researcher at Fred Hutchinson Cancer Research Center, which studies viral evolution.
“Vaccination is going to reduce 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 “a few years” for the virus to acquire enough mutations to completely escape existing vaccines. Of the approximately 100,000 possible single-letter mutations for the virus, less than 1% are likely to help the virus avoid antibodies, he said.
A Hopeful Scenario
Although the virus continues to evolve in the short term, one of the most promising scenarios is that it may run out of major moves it can make 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 attach itself efficiently to its human receptor, according to Shane Crotty, a researcher at the La Jolla Institute for Immunology.
“There are not an infinite number of possibilities,” he said. “It’s like putting your foot in a shoe. It still needs to basically have the right shape and size and it must still be recognizable as a shoe. “
Still, evidence from other common cold coronaviruses indicates that they may mutate to escape the immune system over time.
In a recent study, Bloom and 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. A total of 17% of the RNA letters in a key part of the spike protein that binds the virus to cells have been replaced due to mutations.
To test what this meant for human immunity, they obtained blood samples from patients in the 1980s who could neutralize the 1984 viral strain. These people were probably exposed to the 1984 virus and developed protective antibodies against it.
Faded protections
When the researchers tested the samples against strains of the 229E virus that appeared in the 1990s or later, the protection was gone: only 2 out of 8 blood samples were able to neutralize the 2016 strain, and these two showed very little activity against the latest virus.
This gives you some hints on how much you can change in the future, with enough time. “It is very clear that human coronaviruses undergo substantial antigenic evolution,” Bloom said in an interview.
However, it remains to be seen whether the virus can maintain its ability to cause serious illnesses as it mutates and more people gain immunity through infections or vaccines.
In research published in January in the journal Science, disease modellers in Emory University has found that a key factor 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.
Although the study was done before the emergence of current variants, its basic conclusions are supported, 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 inconsistent with what we see with endemic coronaviruses,” said Lavine, who was the lead author of the article. “Immunity goes down, but not everything goes down quickly.”