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The coronavirus is mutating - does it matter?
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Different SARS-CoV-2 strains haven't yet had a major impact on the course of the pandemic, but they might in future.
08 September 2020
https://www.nature.com/articles/d41586-020-02544-6
earlier this year there were publications on this 614 mutation & whether it is relevant. Here months later is further discussion & research on this question. Some say this 614 mutation increases transmissibility, but in this paper & others say its too soon to know, it remains unclear still. This report are excerpts, read the full paper to see the full discussion. Jules
"Even these experiments might not offer absolute clarity......In April, Korber, Montefiori and others warned in a preprint posted to the bioRxiv server that "D614G is increasing in frequency at an alarming rate"1. It had rapidly become the dominant SARS-CoV-2 lineage in Europe and had then taken hold in the United States, Canada and Australia. D614G represented a "more transmissible form of SARS-CoV-2", the paper declared, one that had emerged as a product of natural selection.....These assertions dismayed many scientists. It wasn't clear that the D614G viral lineage was more transmissible, or that its rise indicated anything unusual, they said.......So far, the upshot of this work is less clear than Montefiori and Korber's preprint suggested. Some experiments suggest that viruses carrying the variant infect cells more easily. Other work has revealed possible good news: the variant might mean that vaccines can target SARS-CoV-2 more easily. But many scientists say there remains no solid proof that D614G has a significant effect on the spread of the virus, or that a process of natural selection explains its rise. "The jury's out," says Timothy Sheahan, a coronavirologist at the University of North Carolina at Chapel Hill. "This mutation might mean something, or it might not.".....Researchers still have more questions than answers about coronavirus mutations, and no one has yet found any change in SARS-CoV-2 that should raise public-health concerns, Sheahan, Grubaugh and others say. But studying mutations in detail could be important for controlling the pandemic. It might also help to pre-empt the most worrying of mutations: those that could help the virus to evade immune systems, vaccines or antibody therapies......Many scientists weren't convinced that D614G's rise was remarkable - or all that relevant to the pandemic. "I thought that preprint was incredibly premature," says Sheahan.......The first team to report pseudovirus experiments on D614G, in June, was led by Hyeryun Choe and Michael Farzan, virologists at the Scripps Research Institute in La Jolla, California5. Several other teams have posted similar studies on bioRxiv (Montefiori's experiments, and those of another collaborator, appeared in the Cell paper2). The teams used different pseudovirus systems and tested them on various kinds of cell, but the experiments pointed to the same conclusion: viruses carrying the G mutation infected cells much more ably than did D viruses - up to ten times more efficiently, in some cases....."
In laboratory tests, "all of us agree that D to G is making the particles more infectious", says Jeremy Luban, a virologist at the University of Massachusetts Medical School in Worcester. But these studies come with many caveats - and their relevance to human infections is unclear. "What's irritating are people taking their results in very controlled settings, and saying this means something for the pandemic. That, we are so far away from knowing," says Grubaugh. The pseudoviruses carry only the coronavirus spike protein, in most cases, and so the experiments measure only the ability of these particles to enter cells, not aspects of their effects inside cells, let alone on an organism. They also lack the other three mutations that almost all D614G viruses carry. "The bottom line is, they're not the virus," says Luban.
Some labs are now working with infectious SARS-CoV-2 viruses that differ by only the single amino acid. These are tested in laboratory cultures of human lung and airway cells, and in lab animals such as ferrets and hamsters. For labs with the experience and the biosafety capabilities to manipulate viruses, "this is like bread-and-butter kind of work", says Sheahan. The first of those studies, led by researchers at the University of Texas Medical Branch in Galveston, was reported in a 2 September preprint6. It found that viruses with the mutation were more infectious than were D viruses in a human lung cell line and in airway tissues, and that mutated viruses were present at greater levels in the upper airways of infected hamsters6.
Even these experiments might not offer absolute clarity. Some studies show that certain mutations to the spike protein in the Middle East respiratory syndrome (MERS) virus can cause more-severe disease in mice - yet other mutations in the protein show very little effect in people or in camels, the likely reservoir for human MERS infections, says Stanley Perlman, a coronavirologist at the University of Iowa in Iowa City.
The clearest sign that D614G has an effect on the spread of SARS-CoV-2 in humans comes from an ambitious UK effort called the COVID-19 Genomics UK Consortium, which has analysed genomes of around 25,000 viral samples. From these data, researchers have identified more than 1,300 instances in which a virus entered the United Kingdom and spread, including examples of D- and G-type viruses.
A team led by Andrew Rambaut, an evolutionary biologist at the University of Edinburgh, UK, epidemiologist Erik Volz, at Imperial College London, and biologist Thomas Connor at Cardiff University, studied the UK spread of 62 COVID-19 clusters seeded by D viruses and 245 by G viruses7. The researchers found no clinical differences in people infected with either virus. However, G viruses tended to transmit slightly faster than lineages that didn't carry the change, and formed larger clusters of infections. Their estimates of the difference in transmission rates hover around 20%, Volz says, but the true value could be a bit higher or lower. "There's not a large effect in absolute terms," says Rambaut.
It's possible that D614G is an adaptation that helps the virus to infect cells or compete with viruses that don't carry the change, while altering little about how SARS-CoV-2 spreads between people or through a population, Rambaut says. "This might be a bona fide adaptation to humans or some human cells," agrees Grubaugh, "but that doesn't mean anything changes. An adaptation doesn't have to make it more transmissible."
Grubaugh thinks that D614G has received too much attention from scientists, in part because of the high-profile papers it has garnered. "Scientists have this crazy fascination with these mutations," he says. But he also sees D614G as a way to learn about a virus that doesn't have much in the way of genetic diversity. "The virologist in me looks at these things and says it would be a lot of fun to study," he says. "It creates this whole rabbit hole of different things you can go into."
No escape from antibodies - yet
Most available evidence suggests that D614G doesn't stop the immune system's neutralizing antibodies from recognizing SARS-CoV-2, as Montefiori had worried. That might be because the mutation is not in the spike protein's receptor-binding domain (RBD), a region that many neutralizing antibodies target: the RBD binds to the cell-receptor protein ACE2, a key step in the virus's entry to cells.
But evidence is emerging that other mutations could help the virus to avoid some antibodies. A team led by virologists Theodora Hatziioannou and Paul Bieniasz, at Rockefeller University in New York City, genetically modified the vesicular stomatitis virus - a livestock pathogen - so that it used the SARS-CoV-2 spike protein to infect cells, and grew it in the presence of neutralizing antibodies. Their goal was to select for mutations that enabled the spike protein to evade antibody recognition. The experiment generated spike-protein mutants that were resistant to antibodies taken from the blood of people who had recovered from COVID-19, as well as to potent 'monoclonal' antibodies that are being developed into therapies. Every one of the spike mutations was found in virus sequences isolated from patients, report Hatziioannou, Bieniasz and their team - although at very low frequencies that suggest positive selection is not yet making the mutations more common11.
.......The researchers didn't test whether any of the mutations allow the virus to thwart the action of antibodies, but his team's results suggest that such changes are possible. "It is a possibility, but by no means a certainty, that the virus will acquire mutations that change its susceptibility to antibodies and immunity," says Bloom.
With most of the world still susceptible to SARS-CoV-2, it's unlikely that immunity is currently a major factor in the virus's evolution. But as population-wide immunity rises, whether through infection or vaccination, a steady trickle of immune-evading mutations could help SARS-CoV-2 to establish itself permanently, says Sheahan, potentially causing mostly mild symptoms when it infects individuals who have some residual immunity from a previous infection or vaccination. "I wouldn't be surprised if this virus is maintained as a more common, cold-causing coronavirus." But it's also possible that our immune responses to coronavirus infections, including to SARS-CoV-2, aren't strong or long-lived enough to generate selection pressure that leads to significantly altered virus strains.
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