Mutant virus: should we be worried that Sars-CoV-2 is changing ?

Scientists have had eyes on Sars-CoV-2, the virus that causes Covid-19, since the beginning of this pandemic.

They can see it is evolving, but it is happening at a glacial pace compared with two other viruses with pandemic potential: those that cause flu and Aids. That is good news for efforts to develop vaccines and treatments, but scientists remain wary that anything could still happen.

“This virus is evolving and that’s what we expect it to do,” says Thushan de Silva, an infectious diseases doctor at the University of Sheffield and member of the Covid-19 Genomics UK Consortium (COG-UK), which has contributed more than 50,000, or roughly half, of the viral genome sequences that have been collected globally to date.

Tracking the virus: the ‘G’ mutation

All Sars-CoV-2 sequences are being deposited in GISAID (Global Initiative on Sharing All Influenza Data). Each sequence comes from an infected individual, and by pooling and comparing them, scientists can track mutations in the viral genetic code and, in a sense, the life history of Sars-CoV-2.

Mutations arise through viral replication, because in reproducing itself the virus must copy its genetic code, and it rarely does so perfectly. Coronaviruses are less error-prone than flu viruses, because they have a better inbuilt proofreading mechanism. Nevertheless, ever since Sars-CoV-2 emerged as a human pathogen, somewhere in the vicinity of Wuhan, China, thousands of such mutations have been observed.

The vast majority of mutations have no effect on the virus. A mutation can vanish as soon as it appears or it can seed a new lineage. Most lineages also die out in time – lockdown helped with that – but not all.

Scientists are wary of mutations that spread rapidly, especially if they do so in separate locations, because they might belong to that rare minority that change the way the virus behaves – perhaps by making it more transmissible between people or better able to evade the host’s immune system. That change could push the variant to dominate the viral population through natural selection, if it renders the virus fitter or better able to survive and reproduce, and it could be bad news for humans.

Back in the spring, at the Los Alamos National Laboratory in New Mexico, the computational biologist Bette Korber and her team were busy building the mathematical tools that would flag up such repeat offenders in the GISAID data.

“We didn’t expect to see anything so quickly,” she says. But already they had a candidate: “The D614G mutation stood out as such a case by early April.”

D614G refers to a switch in amino acid – from aspartate (D) to glycine (G) – at position 614 in the sequence of the protein that makes up the spikes of Sars-CoV-2. The spike is the protruding structure on the surface of the virus that binds to a human cell, allowing the virus to break in . After it has replicated inside the cell, its offspring break out again – killing the cell – and go on to infect others.

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When Sars-CoV-2 emerged in Wuhan, it had a D at position 614. By June, G had replaced D almost everywhere in the world.

‘More transmissible … but no less dangerous’

Korber and others reported their finding officially in the journal Cell in August, along with their conclusion that the switch had made the virus more transmissible but not more – or less – dangerous. Whether the virus has become better at spreading between people since the spring is a matter of lively debate, but most researchers agree that the switch has had no impact on disease severity.

“In our cohort of 1,000 sequenced Covid-positive individuals, those carrying the G mutation weren’t more likely to end up being hospitalised or in intensive care,” says De Silva.

Andrew Rambaut, a professor of molecular evolution at the University of Edinburgh, points out that the G form was already dominant in Europe when outbreaks were raging there in the spring, “so it really isn’t the cause of the apparently lower mortality and morbidity in recent months”.

If death rates have dropped recently, even as infections have risen, that probably has more to do with improved diagnosis and care – though changes in testing capacity and reporting of deaths make the evidence hard to interpret. In fact, there is little evidence that the undeniable evolution of Sars-CoV-2 has affected its behaviour much at all.

The east and west coasts of the US may well have received different lineages – the former mainly from Europe, the latter mainly from east Asia – but there is no reason to believe these caused different diseases. Likewise, speculation that Africa received different forms of the virus from Europe and the US, and that this explains why infections in Africa appear to have been generally late and mild by comparison, is not supported by the data.

The global sequencing effort has been impressive overall but patchy in its coverage, with richer countries inevitably contributing more sequences than poorer ones. Nevertheless, an Africa-wide effort coordinated by the Africa Centres for Disease Control and Prevention had contributed more than 1,000 sequences to GISAID by the end of July, and based on those it is clear that all the genomic diversity seen in Sars-CoV-2 globally is also present in Africa.

According to Nextstrain, a project tracking the expanding Sars-CoV-2 family tree in real time, the virus had been introduced to Africa at least 270 times by then, from every other continent.

The World Health Organization reports that death rates from Covid-19 have been lower in Africa than in other parts of the world, despite the relatively poor health infrastructure in many African countries. It is hard to know if this is an artefact generated by testing and reporting differences, but if it is real, it is not a result of viral evolution.

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The reasons why Africa’s Covid-19 experience has been different, if it has, must lie in the host populations or in the environment, according to Jinal Bhiman of South Africa’s National Institute for Communicable Diseases in Johannesburg.

One contributing factor is almost certainly the comparative youth of the population on average. Another theory being explored in South Africa is that lockdown did not prevent the virus from spreading through the country’s densely populated informal settlements, where restrictions were less rigorously applied. “That’s why now, with the loosening of restrictions, we’re not seeing an increase in cases or hospitalisations,” says Bhiman.

Some good news: vaccines and treatments may work better against the mutated virus

When Korber and colleagues reported their findings on D614G in August, there was one question they could not yet answer, but that worried them deeply: would the switch reduce the protective power of the vaccines in development, most of which elicit antibodies that target the original D form of the spike?

David Montefiori, an immunologist at Duke University in North Carolina, and an author on the Cell paper, extracted antibodies from blood taken from people in the Sheffield cohort who had been infected with both forms of the virus, and from animals and people who had received experimental vaccines, including one being developed by Pfizer.

Mixing those antibodies with a pseudovirus – a harmless virus engineered to sport the Sars-CoV-2 spike – he found to his surprise that pseudoviruses carrying the G form of the spike were more easily blocked or neutralised by the antibodies than those carrying the D form. “We hypothesise that this mutation was acquired to give the virus a fitness advantage for transmission, but it came at a modest cost of making it a little more sensitive to neutralisation,” he says.

The implication is that vaccines in the pipeline will actually work slightly better against the dominant G form of the virus than against the original D form. That finding has not yet been published in a peer-reviewed journal, but others have come to similar conclusions.

If they are right, that is good news. And more good news has come out of the lab of Paul Bieniasz, a virologist at the Rockefeller University in New York City, who has spent most of this year trying to identify antibodies to the virus that could be cloned and used therapeutically in Covid-19 patients – two such antibodies are about to enter clinical trials.

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“Whenever you develop an antiviral therapeutic you have to think about resistance,” says Bieniasz. Resistance of the virus to antibodies is obviously something to be avoided if an antibody therapy is to remain effective for a long time, but to avoid it scientists first have to understand how it emerges. Thanks to the stability of Sars-CoV-2 – and its novelty – resistant forms have not yet been observed in people.

There has not been sufficient buildup of natural immunity, and there is no vaccine either, to apply selective pressure to the virus, forcing it to adapt. But by using a similar approach to Montefiori’s and bombarding an engineered form of Sars-CoV-2 with different antibodies, Bieniasz has created antibody-resistant forms of the virus in a dish.

Simply giving patients a combination of two different antibodies should be enough to prevent this happening, he says – a lesson learned previously with HIV. “That reduces by a huge number the likelihood of resistant viruses emerging, because the virus has to acquire resistance to both antibodies to replicate.” And though nobody yet knows how the virus will respond once there is substantial immunity in the population, or a vaccine, he suspects antibody resistance will not be a major problem.

Given the virus’s stability, vaccines against it are also less likely to need updating annually, he says, as happens with flu.

The virus doesn’t need to change

De Silva says that a global second wave of Covid-19 caused by viral mutation, as was seen with the 1918 flu pandemic, remains highly unlikely, because this virus seems less prone to change in ways that affect its behaviour.

But Sars-CoV-2 could do anything next, which is why the surveillance continues .And other potentially troublesome mutations have appeared. A “mutation of interest”, as Korber calls it, is spreading fast in the Australian state of Victoria, for example.

As it also affects the spike, Montefiori has begun testing its effect on the ability of antibodies to neutralise the virus, as he did with D614G. Meanwhile, a viral variant has been reported in Singapore that seems to elicit a more robust immune response in humans and to cause milder disease.

Though the news is heartening, or at least not all bad, there is one popular idea about pandemics that Sars-CoV-2 is proving wrong: that a dangerous virus capable of global spread will evolve to become more benign over time. As De Silva says, this particular virus has spread easily while causing mild or no disease in the majority of those it infects, and only severe disease in a minority, meaning there is no pressure on it to reduce its virulence further. “It’s surviving perfectly well as is.”

It may have many more lessons to teach us before this pandemic is over.



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