The threat of Covid-19 mutations
Much of Western Australia’s population was plunged into lockdown this week after a hotel security worker tested positive for Covid-19, an infection that has since been confirmed as a case of the British variant, more formally referred to as B.1.1.7. This mutation of the SARS-CoV-2 virus has been widely reported on in recent weeks – largely due to concerns about its transmissibility. This week in Melbourne it reportedly passed from one hotel quarantine room to another across the hall.
But it’s not the only mutation in the news. In South Africa there are reports of the 501Y.V2 variant becoming more prominent, and in Brazil another strain, P.1, has reportedly devastated an area already hit hard by Covid-19, prompting concerns about what this means for immunity against the virus.
The variants have quickly become bogeymen of sorts. When reports of cases now come through, including the hotel worker who tested positive in Melbourne on Wednesday, one question has become the common refrain: Is it “regular” Covid-19, or is it one of the new mutations? And, as the world begins the project of mass vaccination, could these mutations undo all the work?
Mutation is a loaded word – and the image of a virus clawing its way across a hotel carpet to find a victim across the hall is an evocative one. But the truth is that viral mutation is normal and expected. The new variants each bring with them their own challenges, but their emergence doesn’t come as a surprise to the medical community, and they are not going to render the current vaccines obsolete.
Viruses work by making their way into host cells and then making copies of themselves. This is their main drive; it’s how they spread and survive. It’s in this process of replicating that mistakes can be made – and mutations can arise.
“Anything that’s dividing can mutate – cells, viruses, anything else,” explains Professor Peter Doherty, viral immunologist, Nobel laureate in medicine and patron of the Peter Doherty Institute.
Essentially, it’s a numbers game. “The more viruses out there, the more people are infected, the more mutation you’ll get,” says Doherty.
Some mutations have no effect – the virus basically throws a bunch of stuff to the wall and sees what sticks. “These mutations, sometimes they do nothing, sometimes they’re actually detrimental to the virus, but just every now and then they’re actually beneficial to the virus,” explains Dr Kirsty Short, virologist at the University of Queensland. “So, they’ll let the virus infect better, transmit better, evade the immune response, anything like that.”
Other mutations lead to the opposite outcome. “Losing the ability to bind receptors, for example, those mutations will be a dead end,” explains Dr Mohammed Alsharifi, vaccinologist and virologist at the University of Adelaide.
It’s survival of the fittest – mutations with features that avoid a host’s immune system are more likely to survive and therefore replicate. During a pandemic we see more mutations simply because the virus is more widespread, and infects more people, and thus has more opportunity to replicate – and make errors. “For SARS-CoV-2,” says Professor Raina MacIntyre, head of The Kirby Institute’s biosecurity program, “we also know that the virus can mutate within a person who is immunosuppressed and is infected for prolonged periods of time.”
So, with mutations being so common, when does one become a variant of concern? There isn’t a hard and fast definition but, as a rule of thumb, “it’s something that we think is going to make a difference to how the virus behaves,” says Professor William Rawlinson, senior medical virologist at the University of New South Wales. Particularly, he says, if the mutation affects an area that is a target for therapeutics or vaccines.
All three of the major variants we’ve seen in the past few months have an impact on the spike protein on SARS-CoV-2, which is also the target of vaccines. The vaccines work by making the body recognise the spike protein and start an immune response, preventing the virus from taking hold and making more of itself.
“Any mutation within the spike protein that allows the virus to escape from our pre-existing immunity or from vaccine efficacy, this mutation will be of concern,” says Alsharifi.
“There’s a site on the virus, on the spike protein, called the receptor binding domain,” says Doherty. It’s this site that reacts to a particular molecule on the host cell, allowing the virus to enter and begin replication. “But [the receptor binding domain is] also the main target for antibodies, which can stop that [entry] happening – they’re neutralising antibodies,” he says.
When the body recognises that site, either from vaccination or from previous exposure, it can launch an immune response. However, as Doherty says, “that receptor binding domain is changing”.
The impact of this on vaccine efficacy isn’t clear cut. Mutations cause the spike protein to look slightly different, and so the body may not fully recognise it. But that doesn’t mean it will not respond at all.
Rawlinson points to recent tests of people who have been vaccinated against SARS-CoV-2. “They are still able to neutralise the variants of concern, although they’re slightly less effective,” he says. “So it’s not a dichotomy. It’s not one day your vaccine works, the next day it doesn’t.”
SARS-CoV-2, like influenza and HIV, is an RNA virus, which are generally more prone to mutations than DNA viruses. This is because, traditionally, RNA viruses lack a proofreading enzyme, meaning that as they copy themselves, they aren’t checking for errors. It’s why we don’t have a vaccine for HIV, which changes too quickly. It’s also why we don’t have a cover-all vaccine for influenza – there are too many strains. Instead, predictions are made about what influenza strains are most likely to be circulating and the vaccine is tweaked to target these.
Unusually for an RNA virus, SARS-CoV-2 does actually have a proofreading mechanism, which means it isn’t mutating at as high a rate as influenza – but it is still mutating. Whether this means that, in future, Covid-19 vaccination will follow a similar strategy as we have for influenza is unclear, but it remains open as a possibility.
“It may indicate that we need to be updating our vaccines. But again, we have the capacity to do that,” says Short. “And the beauty of the mRNA technology that underscores the Pfizer vaccine and the Moderna vaccine is that those can be rapidly updated within six weeks or so.”
Rawlinson, too, emphasises the value of the vaccines we have. “Are we concerned? Yes. That’s why they’re called variants of concern,” he says. “Do we think this is the end of the utility of vaccines? No. I think they’re still going to be useful. Does it mean we will have to look at redesigning? Yes, we sort of always knew that.”
While studies on the efficacy of current vaccines against the newest variants are positive – reduced efficacy is still better than no efficacy – Doherty is looking beyond this at the next steps. He points to the increase in coronaviruses more broadly over the past few decades – not just SARS-CoV-2, but also the original SARS and MERS viruses, among others – and flags it as a trend that is likely to continue.
“The problem is, how are we going to open up internationally if the virus keeps changing?” Doherty says. “That’s always been the Australian problem. You know, we’re sort of living in a gilded cage – but how do we get out of the cage?
“My personal view is the international community now needs to put an enormous amount more effort into making very good drugs against this infection. That’s been let slide a bit while people have been focusing on vaccines.”
The vaccine is important, but specific to SARS-CoV-2. Doherty highlights the importance of a broader approach as we look to the future. While eradication would be ideal, we will need a two-pronged strategy – prevention wherever possible, and treatment to mitigate illness and death in those who still get infected.
But until then, as we hear increasing stories about mutations and variants, Rawlinson highlights the importance of keeping things in context. Although the B.1.1.7 strain is reportedly more transmissible, and the other two major variants appear to be more antibody resistant, “mutants aren’t necessarily causing more severe illness. And all the evidence so far, in fact, is that they’re not,” he says.
“Just because it’s more easily spread doesn’t mean that it’s going to cause more severe disease in an individual person. Clearly, if you infect a million people instead of 1000 people, then the chances of getting more severe disease in a larger number occur, but that’s not necessarily a larger percentage,” he says. “And I think, secondly, these mutations are something that we expected – and that we are able to do some things about.”
This article was first published in the print edition of The Saturday Paper on Feb 6, 2021 as "Viral codes".
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