For more than three months the patient struggled against Covid-19. His immune system was already in a bad way when he caught the virus – he had been receiving a drug treatment for lymphoma, a type of blood cancer, that depleted some of his immune cells. With fewer of the usual defences against infection, the virus was able to spread in his body relatively unchecked.
As doctors tried to help the elderly patient fight the virus, they gave him blood plasma collected from people who had already recovered from Covid-19. Contained within this milky-brown liquid – also known as convalescent plasma – were antibodies against the virus that might help to neutralise it.
Over the course of 101 days as they treated the man, clinicians at Addenbrookes Hospital in Cambridge, UK, took 23 swab samples as he fought against the disease. Each swab was sent off to a nearby laboratory to be analysed. But when virologists looked at the virus’s genetic material in the samples, they noticed something astonishing – Covid-19 was evolving before their eyes.
"We saw some remarkable changes in the virus over that time," says Ravinda Gupta, an infectious diseases consultant at the hospital and a clinical microbiologist at the University of Cambridge who analysed the patient’s samples. "We saw mutations that seemed to suggest the virus was showing signs of adaptation to avoid the antibodies in the convalescent plasma treatment. It was the first time we had seen something like this happening in a person in real time."
Nearly a year after the global Covid-19 pandemic started, the issue of mutations looms large. New variants capable of spreading faster are emerging and leading to inevitable questions about whether they will make the newly approved vaccines less effective. To date, there is little evidence they are, but scientists are already starting to explore how the Covid-19 virus will mutate in the future and whether they might be able to head it off. In the first of a two part series looking at Covid-19 mutations, we look at what they have learned so far.
The worldwide effort to test and sequence samples of Covid-19 is helping to reveal new variants as they emerge (Credit: Jeff Pachoud/Getty Images)
Among the mutations Gupta and his colleagues identified was a deletion of two amino acids – known as H69 and V70 – in the spike protein sitting on the outside of the Covid-19 virus. This protein plays a key role in the ability of the coronavirus to infect cells.
The oily capsule that surrounds most of the virus is studded with these spikes sticking outwards, making it look like a crown when viewed through an electron microscope. It is this appearance that gives the coronavirus family its name – corona is Latin for crown. The spikes are also the main way Covid-19 recognises the cells it can infect and helps the virus penetrate them.
When Gupta and his team looked closer at the spike protein deletion they had spotted, it produced worrying results. "We did some infection experiments using artificial viruses and they showed that the H69/V70 deletion mutation increases the infectivity by twofold," says Gupta. This prompted the researchers to scour the international genetic databases of Covid-19. There they found that something more alarming was taking place.
"We wanted to see what was happening worldwide and we stumbled upon this big expanding group of [H69/V70 deletion] sequences in the UK," says Gupta. "When we looked more closely, we found that there was a new variant causing a big outbreak."
Even as they made this discovery in early December last year, infectious disease experts elsewhere in England were struggling to understand rapidly rising case numbers in London and the south-east of England despite a national lockdown. They started to notice something strange in the results of Covid-19 tests being carried out on samples.
To me these seem like a glimpse into the future where we are going to be in an arms race with this virus – Michael Worobey
The main diagnostic tool for Covid-19 has been polymerase chain reaction (PCR) tests, which search for traces of the virus's genetic material in samples. Usually, it targets three parts of the virus to confirm the presence of an infection. But one of these targets was increasingly coming back negative in samples from the areas of England with rapidly rising case numbers, while the other two targets in the tests continued to work.
"We were not missing cases but it is unusual to see two of the tests working but a third not," Wendy Barclay, a virologist at Imperial College London and a member of the UK’s New and Emerging Respiratory Virus Threats Advisory Group, told the BBC’s Today programme on 22 December.
The part of the virus that this part of the PCR test targeted was a sequence on the spike protein. When the scientists delved deeper, they found that the virus in these samples had picked up a mutation – a deletion at the same H69 and V70 positions in the protein seen by Gupta – that meant the PCR test was failing to pick it up sometimes.
Alongside this genetic change, they also found 16 other mutations that had altered the viral proteins they coded for, including several on the spike protein. What they had discovered was a new lineage of the Covid-19 virus that had picked up multiple mutations over a relatively short period of time. They designated it B117 – the new British Covid-19 variant, also known as VOC 202012/01 in the messy world of coronavirus nomenclature. It has cut a swathe across the UK and had spread to 50 other countries by mid-January.
The spike proteins (red) that stud the surface of the Covid-19 virus help it to get inside cells, but are also targetted antibodies (Credit: CDC/Getty Images)
The emergence of this new variant – which is estimated to be 50-75% more transmissible than the original Covid-19 virus – along with others now being detected such as the South African and Brazilian variants, has shone a spotlight on how the coronavirus is mutating as the pandemic rumbles on. It has also raised concerns about how it might continue to change in the future as we try to fight it with vaccines.
"To me these seem like a glimpse into the future where we are going to be in an arms race with this virus, just like we are with flu," says Michael Worobey, a viral evolutionary biologist at the University of Arizona. Each year the flu vaccine has to be updated as the influenza virus mutates and adapts to escape the immunity already present in the population, says Worobey. If the coronavirus shows similar capabilities, it could mean we will have to adopt similar tactics to keep it at bay, by regularly updating vaccines.
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Many believe that drug companies should already be updating their vaccines to target mutated versions of the Covid-19 spike protein. But can the patterns of mutations scientists are seeing popping up in Covid-19 around the world offer any clues about how the virus will continue to evolve?
"It is hard to speculate, but it is interesting that all of a sudden there does seem to be a lot of mutations appearing that could be associated with immune escape or immune recognition," says Brendan Larsen, a PhD student working with Worobey in Arizona. He recently identified a new variant of Covid-19 circulating in Arizona that has the H69/V70 deletion seen in several other versions of the virus. While still only spreading at a relatively low level there and in other states of the US, it suggests that this particular mutation is recurring independently around the world, says Larsen.
This repeated occurrence of the same mutations in different variants provides some clues as to what is going on – as the virus has spread through millions of people, it may be facing similar evolutionary pressures that are causing it to change in particular ways.
In most viruses and disease-causing bacteria, the use of treatments and vaccines causes them to evolve ways of escaping them so they can continue to spread
"By themselves they are likely to have a minor impact overall," says Larson. "But together all of these different mutations might make it more difficult for the immune system to recognise the virus." This could then lead to more patients catching the disease twice and perhaps also mean the vaccines may need to be altered.
"Even a relatively small amount of immune escape could make it harder to achieve herd immunity," adds Worobey.
Researchers in Illinois have also recently identified another new variant, called 20C-US, which has a number of unique and specific mutations that may alter the virus’s ability to replicate itself once inside human cells. It also features a mutation close to a site on the Covid-19 spike protein that is thought to have been crucial in allowing the virus to jump species to humans towards the end of 2019.
This site, known as a furin cleavage site, allowed the virus to hijack an important enzyme that operates in the human body. The enzyme snips open the spike protein at this point, causing it to open out and reveal hidden sequences that help it to bind more tightly to cells in the human respiratory tract, among others. A mutation close to this site could alter this behaviour further, the researchers say.
There are concerns that as Covid-19 continues to mutate, it could adapt in ways that make the current vaccines less effective (Credit: Joris Verwijst/Getty Images)
The researchers behind the study say 20C-US has been spreading rapidly through the US since June, and predict it could soon become the dominant variant of Covid-19 in the US.
In early January, another closely related new variant appeared in California, called CAL.20C. There were more than 1,000 cases of this variant reported at the start of February and in Los Angeles accounts for a quarter to one third of all Covid-19 cases. There are also reports of this variant infecting people who have already been infected with a different variant of the virus last year. One of the mutations carried by CAL.20C, called L452R, is found on the spike protein and has been associated with a decreased sensitivity to antibodies, suggesting it may be able to evade parts of the immune system.
Recently, scientists at the University of Manitoba, in Winnipeg, Canada, also identified two emerging variants that have been spreading around the world and are associated with "high fatality rates" compared to the earlier virus. One features a mutation called V1176F in the spike protein, which occurs alongside another mutation called D614G.
The first letter in these mutation names indicates the amino acid that has been replaced, the number is its location on the protein, and the final letter is the new amino acid that has appeared at that site. The D614G mutation alone appeared relatively early on in the pandemic in Europe and caused a dramatic increase in how much virus was shed by patients it infected, helping it to spread more quickly. The addition of the V1176F mutation may alter this behaviour further, the Canadian researchers say, and it has appeared in several countries independently, suggesting it gives the virus an advantage.
The other variant they identified appeared rapidly in Australia and carries a S477N mutation, which seems to have increased the virus's ability to bind to human cells.
The researchers warn that these two new mutations "may pose significant public health concerns in the future" if they continue to spread and provide the virus with an advantage. They add that Covid-19 appears to be "evolving non-randomly and human hosts shape emergent variants with positive fitness that can easily spread into the population".
Researchers in the UK have also recently noticed a mutation called E484K – which is thought to reduce the virus's vulnerability to antibodies in the South African and Brazilian variants – has appeared in some samples of the British variant B117. Although only in a handful of cases so far, it is raising concerns that the faster spreading British variant may also now pick up some ability to escape the immune systems of those who have been vaccinated or already infected.
Another variant of concern found to be circulating in New York in February 2021 has also worried scientists. This variant, designated B1.526, has been increasing in numbers and by mid-February accounted for 12.3% of the viruses analysed. It contains two key mutations – E484K and N501Y – that were also seen in the variants of concern from Brazil and South Africa.
These signs of adaptation by the virus are not entirely surprising to scientists. In most viruses and disease-causing bacteria, the use of treatments and vaccines causes them to evolve ways of escaping them so they can continue to spread. Those that develop resistance to a treatment or can hide from the immune system will survive for longer to replicate and so spread their genetic material.
"I do not see a reason that this evolutionary selective process would differ in a pandemic such as Sars-CoV-2 [the Covid-19 virus], compared to a geographically contained epidemic," says Carolyn Williamson, head of the division of virology at the University of Cape Town and one of the researchers who identified a rapidly spreading South African variant in December. "One could speculate that the virus being exposed to different selective pressures in different regions of the world, together with rapid spread, may see these more favourable properties emerge more quickly, but we really don’t know."
Efforts to spot new variants of Covid-19 as early as possible include testing sewage samples in cities like Belo Horizonte in Brazil (Credit: Douglas Magno/Getty Images)
There could, of course, be other concerning versions of Covid-19 circulating in populations where the genetic sequencing needed to detect them is not readily available. One of the reasons why the UK picked up the B117 variant in the first place is because of its world-leading testing and sequencing setup.
"If new variants emerge in a country where there isn't much genome sequencing, it could be a real problem," says Larson.
One group of Chinese scientists used artificial viruses to test for mutations in the spike protein that could lead the virus to become resistant to antibodies taken from patients who had recovered from Covid-19. They found five mutations that did this, but one in particular – N234Q – dramatically increased the level of resistance to antibodies. Although this has yet to be seen in any of the variants of concern circulating around the world.
Their study, however, also offers some hope as identifying these changes could be useful in the development of future vaccines.
But as scientists watch the virus continue to change over the coming months, they will also be acutely aware of the many personal tragedies that lie behind the databases of virus genomes and graphs showing their spread. More than two million people have lost their lives to Covid-19 so far. Among them is the elderly man who was treated by Gupta’s colleagues at Addenbrookes hospital after his lymphoma treatment.
"He had been given a terminal cancer diagnosis but managed to survive for 10 years before Covid-19 turned up," says Gupta.
* This article has been updated on 9 February 2021 to add details about the CAL.20C variant and also the E484K mutation appearing in B117 samples in the UK.
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