The UK variant emphasizes the role of immunocompromised patients in the COVID-19 pandemic | Science

Buyers are wearing face masks on Regent Street in London on December 19, the day the UK government introduced new restrictions to curb a rapidly expanding new version of SARS-CoV-2.

AP Photo / Alberto Pezzali

Written by Kai Kupferschmidt

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

In June, Ravindra Gupta, a virologist at the University of Cambridge, heard of a cancer patient who had come to a local hospital a month earlier with COVID-19 and was still shedding the virus. The patient was treated for a recurrence of the lymphoma and was given rituximab, a drug that depletes antibody-producing B cells. This made it difficult for him to shake off the SARS-CoV-2 infection.

Gupta, who is studying how HIV drug resistance develops, became interested in the case and helped treat a patient who died in August, 101 days after being diagnosed with COVID-19, despite recovering from the antiviral drug remdesivir and two patient plasma rounds containing antibodies against the virus. When Gupta studied the genome sequences from the coronavirus that infected the patient, he found that SARS-CoV-2 had acquired several mutations that could allow him to avoid antibodies.

Now its analysis, published in a preprint at medRxiv earlier this month, has become a key piece of the puzzle for researchers trying to understand the importance of B.1.1.7, a new variant of SARS-CoV-2 first found in the UK. This strain, which appears to spread faster than the others, contains one of the mutations found by Gupta, and the researchers believe that B.1.1.7 may also have originated in an immunocompromised patient who had a long-term infection. “It’s a perfectly logical and rational hypothesis,” says infectious disease scientist Jeremy Farrar, director of the Charity Fund.

Scientists are still trying to discover the effects of mutations in B.1.1.7, the appearance of which has led the UK government to tighten coronavirus control measures and other countries in Europe to introduce travel bans in the UK. But the new variant, along with research by Gupta et al., Also drew attention to the potential role of people with weakened immune systems in COVID-19. If they give the virus a chance to develop lines that spread faster, are more pathogenic, or evade vaccines, these chronic infections are not only dangerous to patients, but can have the potential to alter the course of a pandemic.

It is still very unclear if this is the case, but Farrar believes it is important to ensure that doctors take extra precautions when caring for such people: “Until we know for sure, we treat these patients under fairly controlled conditions, as we would like someone to who has drug-resistant tuberculosis actually makes sense. “

The researchers’ concern is mainly focused on cancer patients who are being treated for chemotherapy and a similar situation. “For example, we still don’t know about people who are debilitated because of HIV,” Farrar says.

Hinting the future

B.1.1.7 attracted the attention of scientists because it was associated with an outbreak in the English county of Kent that was growing faster than usual. Sequences showed that the virus accumulated a multitude of mutations that together caused 17 amino acid changes in the virus proteins, eight of which in the key spike protein. Among them are at least three of particular concern.

One is 69-70del, an erasure that Gupta also found in his Cambridge in the UK, a patient whose virus seems to be evading the immune system. This leads to the loss of two amino acids in the protein class. In laboratory experiments, Gupta discovered that lentivirus was designed to carry the SARS-CoV-2 class protein with this deletion twice as contagious.

The other is N501Y, a mutation that evolutionary biologist Jesse Bloom of the Fred Hutchinson Center for Cancer Research has shown increases the strength of a protein that binds to the angiotensin-converting enzyme 2 receptor (ACE2), its entry point into human cells. The mutation is also present in 501Y.V2, a variant discovered by researchers in South Africa who investigated rapidly growing epidemics in three coastal provinces. “We found that this lineage seems to be spreading much faster,” says Tulio de Oliveira, a virologist at KwaZulu-Natal University, whose work first alerted British scientists to the importance of the N501Y. “Whenever you see the same mutation being independently selected multiple times, it increases the weight of evidence that that mutation is probably beneficial to the virus in some way,” Bloom says.

A third worrying change is P681H, which changes the place where the protein spike must split in order to enter human cells. It is one of the places on the spike where SARS-CoV-2 differs from SARS-CoV-1, the virus that caused the outbreak of severe acute respiratory syndrome in the world in 2003, and the change there may allow it to spread more easily. “This one is probably as important as the N501Y,” says Christian Drosten, a virologist at Charité University Hospital in Berlin.

So far, SARS-CoV-2 typically achieves only one to two mutations per month. A B.1.1.7 has returned to this rate now, suggesting it does not mutate faster normally than other lineages. Therefore, scientists believe that it may have gone through a long period of evolution in chronically infected patients who transmitted the virus late in their infection. “We know this is rare, but it can happen,” says World Health Organization epidemiologist Maria Van Kerkhove. Stephen Goldstein, a virologist at the University of Utah, agrees. “There are simply too many mutations to accumulate under normal evolutionary circumstances. That suggests a longer period of evolution within the host, ”he says.

People with a weakened immune system can give the virus this opportunity, as Gupta’s data show. More evidence comes from the paper published in New England Journal of Medicine December 3, which described an immunocompromised patient in Boston infected with SARS-CoV-2 for 154 days before he died. Again, the researchers found several mutations, including N501Y. “It suggests that you can get a relatively large number of mutations that occur in a relatively short period of time in an individual patient,” says William Hanage of the Harvard TH Chan School of Public Health, one of the authors. (In patients who are infected for a few days and then clear the virus, there is simply not enough time for that, he says.) When such patients are given treatments against COVID-19 late in the illness, there may already be so many variants present that one of them resistant, Goldstein says.

There are simply too many mutations to accumulate under normal evolutionary circumstances. It suggests a longer period of evolution within the host.

Stephen Goldstein, University of Utah

The question is whether mutations that occur in such patients could help the virus to spread faster. In a study published a few years ago, Bloom showed some of the mutations produced in influenza viruses in immunocompromised patients that later spread globally. “It’s entirely possible that what happens in immunocompromised patients could hint at what’s going to happen in the future,” with a pandemic, Bloom says. But adaptations that help the virus outperform other viruses in a patient can also be very different from what the virus needs for better transmission from patient to patient, he says.

British scientists and others were initially cautious when they concluded that mutations B.1.1.7 made the virus spread better from person to person. But the new variant is rapidly replacing other viruses, says Müge Çevik, a infectious disease specialist at St. Petersburg University. Andrews. “We can’t really rule out that seasonality and human behavior explain some of the increases,” she says. “But it certainly seems to have something to do with this variant.” Drosten says he was suspicious at first, but also became more confident.

But exactly what impact each mutation has is much harder to assess than to spot or show that they are on the rise, says Seema Lakdawala, a biologist at the University of Pittsburgh. Animal experiments can help show the effect, but they have limitations. Hamsters, for example, are already rapidly transmitting the SARS-CoV-2 virus, which could mask any effect of the new variant. Ferrets transmit it less efficiently, so the difference may be easier to detect, Lakdawala says. “But does it really translate for people?” I doubt it. ”The final answer could be months free, she predicts.

One of the hypotheses that scientists are discussing is that the virus has increased how strongly it binds to the ACE2 receptor on human cells, and that this allows it to infect children better than before, expanding its playing field. But the evidence for that is very thin so far, says Cevik. Even if it turns out that children make up a larger proportion of people infected with the new variant, it could be because the variant spread at the time the lock-in occurred, but schools were open. Another hypothesis is that P681H helps the virus to better infect cells more in the respiratory tract, from where it can spread more easily than from the deep lungs, Drosten says.

There is no reason for madness

One important question is whether the lineage of South Africa or the UK can lead to a more serious disease or even avoid vaccine-induced immunity. So far, there is little reason to think so. Although some mutations have been shown to allow the virus to avoid monoclonal antibodies, both vaccines and natural infections appear to lead to a broad immune response that targets many parts of the virus, says Shane Crotty of the La Jolla Institute of Immunology. “It would be a real challenge for the virus to escape from that.” Measles and polio viruses have never learned to avoid vaccines that target them, he notes: “These are historical examples that suggest that you should not go crazy.”

At yesterday’s press conference, BioNTech CEO Uğur Şahin pointed out that the British variant differs in just nine of the more than 1,270 amino acids of the classic RNA-encoded RNA protein in a highly effective COVID-19 vaccine developed by his company with Pfizer. “It is scientifically very likely that the immune response of this vaccine can also be carried by the new virus,” he said. Experiments are underway that should confirm this in the first week of 2021, Şahin added.

Sebastien Calvignac-Spencer, an evolutionary virologist at the Robert Koch Institute, says this is the first time countries have taken such drastic actions as locking the UK and travel bans based on genomic surveillance combined with epidemiological data. “It’s pretty unprecedented on this scale,” he says. But the question of how to respond to disturbing mutations in pathogens will emerge more often as gene control expands, he predicts. People are happy to have prepared for a Category 4 hurricane, even if the predictions turn out to be wrong and the storm is less strong, Calvignac-Spencer says. “This is a bit the same, except we have a lot less experience with genomic surveillance than we have with weather forecasting.”

While the rise in B.1.1.7 in the UK is worrying, Farrar says he is equally concerned about another variant that is spreading rapidly in South Africa, which has now been discovered in two travelers in the UK. It involves two further mutations in the portion of the spike protein that binds to its receptor on human cells, K417N and E484K. This could affect the binding of the virus to human cells, as well as its recognition by the immune system, Farrar says. “These South African mutations I think are worrying from the constellation of the British variant.” South African hospitals are already having problems, he adds. “We always asked,‘ Why has sub-Saharan Africa avoided a pandemic to this day? “The answers focused on the relative youth of the population and the climate.” Maybe if you increase the transmission a little, that’s enough to overcome these factors, “says Farrar.

Van Kerkhove’s arrival of B.1.1.7 shows how important it is to closely monitor viral evolution. The United Kingdom has one of the most complex tracking systems in the world, she says. “My concern is: How much of this is happening globally, where we don’t have the sequencing capacity?” Other countries should step up efforts, she says. And all countries should do everything in their power to reduce SARS-CoV-2 transmission in the coming months, Van Kerkhove says. “The more of this virus circulates, the more opportunities there will be for change,” she says. “We’re playing a very dangerous game here.”