There is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+ T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.
Ugur Sahin, CEO of BioNTech that is collaborating with Pfizer for a coronavirus vaccine candidate, has said that he expects the virus to be around for the next 10 years. He, talking at a press conference, however, sounded hopeful that a 'new normal' would set in by the end of summer.
When asked about when he believes the world will return to normal, Sahin said, "We need a new definition of 'normal'. The virus will stay with us for the next 10 years. We need to get used to the fact there'll be more outbreaks."
The 'new normal', Sahin explained, would mean that countries do not have to go under lockdown. "This winter, we will not have an impact on the infection numbers. But we must have an impact so that next winter can be the new normal," he said.
Talking about whether vaccinating 60-70 per cent of the world's population would prevent future outbreaks, Sahin said that if the virus mutates, a higher uptake of the vaccine would be required to return to normal.
BioNTech is aiming to find if the vaccine is effective against the new strain of coronavirus discovered in the UK. Sahin said that the company would need another two weeks to see if the vaccine can stop the mutant coronavirus strain. He said that scientifically it is likely that the immune response generated by the vaccine can deal with the virus. Sahin said that the BioNTech vaccine contains over 1,270 amino acids and only nine of them are changed in the mutant virus. He said that 99 per cent of the protein is still the same.
The new coronavirus strain has caused panic around the globe. More than 40 countries have suspended their flights to and from the UK. In India, separate SOPs have been issued for passengers who have arrived from the country. UK passengers are also rigorously tracked and tested to ensure there is no coronavirus symptom.
Dr.Gianrico Farrugia, CEO of the Mayo Clinic, is urging Americans to take the first Covid-19 vaccine available to them.
“My message is very simple: Don’t wait for a particular vaccine,” he told CNBC’s “Squawk Box” on Tuesday. “Get the first vaccine that is offered because their benefits far outweigh any potential risk.”
Two coronavirus vaccines have been approved in the U.S. by the Food and Drug Administration for emergency use — one developed by Pfizer and BioNTech and the other from Moderna. The Moderna vaccine, after receiving limited clearance Friday, is being rolled out this week. The first Americans outside of clinical trials started receiving shots of the Pfizer vaccine last week.
Currently, health-care workers and residents of long-term care facilities are receiving priority in the initial round of vaccinations. However, as the number of available doses increases, a broader range of people will become eligible to be immunized. On Sunday, a Centers for Disease Control and Prevention panel recommended that front-line essential workers and people 75 years of age and older be next in line.
Doctor Diana Rodriguez receives the Covid-19 vaccine with the first batch of Moderna’s vaccine at Hartford hospital in Hartford, Connecticut on December 21, 2020.
Joseph Prezioso | AFP | Getty Images
The vaccines from Pfizer-BioNTech and Moderna, which both are two shots, demonstrated strong efficacy in clinical trials. Pfizer reported efficacy of 95% in its large-scale study, while Moderna’s vaccine was more than 94% effective at preventing Covid.
“To have a vaccine that is 95% effective, as the two vaccines we currently have are, is a medical marvel,” said Farrugia, who has led the Rochester, Minnesota-based Mayo Clinic since January 2019.
Other vaccines may receive FDA clearance next year, which could help expand the pool of Americans who could receive the shots. Johnson & Johnson expects to receive data from its late-stage vaccine trial early next year and potentially apply for emergency use authorization in February.
The vaccines come at a critical moment in the global pandemic. As of Monday, the nation’s seven-day average of new infections was 215,429, the sixth highest ever, according to a CNBC analysis of data compiled by Johns Hopkins University. The record high came last week. The latest seven-day average of daily new U.S. deaths was 2,655, the worst run-rate yet.
“It is essential that people get educated and then they get vaccinated. It’s the only way we’re going to get out of this pandemic,” Farrugia said.
In June, Ravindra Gupta, a virologist at the University of Cambridge, heard about a cancer patient who had come into a local hospital the month before with COVID-19 and was still shedding virus. The patient was being treated for a lymphoma that had relapsed and had been given rituximab, a drug that depletes antibody-producing B cells. That made it hard for him to shake the infection with SARS-CoV-2.
Gupta, who studies how resistance to HIV drugs arises, became interested in the case and helped treat the patient, who died in August, 101 days after his COVID-19 diagnosis, despite being given the antiviral drug remdesivir and two rounds of plasma from recovered patients, which contained antibodies against the virus. When Gupta studied genome sequences from the coronavirus that infected the patient, he discovered that SARS-CoV-2 had acquired several mutations that might have allowed it to elude the antibodies.
Now, his analysis, reported in a preprint on medRxiv earlier this month, has become a crucial puzzle piece for researchers trying to understand the importance of B.1.1.7, the new SARS-CoV-2 variant first found in the United Kingdom. That strain, which appears to spread faster than others, contains one of the mutations that Gupta found, and researchers believe B.1.1.7, too, may have originated in an immunocompromised patient who had a long-running infection. “It’s a perfectly logical and rational hypothesis,” says infectious disease scientist Jeremy Farrar, director of the Wellcome Trust.
Scientists are still trying to figure out the effects of the mutations in B.1.1.7, whose emergence led the U.K. government to tighten coronavirus control measures and other countries in Europe to impose U.K. travel bans. But the new variant, along with research by Gupta and others, has also drawn attention to the potential role in COVID-19 of people with weakened immune systems. If they provide the virus with an opportunity to evolve lineages that spread faster, are more pathogenic, or elude vaccines, these chronic infections are not just dangerous for the patients, but might have the potential to alter the course of the pandemic.
It’s still very unclear whether that is the case, but Farrar believes it’s important to ensure doctors take extra precautions when caring for such people: “Until we know for sure, I think, treating those patients under pretty controlled conditions, as we would somebody who has drug resistant tuberculosis, actually makes sense.”
Researchers’ concern mostly focuses on cancer patients being treated for chemotherapy and similar situations. “We don’t yet know about people who are immunocompromised because of HIV, for instance,” Farrar says.
Foreshadowing the future
B.1.1.7 attracted scientists’ attention because it was linked to an outbreak in England’s Kent county that was growing faster than usual. Sequences showed that virus had accumulated a slew of mutations that together caused 17 amino acid changes in the virus’ proteins, eight of them in the crucial spike protein. Among them are at least three particularly concerning ones.
One is 69-70del, a deletion that Gupta also found in his Cambridge, U.K., patient whose virus seemed to evade the immune system. It leads to the loss of two amino acids in the spike protein. In lab experiments, Gupta found that lentivirus engineered to carry the SARS-CoV-2 spike protein with this deletion was twice as infectious.
The second is N501Y, a mutation that evolutionary biologist Jesse Bloom of the Fred Hutchinson Cancer Research Center has shown to increase how tightly the protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor, 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 outbreaks in three coastal provinces. “We found that this lineage seems to be spreading much faster,” says Tulio de Oliveira, a virologist at the University of KwaZulu-Natal whose work first alerted U.K. scientists to the importance of N501Y. “Anytime you see the same mutation being independently selected multiple times, it increases the weight of evidence that that mutation is probably beneficial in some way for the virus,” Bloom says.
The third worrisome change is P681H, which alters the site where the spike protein has to be cleaved to enter human cells. It is one of the sites on spike where SARS-CoV-2 differs from SARS-CoV-1, the virus that caused the worldwide outbreak of severe acute respiratory syndrome in 2003, and the change there may allow it to spread more easily. “This one is probably as important as N501Y,” says Christian Drosten, a virologist at Charité University Hospital in Berlin.
So far, SARS-CoV-2 typically acquires only one to two mutations per month. And B.1.1.7 is back to this pace now, suggesting it doesn’t mutate faster normally than other lineages. That’s why scientists believe it may have gone through a lengthy bout of evolution in a chronically infected patient who then 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. “It’s simply too many mutations to have accumulated under normal evolutionary circumstances. It suggests an extended period of within-host evolution,” he says.
People with a weakened immune system may give the virus this opportunity, as Gupta’s data show. More evidence comes from a paper published in The New England Journal of Medicine on 3 December that 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 relatively large numbers of mutations happening over a relatively short period of time within an individual patient,” says William Hanage of the Harvard T.H. Chan School of Public Health, one of the authors. (In patients who are infected for a few days and then clear the virus, there simply is not enough time for this, he says.) When such patients are given antibody treatments for COVID-19 late in their disease course, there may already be so many variants present that one of them is resistant, Goldstein says.
It’s simply too many mutations to have accumulated under normal evolutionary circumstances. It suggests an extended period of within-host evolution.
The question is whether the mutations arising in such patients could also help the virus spread more rapidly. In research published a few years ago, Bloom showed some of the mutations that arose in influenza viruses in immunocompromised patients later spread globally. “It’s totally possible that what’s happening in immunocompromised patients could foreshadow what happens in the future” with the pandemic, Bloom says. But adaptations that help a virus outperform other viruses in a patient can also be very different from what a virus needs to better transmit from patient to patient, he says.
U.K. scientists and others were initially cautious about concluding that B.1.1.7’s mutations made the virus better at spreading from person to person. But the new variant is rapidly replacing others, says Müge Çevik, an infectious disease specialist at the University of St. Andrews. “We can’t really rule out the possibility that seasonality and human behavior explain some of the increase,” she says. “But it certainly seems like there is something to do with this variant.” Drosten says he was initially skeptical, but has become more convinced as well.
But exactly what impact each mutation has is much more difficult to assess than spotting them or showing they’re on the rise, says Seema Lakdawala, a biologist at the University of Pittsburgh. Animal experiments can help show an effect, but they have limitations. Hamsters already transmit SARS-CoV-2 virus rapidly, for instance, which could obscure any effect of the new variant. Ferrets transmit it less efficiently, so a difference may be more easily detectable, Lakdawala says. “But does that really translate to humans? I doubt it.” A definitive answer may be months off, she predicts.
One hypothesis 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 better infect children than before, expanding its playing field. But the evidence for that is very thin so far, Çevik says. Even if children turn out to make up a higher proportion of people infected with the new variant, that could be because the variant spread at a time when there was a lockdown but schools were open. Another hypothesis is that P681H helps the virus better infect cells higher up in the respiratory tract, from where it can spread more easily than from deep in the lungs, Drosten says.
No reason to freak out
One important question is whether the South African or U.K. lineage might lead to more severe disease or even evade vaccine-induced immunity. So far there is little reason to think so. Although some mutations have been shown to let the virus evade monoclonal antibodies, vaccines and natural infections both appear to lead to a broad immune response that targets many parts of the virus, says Shane Crotty of the La Jolla Institute for Immunology. “It would be a real challenge for a virus to escape from that.” The measles and polio viruses have never learned to escape the vaccines targeting them, he notes: “Those are historical examples suggesting not to freak out.”
At a press conference yesterday, BioNTech CEO Uğur Şahin pointed out that the U.K. variant differed in only nine out of more than 1270 amino acids of the spike protein encoded by the messenger RNA in the very effective COVID-19 vaccine his company developed together with Pfizer. “Scientifically it is highly likely that the immune response by this vaccine also can deal with the new virus,” he said. Experiments are underway that should confirm that in the first week of 2021, Şahin added.
Sébastien Calvignac-Spencer, an evolutionary virologist at the Robert Koch Institute, says this marks the first time countries have taken such drastic actions as the U.K. lockdown and the travel bans based on genomic surveillance in combination with epidemiological data. “It’s pretty unprecedented at this scale,” he says. But the question of how to react to disconcerting mutations in pathogens will crop up more often as genomic surveillance expands, he predicts. People are happy they prepared for a category 4 hurricane even if predictions turn out to be wrong and the storm is less severe, Calvignac-Spencer says. “This is a bit the same, except that we have much less experience with genomic surveillance than we have with the weather forecast.”
Although the rise of B.1.1.7 in the United Kingdom is troubling, Farrar says he is equally concerned about the other variant spreading quickly in South Africa and that has now been detected in two travelers in the United Kingdom as well. It includes two further mutations in the part of the spike protein that binds to its receptor on human cells, K417N and E484K. These could impact the binding of the virus to human cells and also its recognition by the immune system, Farrar says. “These South African mutations I think are more worrying than the constellation of the British variant.” South African hospitals are already struggling, he adds. “We’ve always asked, ‘Why has sub-Saharan Africa escaped the pandemic to date?” Answers have focused on the relative youth of the population and the climate. “Maybe if you just increase transmission a bit, that is enough to get over these factors,” Farrar says.
To Van Kerkhove, the arrival of B.1.1.7 shows how important it is to follow viral evolution closely. The United Kingdom has one of the most elaborate monitoring systems in the world, she says. “My worry is: How much of this is happening globally, where we don’t have sequencing capacity?” Other countries should beef up their efforts, she says. And all countries should do what they can to minimize transmission of SARS-CoV-2 in the months ahead, Van Kerkhove says. “The more of this virus circulates, the more opportunity it will have to change,” she says. “We’re playing a very dangerous game here.”
