University Of Cambridge Study Shows Neutralizing Antibodies Are Driving Mutations Of Spike Mediated SARS-CoV-2 Evasion Including In B.1.1.7 Variant

Some of the mutations on the B.1.1.7 U.K. variant are actually the result of neutralizing antibodies induced spike protein mutations and warrants concerns according to a new study led by scientist from University of Cambridge that is published on a preprint server and is currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v2


 
SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs.
 
The study team reported the fatal SARS-CoV-2 escape from neutralizing antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days.
 
Little evolutionary change was observed in the viral population over the first 65 days despite two courses of remdesivir.
 
However, following convalescent plasma the team observed dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 NTD of the Spike protein. As serum neutralisation waned, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. 
 
In vitro, the Spike escape variant conferred decreased sensitivity to multiple units of convalescent plasma/sera from different recovered patients, whilst maintaining infectivity similar to wild type.
 
The study findings data reveal strong positive selection on SARS-CoV-2 during convalescent plasma therapy and identify the combination of Spike mutations D796H and ΔH69/ΔV70 as a broad antibody resistance mechanism against commonly occurring antibody responses to SARS-CoV-2.
 
Corresponding and lead author Dr Ravindra Gupta, a virologist at the University of Cambridge, initially 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.
 
Dr Gupta, a leading authority on HIV drug resistance 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.
 
Interestingly when Dr 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.
 
His study findings 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. https://www.thailandmedical.news/news/emerging-sars-cov-2-variants-in-uk-like-the-b-1-1-7-strain-and-the-501-v2-strain-in-south-africa-and-elsewhere-will-change-course-of-covid-19-badly
 
https://www.thailandmedical.news/news/u-s-cdc-indicates-that-vaccines-might-not-protect-against-new-uk-variant-b-1-1-7-new-details-show-new-variant-could-be-the-expected-super-strain
 
The B.1.1.7 UK variant 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.
 
Infectious disease scientist Dr Jeremy Farrar, director of the Wellcome Trust  said, “It’s a perfectly logical and rational hypothesis.”
 
Researchers 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.
 
However the new variant, along with research by Dr 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.
 
To date that is still very unclear whether that is the case, but Dr Farrar believes it’s important to ensure doctors take extra precautions when caring for such people:
 
He said,“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.”
 
Scientists concern mostly focuses on cancer patients being treated for chemotherapy and similar situations.
 
Bur Dr Farrar added,  “We don’t yet know about people who are immunocompromised because of HIV, for instance.”
 
The new UK variant B.1.1.7 attracted researchers’ 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 23 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.
 
Alarmingly 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. https://www.thailandmedical.news/news/new-mutations-exhibiting-sars-cov-2-spike-deletion-h69-v70-that-can-escape-immune-recognition-fast-becoming-prevalent
 
The B.1.1.7 variant had a mutation N501Y, a mutation that evolutionary biologist Dr 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. https://www.thailandmedical.news/news/coronavirus-news-new-sars-cov-2-variant-with-n501y-mutation-in-receptor-binding-motif-of-the-spike-protein-fast-becoming-prevalent-in-uk
 
This mutation is also present in 501Y.V2, a variant discovered by researchers in South Africa who investigated rapidly growing outbreaks in three coastal provinces.
 
Dr Tulio de Oliveira, a virologist at the University of KwaZulu-Natal whose work first alerted U.K. scientists to the importance of N501Y added, We found that this lineage seems to be spreading much faster.”
 
Dr Bloom warned, “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.”
 
Another worrisome mutation on the B.1.1.7 strain 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.
 
Typically the SARS-CoV-2 virus only acquires only one to two mutations per month. The B.1.1.7 is back to this pace now, suggesting it doesn’t mutate faster normally than other lineages.
 
This is 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.
 
World Health Organization epidemiologist Dr Maria Van Kerkhove. Stephen Goldstein, a virologist at the University of Utah, said, “We know this is rare but it can happen It’s simply too many mutations to have accumulated under normal evolutionary circumstances. It suggests an extended period of within-host evolution.”
 
Individuals with a weakened immune system may give the virus this opportunity, as Gupta’s data show.
 
A previous study 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. https://www.nejm.org/doi/full/10.1056/NEJMc2031364
 
Dr William Hanage of the Harvard T.H. Chan School of Public Health, one of the authors said, “It suggests that you can get relatively large numbers of mutations happening over a relatively short period of time within an individual patient. In patients who are infected for a few days and then clear the virus, there simply is not enough time for this.
 
The key question is whether the mutations arising in such patients could also help the virus spread more rapidly.
 
In another past research Dr Bloom showed some of the mutations that arose in influenza viruses in immunocompromised patients later spread globally. https://elifesciences.org/articles/26875
 
Dr Bloom said, “It’s totally possible that what’s happening in immunocompromised patients could foreshadow what happens in the future with the pandemic.”
 
However 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 said.
 
Initially 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.
 
However the new variant is rapidly replacing others, says Dr Müge Çevik, an infectious disease specialist at the University of St. Andrews.
 
However exactly what impact each mutation has is much more difficult to assess than spotting them or showing they’re on the rise, says Dr 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, Dr Lakdawala says. “But does that really translate to humans? I doubt it.” A definitive answer may be months off, she predicts.
 
A current 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.
 
However the evidence for that is very thin so far, Dr 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.
 
According to Dr Van Kerkhove from the WHO, 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?”
 
Importantly 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, Dr 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.”
 
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