New SARS-CoV-2 Mutations Emerge in Patient with Cancer and COVID-19

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RNA strands inside corona virus
[Source: Joao Paulo Burini/Getty Images]

The SARS-CoV-2 virus acquired new mutations in a patient who was treated for the infection for about 100 days in a British hospital who also had marginal B cell lymphoma. At least one of these mutations appears to allow the virus to escape antibodies against it, actually making it more resistant. This finding raises concerns about whether immune-compromised patients should receive antibody-treatments, such as convalescent plasma, and how they will respond to vaccines.

The patient, a seventy-year-old  man, had received chemotherapy prior to this hospitalization, so his immune system was weakened. After being given remdesivir during the first 57 days, he was switched to rounds of convalescent plasma. During the duration of his hospitalization he was regularly tested for the virus, and those samples underwent ultra-deep sequencing, which is how the mutations were noticed.

The report of these findings is in last week’s issue of Nature. The study’s senior author is Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology & Infectious Disease in the UK. https://www.nature.com/articles/s41586-021-03291-y

The mutations that arose during the patient’s hospitalization were not present during the earlier phase of his illness. They only arose after he was given convalescent therapy.  Notably, one of the mutations researchers found was one that was also seen in the new B.1.1.7 UK variant, which forced that country into lockdown recently.

Specifically, after the plasma therapy began, the researchers reported seeing “large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein.” When plasma therapy was paused, viruses carrying the mutations that helped them escape the antibodies were reduced in number. After a final course of plasma, the “escape” antibodies prevailed again.

“What we were seeing was essentially a competition between different variants of the virus, and we think it was driven by the convalescent plasma therapy,” says  Gupta. “The virus that eventually won out – which had the D796H mutation and ΔH69/ΔV70 deletions—initially gained the upper hand during convalescent plasma therapy before being overtaken by other strains, but re-emerged when the therapy was resumed. One of the mutations is in the new UK variant, though there is no suggestion that our patient was where they first arose.”

Under strictly-controlled conditions, the researchers created and tested a synthetic version of the virus with the ΔH69/ΔV70 deletions and D796H mutations both individually and together. The combined mutations made the virus less sensitive to neutralization by convalescent plasma, though it appears that the D796H mutation alone was responsible for the reduction in susceptibility to the antibodies in the plasma. The D796H mutation alone led to a loss of infection in absence of plasma, typical of mutations that viruses acquire in order to escape from immune pressure.

The researchers found that the ΔH69/ΔV70 deletion by itself made the virus twice as infectious as the previously dominant variant, and they believe the role of the deletion was to compensate for the loss of infectiousness due to the D796H mutation. This paradigm is classic for viruses, whereby escape mutations are followed by or accompanied by compensatory mutations.

“Given that both vaccines and therapeutics are aimed at the spike protein, which we saw mutate in our patient, our study raises the worrying possibility that the virus could mutate to outwit our vaccines,” says Gupta.

“This effect is unlikely to occur in patients with functioning immune systems, where viral diversity is likely to be lower due to better immune control. But it highlights the care we need to take when treating immunocompromised patients, where prolonged viral replication can occur, giving greater opportunity for the virus to mutate.”

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