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expert reaction to paper on SARS-CoV-2 mutations arising during treatment of chronic infection

A study published in Nature looks at the evolution of SARS-CoV-2 during treatment of chronic infection.


Dr Simon Clarke, Associate Professor in Cellular Microbiology, University of Reading, said:

“This latest paper in Nature provides a fascinating insight into the real-time mutation of the coronavirus in a single patient. Sadly, the patient died, and for the rest of us, this is a demonstration about the sneakiness of this virus to simultaneously evade the immune system and stay infectious.

“In this case, the virus acquired a mutation to help it escape antibodies, which also had the effect of making it less infectious.  To compensate for that, another mutation occurred to counterbalance that defect, so the virus maintained its infectiousness.

“The authors believe that such events are less likely to occur in people with fully functioning immune systems, which seems entirely plausible.  But it should not be forgotten that people with weakened immune systems account for a significant proportion of those who suffer most with Covid-19.  And while mutations like these may be more likely to arise in such unfortunate individuals, the consequences for their escape into the general population are potentially severe for everyone.”


Dr Julian Tang, Honorary Associate Professor/Clinical Virologist, University of Leicester, said:

“So we have seen this phenomenon before:

where a 45 yr old immunocompromised patient on steroids, cyclophosphamide and rituximab for antiphospholipd syndrome, acquired COVID-19 and received remdesivir and Regeneron therapy, leading to the emergence of the N501Y and E484K mutations – both present in the new Kent variant – after 128 days.

“This new paper describes another immunocompromised patient with a different clinical syndrome who acquired COVID-19 who was treated with remdesivir and convalescent plasma, leading to the emergence of the 69-70del – already in the Kent variant – with a novel new mutation D796H.

“This new D796H mutation is in the S protein but outside the RBD and appears to be an adaptive mutation to escape some convalescent plasma antibodies, with the 69-70del mutation arising to compensate for some loss of fitness due to this D796H mutation.

“So this D796H mutation may be unique to the batches of convalescent plasma used in this patient – and seems fairly detrimental to the virus as it disappeared quickly between convalescent plasma dosing.

“Such viral mutations cases may not be so uncommon where the virus can replicate for long periods inside one host during therapy, and indeed we see such viral escape mutations arising in response to prolonged antiviral and/or immune therapy in other viruses such as HIV, hepatitis B and C, CMV, and influenza, for example. These often disappear once the drug is stopped as that selection pressure is then removed.”


Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:

“This is an interesting study that shows how quickly coronavirus variants can emerge in response to antibody pressure. However, when serum antibody treatment faded over time, the variant decreased in frequency, suggesting that the variant was less fit than the original infecting wild type virus. This is important and highlights that the virus will be experiencing lots of different, often opposing, selective pressures, and we need to remember that whenever we consider the potential impact and spread of new variants.”


Prof Lawrence Young, Virologist and Professor of Molecular Oncology, University of Warwick, said:

“Confirmation that an inadequate immune response drives development of virus variants. This study provides a detailed examination of the emergence of SARS-CoV-2 variants in a single immunosuppressed individual treated with convalescent plasma. It clearly shows the dynamic nature of variations in the virus population within a single individual and how the virus adapts in response to passive antibodies in a host with a weakened immune response. It shows that one of the changes observed in the UK variant (69-70del) was generated in this individual and accounts for the increased infectiousness of this variant. Another mutation that emerged along with 69-70del, D796H, reduced sensitivity to neutralisation by convalescent plasma. The study highlights the need for careful monitoring of immune compromised patients treated with convalescent plasma and assumes that it is the lack of a more sustained immune response including cytotoxic T cells that favours the emergence of virus escape mutations. It is difficult to extrapolate from a single case report but the data is consistent with our growing understanding of the mutations present in SARS-CoV-2 variants and how these are emerging as the virus adapts to us in terms of transmissibility and immune evasions. It reinforces concerns that weakened immune responses in either immunocompromised individuals or those with a partial immune response to the virus (e.g. by waning immunity post-infection or inadequate response to vaccination) could be the source of further variations in the virus.”



‘SARS-CoV-2 evolution during treatment of chronic infection’ by Steven Kemp et al was published in Nature at 16:00 UK time on Friday 5 February.

DOI: 10.1038/s41586-021-03291-y



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