SARS-CoV-2 evolution during treatment of chronic infection

Steven A. Kemp, Dami A. Collier, Rawlings P. Datir, Isabella A. T. M. Ferreira, Salma Gayed, Aminu Jahun, Myra Hosmillo, Chloe Rees-Spear, Petra Mlcochova, Ines Ushiro Lumb, David J. Roberts, Anita Chandra, Nigel Temperton, Katherine Sharrocks, Elizabeth Blane, Yorgo Modis, Kendra E. Leigh, John A. G. Briggs, Marit J. Gils, Kenneth G. C. Smith, John R. Bradley, Chris Smith, Rainer Doffinger, Lourdes Ceron-Gutierrez, Gabriela Barcenas-Morales, David D. Pollock, Richard A. Goldstein, Anna Smielewska, Jordan P. Skittrall, Theodore Gouliouris, Ian G. Goodfellow, Effrossyni Gkrania-Klotsas, Christopher J. R. Illingworth, Laura E. McCoy and Ravindra K. Gupta ()
Additional contact information
Steven A. Kemp: University College London
Dami A. Collier: University College London
Rawlings P. Datir: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Isabella A. T. M. Ferreira: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Salma Gayed: Cambridge University NHS Hospitals Foundation Trust
Aminu Jahun: University of Cambridge
Myra Hosmillo: University of Cambridge
Chloe Rees-Spear: University College London
Petra Mlcochova: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Ines Ushiro Lumb: University of Oxford
David J. Roberts: University of Oxford
Anita Chandra: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Nigel Temperton: University of Kent
Katherine Sharrocks: Cambridge University NHS Hospitals Foundation Trust
Elizabeth Blane: University of Cambridge
Yorgo Modis: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Kendra E. Leigh: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
John A. G. Briggs: Medical Research Council Laboratory of Molecular Biology
Marit J. Gils: University of Amsterdam
Kenneth G. C. Smith: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
John R. Bradley: University of Cambridge
Chris Smith: Cambridge University NHS Hospitals Foundation Trust
Rainer Doffinger: Addenbrooke’s Hospital
Lourdes Ceron-Gutierrez: Addenbrooke’s Hospital
Gabriela Barcenas-Morales: Addenbrooke’s Hospital
David D. Pollock: University of Colorado School of Medicine
Richard A. Goldstein: University College London
Anna Smielewska: University of Cambridge
Jordan P. Skittrall: Cambridge University NHS Hospitals Foundation Trust
Theodore Gouliouris: Cambridge University NHS Hospitals Foundation Trust
Ian G. Goodfellow: University of Cambridge
Effrossyni Gkrania-Klotsas: Cambridge University NHS Hospitals Foundation Trust
Christopher J. R. Illingworth: University of Cambridge
Laura E. McCoy: University College London
Ravindra K. Gupta: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)

Nature, 2021, vol. 592, issue 7853, 277-282

Abstract: Abstract The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (18)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03291-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:592:y:2021:i:7853:d:10.1038_s41586-021-03291-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03291-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().