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Cited by 1,097SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesEvolution and Genetic Dynamics

SARS-CoV-2 evolution during treatment of chronic infection

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Kemp, Steven A., Collier, Dami A., Datir, Rawlings P., Ferreira, Isabella A. T. M., Gayed, Salma, Jahun, Aminu, Hosmillo, Myra, Rees-Spear, Chloe +1134 more·2021·Nature
DOI 10.1038/s41586-021-03291-yPMC PMC7610568

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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 protein 1 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.

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  • The authors say that immune evasion can arise in chronically infected immunocompromised patients under treatment with immune plasma or monoclonal antibodies.

    “The possible theories about the origin of novel variants are the evolution of circulating intermediate mutants in the chronically infected immunocompromised patients supporting high viral replication while on treatment with immune plasma or monoclonal antibodies [88, 89].”

    From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [89]

    The Discussion (page not available) reports viral evolution during persistent infection in an immunocompromised patient treated with convalescent plasma, with evidence of reduced antibody susceptibility. The paper tested monoclonal antibodies in the laboratory but does not report monoclonal-antibody treatment of the patient; it also presents a single case, not an established explanation for the origin of novel variants. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The recent emergence of B.1.1.7, B.1.351 and P.1 marks the beginning of SARS-CoV-2 antigenic drift.

    “The recent emergence of B.1.1.7,B.1.351and P.1 marks the beginning of SARS-CoV-2 antigenic drift.”

    From Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 (2021) · cites this paper as [44]

  • Previous studies showed that the binding affinity of SARS-CoV for human ACE2 correlated with the rate of viral replication in distinct species, transmissibility and disease severity.

    “Previous studies showed that the binding affinity of SARS-CoV for human ACE2 correlated with the rate of viral replication in distinct species, transmissibility and disease severity 29–31.”

    From Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies (2021) · cites this paper as [31]

  • In vitro evolution experiments have shown that repeated use of plasma therapy in an immunocompromised individual led to transient emergence of N501Y and 69-70 deletion in NTD.

    “Interestingly, repeated use of plasma therapy in an immunocompromised individual led to the transient emergence of the N501Y mutation as well as the 69–70 deletion in the NTD, which is characteristic of B.1.1.7 (Kemp et al., 2021).”

    From Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera (2021) · cites this paper as Kemp et al., 2021

  • The B.1.1.7 variant emerged in the United Kingdom, B.1.351 in South Africa, and P.1 and P.2 lineages in Brazil.

    “The B.1.1.7 variant emerged in the United Kingdom, the B.1.351variant (also termed 501Y.V2) in South Africa and the P.1 and P.2 lineages in Brazil 2,3,5,9-12 .”

    From Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies (2021) · cites this paper as [3]

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Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., The CITIID-NIHR BioResource COVID-19 Collaboration, Principal investigators, Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., nurses, C. &. V. R., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O’Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., logistics, S., Bullman, B., Dunmore, B. J., Fawke, S., Gräf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O’Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., acquisition, S. P. &. D., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., collection, C. D., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Royal Papworth Hospital, I. C. U., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Addenbrooke’s Hospital, I. C. U., Polgarova, P., di Stefano, G., Cambridge & Peterborough Foundation Trust, Fahey, C., Michel, R., ANPC & Centre for Molecular Medicine & Innovative Therapeutics, Bong, S.-H., Coudert, J. D., Holmes, E., BioResource, N., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., The COVID-19 Genomics UK (COG-UK) Consortium, Funding acquisition, L. &. S., Robson, S. C., Funding acquisition, L. &. S., Loman, N. J., Connor, T. R., Leadership & supervision, M. C., Golubchik, T., Funding acquisition, M. C., Martinez Nunez, R. T., Funding acquisition, L. &. S., Ludden, C., Funding acquisition, L. &. S., Corden, S., Funding acquisition, L. &. S., Johnston, I., Bonsall, D., Funding acquisition, L. &. S., Smith, C. P., Awan, A. R., Funding acquisition, S. &. 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D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Stanley, R., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Taylor, S., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Tonkin-Hill, G., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Jansen Van, P., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Weldon, D., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., analysis, S. &., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., McCarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O’Brien, S., Baker, D. 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Affiliations
  • University College London (GB)
  • University of Cambridge (GB)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
  • NHS Blood and Transplant (GB)
  • Medway School of Pharmacy (GB)
  • University of Basel (CH)
  • Addenbrooke's Hospital (GB)
  • Papworth Hospital NHS Foundation Trust (GB)
  • Fulbourn Hospital (GB)
  • Murdoch University (AU)
  • King's College London (GB)
  • Public Health Wales (GB)
  • Wellcome Sanger Institute (GB)
  • University of Oxford (GB)
  • University of Brighton (GB)
  • Guy's Hospital (GB)
  • University Hospital Southampton NHS Foundation Trust (GB)
  • St Thomas' Hospital (GB)
  • Belfast Health and Social Care Trust (GB)
  • East Kent Hospitals University NHS Foundation Trust (GB)
  • University of Birmingham (GB)
  • Public Health England (GB)
  • University of Sheffield (GB)
  • University of Nottingham (GB)
  • Northumbria University (GB)
  • Queen's University Belfast (GB)
  • University of Kent (GB)
  • Quadram Institute (GB)
  • Public Health Scotland (GB)
  • Portsmouth Hospitals NHS Trust (GB)
  • University of Liverpool (GB)
  • Imperial College London (GB)
  • MRC University of Glasgow Centre for Virus Research (GB)
  • NHS Lothian (GB)
  • University Hospitals Coventry and Warwickshire NHS Trust (GB)
  • University of East Anglia (GB)
  • University of Exeter (GB)
  • Brighton and Sussex University Hospitals NHS Trust (GB)
  • Betsi Cadwaladr University Health Board (GB)
  • Centre for Human Genetics (GB)
  • Cardiff and Vale University Health Board (GB)
  • Gloucestershire Hospitals NHS Foundation Trust (GB)
  • Sandwell & West Birmingham Hospitals NHS Trust (GB)
  • Norfolk and Norwich University Hospital (GB)
  • University of Warwick (GB)
  • Barking, Havering And Redbridge University Hospitals NHS Trust (GB)
  • Queen Elizabeth Hospital Birmingham (GB)
  • Wye Valley NHS Trust (GB)
  • University Hospitals of Leicester NHS Trust (GB)
  • Great Ormond Street Hospital (GB)
  • Royal Free London NHS Foundation Trust (GB)
  • South Tees Hospitals NHS Foundation Trust (GB)
  • North Cumbria Integrated Care NHS Foundation Trust (GB)
  • North Tees and Hartlepool NHS Foundation Trust (GB)
  • County Durham and Darlington NHS Foundation Trust (GB)
  • Basingstoke and North Hampshire Hospital (GB)
  • University of Portsmouth (GB)
  • Kettering General Hospital (GB)
  • North West London Pathology (GB)
  • University of Surrey (GB)
  • Swansea University (GB)
  • Royal Hampshire County Hospital (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Royal Devon & Exeter NHS Foundation Trust (GB)
  • National Institute for Health and Care Research (GB)
  • NHS Greater Glasgow and Clyde (GB)
  • Leeds Teaching Hospitals NHS Trust (GB)
  • London School of Hygiene & Tropical Medicine (GB)
  • Maidstone and Tunbridge Wells NHS Trust (GB)
  • University of Edinburgh (GB)
  • Norfolk County Council (GB)
  • East Suffolk and North Essex NHS Foundation Trust (GB)
  • Queen's Medical Centre (GB)
  • Manchester University NHS Foundation Trust (GB)
  • Princess Alexandra Hospital NHS Trust (GB)
  • Guy's and St Thomas' NHS Foundation Trust (GB)
  • MRC Laboratory of Molecular Biology (GB)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Facultad de Estudios Superiores Cuautitlán (MX)
  • Newcastle University (GB)
  • Cardiff University (GB)
  • University of Colorado Anschutz (US)
Corresponding author
Gupta, Ravindra K.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-02-05
Volume
592
Issue
7853
Pages
277-282
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03291-y
PMC
PMC7610568
OpenAlex
W3128154910
Cited by
1,097
References
54
Citations by year
2026: 36 · 2025: 72 · 2024: 121 · 2023: 157 · 2022: 283 · 2021: 411 · 2020: 5 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 1
FWCI
77.05
Type
journal article
Language
en
Update notices
correction (2022-07-21)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • PubMed Central (acceptedVersion)
  • Kent Academic Repository (University of Kent) (acceptedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Funders
  • Bill and Melinda Gates Foundation (OPP 1175094)
  • Wellcome Trust (108082/A/15/Z, 108082, 204911/Z/16/Z, Z/17/Z, WT108082AIA, 217191, 206618/Z/17/Z, 207498, 207498/Z/17/Z)
  • UK Research and Innovation (MC_UU_00002/11)
  • Cancer Research UK (23923)
  • National Institute for Health and Care Research (NF-SI-0514-10109, 207498, RP-PG-0514-20018, ACF-2017-15-004, ACF-2018-04-014, COVID-19-RECPLAS)
  • Academy of Medical Sciences (AMS-CSF4-Torok)
  • National Institutes of Health (COVID-19)
  • NIHR BioResource
  • Medical Research Council (MC_UU_00002/11, MR/R015600/1, MR/R008698/1, COVID-19, MC_UP_1201/16)
  • Biotechnology and Biological Sciences Research Council (BBS/E/F/000PR10348, BB/P007562/1)
  • NIHR Cambridge Biomedical Research Centre
  • National Institute of General Medical Sciences (R01GM083127)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
SARS-CoV-2, chronic infection, viral evolution, spike protein, convalescent plasma therapy, neutralizing antibodies, antibody escape, remdesivir, immunosuppression, viral selection, viral infectivity, ultra-deep sequencing

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