Discovery of neutralizing SARS-CoV-2 antibodies enriched in a unique antigen specific B cell cluster

Stine Sofie Frank Lende*, Nanna Møller Barnkob, Randi Westh Hansen, Harsh Bansia, Mike Vestergaard, Frederik Holm Rothemejer, Anne Worsaae, Deijona Brown, Maria Lange Pedersen, Anna Halling Folkmar Rahimic, Anna Karina Juhl, Torben Gjetting, Lars Østergaard, Amédée Des Georges, Laurent-Michel Vuillard, Mariane Høgsbjerg Schleimann, Klaus Koefoed, Martin Tolstrup*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Despite development of effective SARS-CoV-2 vaccines, a sub-group of vaccine non-responders depends on therapeutic antibodies or small-molecule drugs in cases of severe disease. However, perpetual viral evolution has required continuous efficacy monitoring as well as exploration of new therapeutic antibodies, to circumvent resistance mutations arising in the viral population. We performed SARS-CoV-2-specific B cell sorting and subsequent single-cell sequencing on material from 15 SARS-CoV-2 convalescent participants. Through screening of 455 monoclonal antibodies for SARS-CoV-2 variant binding and virus neutralization, we identified a cluster of activated B cells highly enriched for SARS-CoV-2 neutralizing antibodies. Epitope binning and Cryo-EM structure analysis identified the majority of neutralizing antibodies having epitopes overlapping with the ACE2 receptor binding motif (class 1 binders). Extensive functional antibody characterization identified two potent neutralizing antibodies, one retaining SARS-CoV-1 neutralizing capability, while both bind major common variants of concern and display prophylactic efficacy in vivo. The transcriptomic signature of activated B cells harboring broadly binding neutralizing antibodies with therapeutic potential identified here, may be a guide in future efforts of rapid therapeutic antibody discovery.

Original languageEnglish
Article numbere0291131
JournalPLOS ONE
Volume18
Issue9
ISSN1932-6203
DOIs
Publication statusPublished - Sept 2023

Keywords

  • Humans
  • SARS-CoV-2
  • COVID-19 Vaccines
  • COVID-19
  • Blood Group Antigens
  • Antibodies, Viral
  • Antibodies, Neutralizing
  • Epitopes

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