Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability

Burnett, Deborah L. and Jackson, Katherine J.L. and Langley, David B. and Aggarwal, Anupriya and Stella, Alberto Ospina and Johansen, Matt D. and Balachandran, Harikrishnan and Lenthall, Helen and Rouet, Romain and Walker, Gregory and Saunders, Bernadette M. and Singh, Mandeep and Li, Hui and Henry, Jake Y. and Jackson, Jennifer and Stewart, Alastair G. and Witthauer, Franka and Spence, Matthew A. and Hansbro, Nicole G. and Jackson, Colin and Schofield, Peter and Milthorpe, Claire and Martinello, Marianne and Schulz, Sebastian R. and Roth, Edith and Kelleher, Anthony and Emery, Sean and Britton, Warwick J. and Rawlinson, William D. and Karl, Rudolfo and Schäfer, Simon and Winkler, Thomas H. and Brink, Robert and Bull, Rowena A. and Hansbro, Philip M. and Jäck, Hans-Martin and Turville, Stuart and Christ, Daniel and Goodnow, Christopher C. (2021) Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability. Immunity, 54 (12). pp. 2908-2921.e6. ISSN 10747613

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Link to published document: http://doi.org/10.1016/j.immuni.2021.10.019

Abstract

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 03 Jun 2022 04:55
Last Modified: 17 Jun 2022 00:36
URI: http://eprints.victorchang.edu.au/id/eprint/1222

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