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