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


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.

Type Journal
ISBN 1097-4180 (Electronic) 1074-7613 (Linking)
Authors Burnett, D. L.; Jackson, K. J. L.; Langley, D. B.; Aggrawal, A.; Stella, A. O.; Johansen, M. D.; Balachandran, H.; Lenthall, H.; Rouet, R.; Walker, G.; Saunders, B. M.; Singh, M.; Li, H.; Henry, J. Y.; Jackson, J.; Stewart, A. G.; Witthauer, F.; Spence, M. A.; Hansbro, N. G.; Jackson, C.; Schofield, P.; Milthorpe, C.; Martinello, M.; Schulz, S. R.; Roth, E.; Kelleher, A.; Emery, S.; Britton, W. J.; Rawlinson, W. D.; Karl, R.; Schafer, S.; Winkler, T. H.; Brink, R.; Bull, R. A.; Hansbro, P. M.; Jack, H. M.; Turville, S.; Christ, D.; Goodnow, C. C.
Responsible Garvan Author Prof Christopher Goodnow
Publisher Name IMMUNITY
Published Date 2021-12-31
Published Volume 54
Published Issue 12
Published Pages 2908-2921 e6
Status Published in-print
DOI 10.1016/j.immuni.2021.10.019
URL link to publisher's version