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

Burnett DL, Jackson KJ, Langley DB, Aggrawal A, Stella AO, Johansen MD, Balachandran H, Lenthall H, Rouet R, Walker G, Saunders BM, Singh M, Li H, Henry JY, Jackson J, Stewart AG, Witthauer F, Spence MA, Hansbro NG, Jackson C, Schofield P, Milthorpe C, Martinello M, Schulz S, Roth E, Kelleher A, Emery S, Britton WJ, Rawlinson WD, Karl R, Schäfer S, Winkler T, Brink R, Bull RA, Hansbro PM, Jäck HM, Turville S, Christ D, Goodnow CC (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 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.

Authors with CRIS profile

Involved external institutions

University of New South Wales (UNSW) Australia (AU) Kirby Institute Australia (AU) University of Sydney (USYD) Australia (AU) Garvan Institute of Medical Research Australia (AU) Australian National University (ANU) Australia (AU) University of Technology Sydney (UTS) Australia (AU)

How to cite

APA:

Burnett, D.L., Jackson, K.J., Langley, D.B., Aggrawal, A., Stella, A.O., Johansen, M.D.,... Goodnow, C.C. (2021). Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability. Immunity. https://dx.doi.org/10.1016/j.immuni.2021.10.019

MLA:

Burnett, Deborah L., et al. "Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability." Immunity (2021).

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