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

Burnett, DL; Jackson, KJL; 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, SR; Roth, E; Kelleher, A; Emery, S; Britton, WJ; Rawlinson, WD; Karl, R; Schäfer, S; Winkler, TH; Brink, R; Bull, RA; Hansbro, PM; Jäck, H-M; Turville, S; Christ, D; Goodnow, CC

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

Burnett, DL Jackson, KJL 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, SR Roth, E Kelleher, A Emery, S Britton, WJ Rawlinson, WD Karl, R Schäfer, S Winkler, TH Brink, R Bull, RA Hansbro, PM Jäck, H-M Turville, S Christ, D Goodnow, CC

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Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: Immunity, 2021, 54, (12), pp. 2908-2921.e6
Issue Date:: 2021-12-14

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Field	Value	Language
dc.contributor.author	Burnett, DL
dc.contributor.author	Jackson, KJL
dc.contributor.author	Langley, DB
dc.contributor.author	Aggrawal, A
dc.contributor.author	Stella, AO
dc.contributor.author	Johansen, MD
dc.contributor.author	Balachandran, H
dc.contributor.author	Lenthall, H
dc.contributor.author	Rouet, R
dc.contributor.author	Walker, G
dc.contributor.author	Saunders, BM
dc.contributor.author	Singh, M
dc.contributor.author	Li, H
dc.contributor.author	Henry, JY
dc.contributor.author	Jackson, J
dc.contributor.author	Stewart, AG
dc.contributor.author	Witthauer, F
dc.contributor.author	Spence, MA
dc.contributor.author	Hansbro, NG
dc.contributor.author	Jackson, C
dc.contributor.author	Schofield, P
dc.contributor.author	Milthorpe, C
dc.contributor.author	Martinello, M
dc.contributor.author	Schulz, SR
dc.contributor.author	Roth, E
dc.contributor.author	Kelleher, A
dc.contributor.author	Emery, S
dc.contributor.author	Britton, WJ
dc.contributor.author	Rawlinson, WD
dc.contributor.author	Karl, R
dc.contributor.author	Schäfer, S
dc.contributor.author	Winkler, TH
dc.contributor.author	Brink, R
dc.contributor.author	Bull, RA
dc.contributor.author	Hansbro, PM
dc.contributor.author	Jäck, H-M
dc.contributor.author	Turville, S
dc.contributor.author	Christ, D
dc.contributor.author	Goodnow, CC
dc.date.accessioned	2022-01-11T06:58:22Z
dc.date.available	2021-10-22
dc.date.available	2022-01-11T06:58:22Z
dc.date.issued	2021-12-14
dc.identifier.citation	Immunity, 2021, 54, (12), pp. 2908-2921.e6
dc.identifier.issn	1074-7613
dc.identifier.issn	1097-4180
dc.identifier.uri	http://hdl.handle.net/10453/152918
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier BV
dc.relation.ispartof	Immunity
dc.relation.isbasedon	10.1016/j.immuni.2021.10.019
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1107 Immunology
dc.subject.classification	Immunology
dc.subject.mesh	Animals
dc.subject.mesh	Antibodies, Neutralizing
dc.subject.mesh	Antibodies, Viral
dc.subject.mesh	Betacoronavirus
dc.subject.mesh	COVID-19 Vaccines
dc.subject.mesh	Conserved Sequence
dc.subject.mesh	Coronavirus Infections
dc.subject.mesh	Evolution, Molecular
dc.subject.mesh	Humans
dc.subject.mesh	Immunization
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Protein Binding
dc.subject.mesh	Protein Domains
dc.subject.mesh	SARS Virus
dc.subject.mesh	Spike Glycoprotein, Coronavirus
dc.subject.mesh	Vaccine Development
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	SARS Virus
dc.subject.mesh	Coronavirus Infections
dc.subject.mesh	Antibodies, Viral
dc.subject.mesh	Immunization
dc.subject.mesh	Evolution, Molecular
dc.subject.mesh	Conserved Sequence
dc.subject.mesh	Protein Binding
dc.subject.mesh	Antibodies, Neutralizing
dc.subject.mesh	Spike Glycoprotein, Coronavirus
dc.subject.mesh	Protein Domains
dc.subject.mesh	Betacoronavirus
dc.subject.mesh	COVID-19 Vaccines
dc.subject.mesh	Vaccine Development
dc.title	Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability.
dc.type	Journal Article
utslib.citation.volume	54
utslib.location.activity	United States
utslib.for	1107 Immunology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.date.updated	2022-01-11T06:58:17Z
pubs.issue	12
pubs.publication-status	Published
pubs.volume	54
utslib.citation.issue	12

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/152918