Key result
Immunization with diverse sarbecovirus receptor-binding domains elicited rare, potently neutralizing cross-reactive antibodies that target the conserved class 4 epitope and obstruct ACE2 interactions.
Why the study?
Viral mutations are reducing SARS-CoV-2 vaccination efficacy, creating a need for vaccines that elicit neutralizing antibodies against evolutionarily conserved sites across the sarbecovirus subgenus.
Identifies a structurally defined pathway for vaccine strategies to elicit escape-resistant SARS-CoV-2 neutralizing antibodies.
Does not alter clinical practice; hypothesis-generating for conserved epitope vaccines in humans.
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.
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Burnett et al. (2021) studied SARS-CoV-2. Immunization with diverse sarbecovirus receptor-binding domains was evaluated on Elicitation of cross-reactive neutralizing antibodies. Immunization with diverse sarbecovirus receptor-binding domains elicited rare, potently neutralizing cross-reactive antibodies that target the conserved class 4 epitope and obstruct ACE2 interactions.
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