Details

Autor(en) / Beteiligte

• Burnett, Deborah L.
• Jackson, Katherine J.L.
• Langley, David B.
• Aggarwal, Anupriya
• 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.

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2021-12, Vol.54 (12), p.2908-2921.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Immunization with diverse sarbecorvirus RBDs induces cross-reactive antibodies•Cross-reactive antibodies use recurrent IGHV/IGKVs that mainly bind the class 4 epitope•Diverse sarbecovirus RBD responses vary in the dominance of class 4 epitope antibodies•Neutralizing class 4 antibodies are rare and extend the RBD beta-sheet main chain Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Burnett et al. immunized humanized mice with different diverse sarbecovirus RBDs to elicit antibodies targeting conserved sites. Non-neutralizing cross-reactive antibodies targeting the conserved class 4 epitope were readily elicited. Neutralizing ability was reserved only for antibodies binding this conserved supersite through an elongated CDRH3 that obstructed ACE2-RBD interactions.