Details

Autor(en) / Beteiligte

• Fan, Chengcheng
• Cohen, Alexander A.
• Park, Miso
• Hung, Alfur Fu-Hsin
• Keeffe, Jennifer R.
• Gnanapragasam, Priyanthi N.P.
• Lee, Yu E.
• Gao, Han
• Kakutani, Leesa M.
• Wu, Ziyan
• Kleanthous, Harry
• Malecek, Kathryn E.
• Williams, John C.
• Bjorkman, Pamela J.

Titel

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Ist Teil von

• Immunity (Cambridge, Mass.), 2022-12, Vol.55 (12), p.2419-2435.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicits cross-reactive polyclonal antibodies against conserved sarbecovirus RBD epitopes. Here, we identified monoclonal antibodies (mAbs) capable of cross-reactive binding and neutralization of animal sarbecoviruses and SARS-CoV-2 variants by screening single mouse B cells secreting IgGs that bind two or more sarbecovirus RBDs. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes. Structural analyses revealed neutralization mechanisms, potentials for intra-spike trimer cross-linking by IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb-resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticle vaccination to generate and identify therapeutic pan-sarbecovirus and pan-variant mAbs. [Display omitted] •mAbs elicited in mosaic nanoparticle-immunized mice exhibit cross-reactive recognition•Fab-spike cryo-EM structures show targeting of conserved class 1/4 and 3 RBD epitopes•Fab-spike structures show increased trimer openness and potential intra-spike binding Sarbecovirus spike receptor-binding domains (RBDs) include conserved and variable epitopes, suggesting that antibodies against conserved regions would protect against future sarbecovirus spillovers and SARS-CoV-2 variants. Fan et al. structurally and functionally characterized monoclonal antibodies elicited by a mosaic-8 RBD-nanoparticle vaccine candidate, demonstrating cross-reactive binding, neutralization, and targeting of desired epitopes.