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Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes
Chengcheng Fan; Alexander A Cohen; Miso Park; Alfur Fu-Hsin Hung; Jennifer R Keeffe; Priyanthi NP Gnanapragasam; Yu E Lee; Leesa M Kakutani; Ziyan Wu; Kathryn E Malecek; John C Williams; Pamela J Bjorkman.
Affiliation
  • Chengcheng Fan; California Institute of Technology
  • Alexander A Cohen; California Institute of Technology
  • Miso Park; City of Hope
  • Alfur Fu-Hsin Hung; City of Hope
  • Jennifer R Keeffe; California Institute of Technology
  • Priyanthi NP Gnanapragasam; California Institute of Technology
  • Yu E Lee; California Institute of Technology
  • Leesa M Kakutani; California Institute of Technology
  • Ziyan Wu; California Institute of Technology
  • Kathryn E Malecek; California Institute of Technology
  • John C Williams; City of Hope
  • Pamela J Bjorkman; California Institute of Technology
Preprint in English | bioRxiv | ID: ppbiorxiv-497989
ABSTRACT
Protection from SARS-related coronaviruses with spillover potential and SARS-CoV-2 variants could prevent and/or end pandemics. We show that mice immunized with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicit cross-reactive anti-sarbecovirus antibodies against conserved class 1/4 and class 3 RBD epitopes. Monoclonal antibodies (mAbs) identified from initial screening of <10,000 single B-cells secreting IgGs binding two or more sarbecovirus RBDs showed cross-reactive binding and neutralization of SARS-CoV-2 variants and animal sarbecoviruses. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes and revealed neutralization mechanisms, potentials for intra-spike trimer crosslinking by single 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-nanoparticles to identify therapeutic pan-sarbecovirus and pan-variant mAbs and to elicit them by vaccination.
License
cc_by_nc
Full text: Available Collection: Preprints Database: bioRxiv Type of study: Rct Language: English Year: 2022 Document type: Preprint
Full text: Available Collection: Preprints Database: bioRxiv Type of study: Rct Language: English Year: 2022 Document type: Preprint
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