tetano
Editor, Senior Moderator
Immunity
. 2022 Oct 27;S1074-7613(22)00560-X.
doi: 10.1016/j.immuni.2022.10.019. Online ahead of print.
Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes
Chengcheng Fan[SUP] 1 [/SUP], Alexander A Cohen[SUP] 1 [/SUP], Miso Park[SUP] 2 [/SUP], Alfur Fu-Hsin Hung[SUP] 2 [/SUP], Jennifer R Keeffe[SUP] 1 [/SUP], Priyanthi N P Gnanapragasam[SUP] 1 [/SUP], Yu E Lee[SUP] 1 [/SUP], Han Gao[SUP] 1 [/SUP], Leesa M Kakutani[SUP] 1 [/SUP], Ziyan Wu[SUP] 1 [/SUP], Harry Kleanthous[SUP] 3 [/SUP], Kathryn E Malecek[SUP] 1 [/SUP], John C Williams[SUP] 2 [/SUP], Pamela J Bjorkman[SUP] 4 [/SUP]
Affiliations
Abstract
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.
Keywords: COVID-19; SARS-CoV-2; X-ray crystallography; coronavirus; cryo-electron microscopy; mosaic nanoparticle; neutralizing antibodies; sarbecovirus; vaccine design.
. 2022 Oct 27;S1074-7613(22)00560-X.
doi: 10.1016/j.immuni.2022.10.019. Online ahead of print.
Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes
Chengcheng Fan[SUP] 1 [/SUP], Alexander A Cohen[SUP] 1 [/SUP], Miso Park[SUP] 2 [/SUP], Alfur Fu-Hsin Hung[SUP] 2 [/SUP], Jennifer R Keeffe[SUP] 1 [/SUP], Priyanthi N P Gnanapragasam[SUP] 1 [/SUP], Yu E Lee[SUP] 1 [/SUP], Han Gao[SUP] 1 [/SUP], Leesa M Kakutani[SUP] 1 [/SUP], Ziyan Wu[SUP] 1 [/SUP], Harry Kleanthous[SUP] 3 [/SUP], Kathryn E Malecek[SUP] 1 [/SUP], John C Williams[SUP] 2 [/SUP], Pamela J Bjorkman[SUP] 4 [/SUP]
Affiliations
- PMID: 36370711
- DOI: 10.1016/j.immuni.2022.10.019
Abstract
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.
Keywords: COVID-19; SARS-CoV-2; X-ray crystallography; coronavirus; cryo-electron microscopy; mosaic nanoparticle; neutralizing antibodies; sarbecovirus; vaccine design.