Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles

• 成果类型: Article
• 署名作者: Fan, Chengcheng; Keeffe, Jennifer R.; Malecek, Kathryn E.; Cohen, Alexander A.; West Jr, Anthony P.; Baharani, Viren A.; Rorick, Annie, V; Gao, Han; Gnanapragasam, Priyanthi N. P.; Rho, Semi; Alvarez, Jaasiel; Segovia, Luisa N.; Hatziioannou, Theodora; Bieniasz, Paul D.; Bjorkman, Pamela J.
• 署名单位: California Institute of Technology; Rockefeller University; Rockefeller University; Rockefeller University; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11249
• DOI: 10.1073/pnas.2501637122
• 发表日期: 2025-05-27
• 关键词: receptor-binding domain; sars-cov-2 neutralizing antibodies; rabbit monoclonal-antibodies; conserved site; variants; SYSTEM

摘要

Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike-antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.