Key result
Mosaic-8b RBD nanoparticle immunization in rabbits elicited broadly cross-reactive neutralizing monoclonal antibodies targeting conserved RBD epitopes, with some on par with FDA-approved Pemgarda.
Why the study?
Broad immune responses are needed to mitigate viral evolution and escape by inducing antibodies against conserved receptor-binding domain regions of sarbecovirus spike proteins.
Mosaic RBD nanoparticle immunization in animal models can efficiently generate broadly cross-reactive therapeutic pan-sarbecovirus mAbs that mimic human antibody recognition.
Supports mosaic RBD nanoparticles for cross-reactive mAb elicitation in models; leaves open human translation and efficacy.
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.
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Fan et al. (2025) studied SARS-CoV-2 and Sarbecovirus infection. Mosaic-8b RBD nanoparticles was evaluated on Elicitation of cross-reactive neutralizing monoclonal antibodies. Mosaic-8b RBD nanoparticle immunization in rabbits elicited broadly cross-reactive neutralizing monoclonal antibodies targeting conserved RBD epitopes, with some on par with FDA-approved Pemgarda.
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