Key result
Three distinct cross-variant neutralizing monoclonal antibodies (S5D2, S5G2, and S3H3) were identified that effectively neutralize multiple SARS-CoV-2 variants by targeting different spike protein sites.
Why the study?
The emergence of multiple SARS-CoV-2 variants of concern threatens the efficacy of approved vaccines and therapeutic monoclonal antibodies, motivating the search for broadly neutralizing antibodies and their epitopes.
The study identifies three distinct cross-variant neutralizing sites on the SARS-CoV-2 spike protein, providing targets for broadly effective vaccines and monoclonal antibody therapies.
May guide pan-variant mAb and vaccine development; leaves open human translation from animal data.
The emergence of multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of currently approved vaccines and authorized therapeutic monoclonal antibodies (MAbs). It is hence important to continue searching for SARS-CoV-2 broadly neutralizing MAbs and defining their epitopes. Here, we isolate 9 neutralizing mouse MAbs raised against the spike protein of a SARS-CoV-2 prototype strain and evaluate their neutralizing potency towards a panel of variants, including B.1.1.7, B.1.351, B.1.617.1, and B.1.617.2. By using a combination of biochemical, virological, and cryo-EM structural analyses, we identify three types of cross-variant neutralizing MAbs, represented by S5D2, S5G2, and S3H3, respectively, and further define their epitopes. S5D2 binds the top lateral edge of the receptor-binding motif within the receptor-binding domain (RBD) with a binding footprint centred around the loop477–489, and efficiently neutralizes all variant pseudoviruses, but the potency against B.1.617.2 was observed to decrease significantly. S5G2 targets the highly conserved RBD core region and exhibits comparable neutralization towards the variant panel. S3H3 binds a previously unreported epitope located within the evolutionarily stable SD1 region and is able to near equally neutralize all of the variants tested. Our work thus defines three distinct cross-variant neutralizing sites on the SARS-CoV-2 spike protein, providing guidance for design and development of broadly effective vaccines and MAb-based therapies.
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Xu et al. (2021) studied SARS-CoV-2. Monoclonal antibodies (S5D2, S5G2, S3H3) vs. Control antibodies was evaluated on Neutralization potency (IC50) against SARS-CoV-2 variants. Three distinct cross-variant neutralizing monoclonal antibodies (S5D2, S5G2, and S3H3) were identified that effectively neutralize multiple SARS-CoV-2 variants by targeting different spike protein sites.
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