However, the binding is quite extensive, almost entirely restricted to the HC, with H1-3 contributing a total of 5972interface area (in contrast the LC contributes only 1102). antibody, receptor-binding domain name, structure, vaccine, neutralization == Graphical abstract == == Imirestat Highlights == Generated 674 antibodies from patients infected with SARS-CoV-2 Beta variant 18 of 27 most potent mAbs target the 3 mutations in Beta RBD A major response to N501Y includes a public IgVH4-39 sequence Two antibodies recognize a neutralizing epitope conserved between SARS-CoV-1 and -2 Liu et al. generated 674 antibodies from patients infected with the SARS-CoV-2 Beta variant. 18 out of 27 most potent neutralizing antibodies isolated target the 3 mutations present in the receptor-binding domain name of this variant. This underscores the poor neutralization by Beta serum of early pandemic and Delta viruses. == Introduction == Genomic surveillance of SARS-CoV-2 has identified many thousands of mutations in structural and non-structural proteins (COVID-19 Genomics UK (COG-UK) consortium, 2020). However, toward the end of 2020, viral variants were described that rapidly became the dominant strains locally and led to global spread and their designation as variants of concern (VoCs) Alpha, Beta, Gamma, and Delta. Imirestat All of these variants contain multiple mutations in S and include changes in the receptor-binding domain name (RBD), N-terminal domain name (NTD), and in some cases the furin cleavage site between S1 and S2. The RBD mutations found in Alpha (N501Y), Beta (K417N, E484K, and N501Y), Gamma (K417T, E484K, and N501Y), and Delta (L452R and T478K) are located in or closely adjacent to the ACE2-interacting surface where they have the potential to modulate ACE2 conversation or disrupt the binding of neutralizing mAbs. Increased affinity for Imirestat ACE2 has been exhibited for Alpha, Beta, Gamma, and Delta (7-, 19-, 19-, and 2-fold, respectively) (Dejnirattisai et al., 2021b;Liu et al., 2021;Supasa et al., 2021;Zhou et al., 2021) and may play a role in increasing viral transmissibility. A number of studies show vaccine efficacy against Beta to be reduced, and this corresponds with significantly reduced neutralization titers to Beta using serum obtained from early pandemic cases or vaccinees, when compared with neutralization of early pandemic strains (Madhi et al., 2021;Shinde et al., 2021;Zhou et al., 2021). The RBD mutations present in Beta (K417N, E484K, and N501Y) disrupt the binding of a number of potent neutralizing mAbs including some being developed for clinical use and likely, together with changes in the NTD, explain the antigenic distance between Beta and early SARS-CoV-2 strains (Zhou et al., 2021). To understand the antigenic scenery of Beta, we produced a substantial panel of mAbs isolated from memory B cells of convalescent Beta cases. Of 674 mAbs generated from 5 donors 27 showed potent neutralizing activity (50% focus reduction neutralization assay [FRNT50] < 100 ng/mL). Neutralization assays against a variety of viral isolates indicated most mAbs showed restricted neutralization of a set of strains. A detailed structure-function analysis comprising 22 X-ray and cryo-EM structures is presented for 16 Fabs most in complexes with RBD PLCG2 or S, which allows an understanding of the changes in antigenicity of the Beta S protein. The majority of potent mAbs are directed to the mutations present in the Beta RBD, principally N501Y, and E484K, underscoring the small antigenic distance between Beta and Gamma, the larger distance between early pandemic strains and Beta, and interestingly, few anti-Beta mAbs can neutralize Imirestat Delta, consistent with the extreme antigenic distance between Beta and Delta (Liu et al., 2021). == Results == == Generation of mAbs from Beta-infected cases == We collected plasma and peripheral blood mononuclear cells (PBMC) from 18 volunteers in the UK who had previously suffered contamination with Beta as evidenced by viral sequencing or were inferred to have suffered Beta as they became infected after being isolated following contact with a proven Beta-infected case. Samples were taken 48 weeks following Beta contamination, ELISA binding assays against full-length Beta S protein Imirestat and.