Rapid escape of new SARS-CoV-2 Omicron variants from BA.2-directed antibody responses

In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titer of vaccine or BA.1, BA.2, or BA.4/5 immune serum. [Display omitted] •25 potent RBD mAbs generated from vaccinees suffering BA.2 breakthrough infections•Potent mAbs bind 3 clusters, 2 correspond to early-pandemic binding hotspots•RBD mutations in recent variants map close to these binding sites•Neutralization activity of all but 1 potent mAb is reduced Dijokaite-Guraliuc et al. analyze potently neutralizing antibodies from vaccinated individuals with BA.2 breakthrough infections. The antibodies bind 3 sites on the receptor-binding domain, 2 of which are in common with early-pandemic antibodies. Mutations in more recent variants map closely to these sites, leading to reduced neutralization in all but one mAb.