Potent cross-reactive antibodies following Omicron breakthrough in vaccinees.

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern. [Display omitted] • Potent RBD antibodies from Omicron breakthrough vaccinees broadly neutralize VoC • These, possible recall antibodies, are focused in two main clusters • Somatic maturation adapts public antibodies to recover potency • BA.2 > BA.1 ACE2 affinity. BA.2 < BA.1 neutralization by vaccine serum and Vir-S309 Analysis of antibodies from SARS-CoV-2 Omicron breakthrough infections reveals their structural and functional properties as well as ability to neutralize different pandemic strains. [ABSTRACT FROM AUTHOR]