Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

TLDR

Omicron variants of SARS‑CoV‑2 are highly transmissible and currently dominate worldwide. The study compares neutralization of Omicron sublineages BA.1, BA.1.1, and BA.2. The authors performed structure‑and‑function analyses of 27 RBD‑binding monoclonal antibodies from vaccinated individuals after Omicron‑BA.1 breakthrough, identifying two main epitope clusters and a predominance of potent right‑shoulder antibodies. BA.2 shows higher ACE2 affinity and modestly reduced vaccine‑serum neutralization, while neutralization differences among sub‑lineages stem from residues near the ACE2 binding site and mutations such as S371F and R346K that diminish therapeutic antibody Vir‑S309 activity; somatic maturation has enhanced potency in less‑mutated epitopes and restored potency in highly mutated ones, and all 27 monoclonal antibodies potently neutralize early pandemic strains and many variants of concern.

Abstract

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.