Somatic Evolution of a Germline Antibody Expands its Breadth to Neutralize Early SARS‐CoV‐2 Omicron Variants
ABSTRACT Rapid antigenic drift of the SARS‐CoV‐2 receptor‐binding domain (RBD) underlies immune escape and continues to challenge the durability of antibody‐mediated protection. Among the major classes of RBD‐directed antibodies, germline‐encoded IGHV3‐53 responses are highly potent against early SARS‐CoV‐2 variants but are generally compromised by Omicron‐associated mutations. Here, we identify an intrinsically cross‐reactive IGHV3‐53 germline antibody that recognizes multiple pre‐Omicron variants, including SARS‐CoV‐2 wild‐type, Alpha, and Delta. Notably, we demonstrate that targeted somatic evolution can further expand this breadth to overcome the immune escape of different Omicron variants. Guided by integrated structural and sequence analyses, we introduce four somatic mutations (G26E, T28I, S53P, and Y58F) into the germline antibody, resulting in markedly enhanced binding and neutralization of Omicron BA.1, and BA.4/5. High‐resolution crystal structures reveal that these mutations re‐establish interactions disrupted by substitutions in the Omicron RBD and improve binding at a remodeled epitope interface. Collectively, our findings define the structural basis by which specific mutations enhance cross‐variant recognition of SARS‐CoV‐2. This work highlights the underappreciated breadth encoded within the naïve B‐cell repertoire and provides a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.