Somatic Hypermutations Enhance Neutralization Breadth of IGHV3‐53/3‐66 Public Antibodies Against SARS‐CoV‐2 Variants

Abstract

ABSTRACT Objective Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continuously evolves to evade antibodies elicited by prior infection or vaccination. Most IGHV3‐53/3‐66 public antibodies potently neutralize the prototype strain, but show limited activity against recent variants. However, some acquire broad neutralizing activity through accumulation of somatic hypermutations. We assessed whether non‐broadly neutralizing IGHV3‐53/3‐66 antibodies could mature into broadly neutralizing antibodies. Methods A series of mutant antibodies was constructed based on the IGHV3‐53/3‐66 antibodies, 9‐105 and K4‐66. Neutralizing and binding activities were compared with the original antibodies. Results Introducing six mutations frequently observed in broadly neutralizing antibodies markedly improved the neutralization and binding of 9‐105 against Omicron variants. Introducing Y66F into K4‐66 enhanced neutralization of variants including BA.4/5 and JN.1. Conclusion These findings show that mutations within the IGHV3‐53/3‐66 gene can enhance antibody breadth and potency, suggesting the potential of vaccine strategies to promote the maturation of these widely prevalent public antibodies.