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

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.

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.

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.

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.