Breakthrough infection elicits hypermutated IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2 variants including BQ and XBB lineages

The rapid emergence of SARS-CoV-2 variants of concern (VOCs) calls for efforts to study broadly neutralizing antibodies elicited by infection or vaccination so as to inform the development of vaccines and antibody therapeutics with broad protection. Here, we identified two convalescents of breakthrough infection with relatively high neutralizing titers against all tested viruses including BQ and XBB lineages. Among 50 spike-specific monoclonal antibodies (mAbs) cloned from their B cells, the top 6 neutralizing mAbs (KXD01-06) belong to previously defined IGHV3-53/3-66 public antibodies. Although most antibodies in this class are dramatically escaped by VOCs, KXD01-06 exhibit broad neutralizing capacity with the IC50s of KXD01 ranging from 0.011∼0.059μg/ml. Deep mutational scanning reveals that KXD01-06 target highly conserved sites on RBD including D420, Y421, L455, F456, A475 and N487. Genetic and functional analysis further indicates that the extent of somatic hypermutation is critical for the breadth of IGHV3-53/3-66 public antibodies. Overall, we discovered and characterized IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2, which provides rationale for novel vaccines and antibody therapeutics based on this class of antibodies.