Antigenic sin and multiple breakthrough infections drive converging evolution of COVID-19 neutralizing responses.

Understanding the evolution of the B cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is fundamental to design the next generation of vaccines and therapeutics. We longitudinally analyze at the single-cell level almost 900 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants belong to the SH cohort. Repertoire analysis shows that the original Wuhan antigenic sin drives the convergent expansion of the same B cell germlines in vaccinated and SH cohorts. Only Omicron breakthrough infections expand previously unseen germ lines and generate broadly nAbs by restoring IGHV3-53/3-66 germ lines. Our analyses find that B cells initially expanded by the original antigenic sin continue to play a fundamental role in the evolution of the immune response toward an evolving virus.