Sequential vaccination matures VRC01-class HIV-1 neutralizing antibodies in humans

Inducing a broadly neutralizing antibody (bnAb) response is a key goal of HIV-1 vaccine development. Despite significant progress, it is unknown whether vaccine-primed B cells can be reactivated and matured to secrete bona fide bnAbs. In the IAVI C107/C110 single-arm, open-label human trial, VRC01-class memory B cells previously primed by the GT1.1 germline-targeting envelope glycoprotein (Env) trimer were reactivated by a BG505 SOSIP.664 trimer boost. Somatic hypermutation in the activated B cells drove higher antibody affinity for the CD4-binding site on fully glycosylated, heterologous Env trimers. Three VRC01-class monoclonal antibodies derived from independent B cell lineages neutralized 18-31% of 119 viruses in a globally diverse panel. This work advances the HIV-1 germline-targeting vaccination concept from proof-of-priming towards proof-of-breadth and defines a benchmark for bnAb induction.