Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naive human B cells

A successful HIV vaccine must overcome the hurdle of being able to activate naive precursor B cells encoding features within their germline B cell receptors (BCR) that allow recognition of broadly neutralizing epitopes. Knowledge of whether broadly neutralizing antibody (bnAb) precursor B cells are circulating at sufficient frequencies within individuals in communities heavily impacted by HIV may be important. Using a germline-targeting eOD-GT8 immunogen and high-throughput droplet-based single cell BCR sequencing, we demonstrate that large numbers of paired BCR sequences from multiple donors can be efficiently screened to elucidate precursor frequencies of rare, naive VRC01-class B cells. The results indicate that IGHV1-2 alleles incompatible with VRC01-class responses are relatively common in various human populations, and germline variation within IGHV1-2 associates with gene usage frequencies in the naive BCR repertoire.