HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogene

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germlinetargeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naive B cells bind germlinetargeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. Using deep mutational scanning and multitarget optimization, we developed a germlinetargeting immunogen (eODGT8) for diverse VRC01class bnAbs. We then used the immunogen to isolate VRC01class precursor naive B cells from HIVuninfected donors. Frequencies of true VRC01class precursors, their structures, and their eODGT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.