Priming of Multiple HIV Neutralizing B Cell Precursors in Humans

ABSTRACT Induction of broadly neutralizing antibodies (bnAbs) remains a major goal of HIV vaccine development. In a Phase I clinical trial, we evaluated the immunogenicity of CH505 transmitted/founder (TF) envelope trimer designed to prime precursors of the heavy chain third complementarity determining region (CDRH3)-dominant class of CD4-binding site (CD4bs) HIV bnAbs. Neutralizing memory B-cell lineages were isolated from all vaccine recipients, including lineages targeting the CD4bs, V1/V3, and gp120/gp41 interface. Candidate CDRH3-dominant, CD4bs bnAb precursor lineages were identified in 73% of vaccinees, including one lineage that exhibited limited heterologous neutralization of global HIV-1 isolates. Structural analyses defined the modes of Env recognition by these three antibody classes. Together, these findings demonstrate that immunization with the CH505 TF trimer can prime a diverse, polyclonal repertoire of bnAb precursor lineages in humans, providing multiple starting points for sequential immunization strategies aimed at eliciting broadly neutralizing HIV-1 antibodies. HIGHLIGHTS CH505 TF trimer immunogen induced autologous tier-2 neutralizing B cell lineages in all vaccine recipients. S365P-sensitive, CDRH3-dominant CD4-binding-site bnAb precursor candidates were detected in 73% of vaccinees. A single immunogen primed neutralizing antibody lineages targeting the CD4bs, V1/V3, and gp120/gp41 interface. High S365P-sensitive CD4bs responses were associated with distinct NK- and CD8⁺ T-cell states.