Induction of multiple HIV-1 neutralizing B Cell Precursors in Humans

Induction of broadly neutralizing antibodies (bnAbs) remains a central goal of HIV vaccine development. In the HVTN300 clinical trial (NCT04915768), we evaluated an HIV CH505 transmitted/founder (TF) envelope trimer designed to prime naive B cell precursors of the CD4 binding site (CD4bs) class of bnAbs that use a CDRH3-dominated binding mode. Autologous tier 2 serum neutralizing activity was detected in 9 of 11 vaccinees, and neutralizing B cells were isolated from all participants. CD4bs-directed, CDRH3-binder bnAb precursors were identified in 8 of 11 vaccinees (73%), including one lineage with nascent heterologous breadth that neutralized 6% of global HIV isolates. Cryo-EM structures confirmed CD4bs CDRH3-binder modes of engagement and additionally revealed vaccine-induced V1/V3-directed antibodies and a neutralizing lineage targeting the gp120/gp41 interface. Together, these results demonstrate that the CH505 TF trimer primes a diverse, polyclonal neutralizing B cell repertoire in humans, providing multiple entry points for sequential boosting strategies to achieve HIV bnAb breadth. HIGHLIGHTSO_LICH505 germline-targeting trimeric immunogen induced autologous tier 2 neutralizing B cell lineages in 100% of vaccinated humans. C_LIO_LICD4 binding site CDRH3-binder bnAb precursors were detected in 73% of vaccinees. C_LIO_LISingle immunogen primed CD4bs, V1/V3, and gp120/gp41 targeting neutralizing antibodies. C_LIO_LIA CD4 binding site B cell clonal lineage was isolated that neutralized 6% of global HIV primary isolates. C_LI