biostudies-literatureLin XBill and Melinda Gates Foundation (GF)NIAID NIH HHSNIGMS NIH HHSe2510163122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12377726biostudies-literatureUnknown122(33)The development of germline-targeting vaccines represents a potentially transformative strategy to elicit broadly neutralizing antibodies (bnAbs) against HIV and other antigenically diverse pathogens. Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. High-resolution X-ray structures of eOD-GT8 monomer complexed with Fabs of five VRC01-class bnAb precursors with >90% germline identity revealed a conserved mode of binding to the HIV CD4-binding site via IGHV1-2-encoded heavy chains, mirroring mature bnAb interactions. The light-chain V-gene diversity emulated VRC01 bnAbs and stabilized antigen engagement, while their conserved five-residue LCDR3 motifs prevenProceedings of the National Academy of Sciences of the United States of AmericaStructural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI G001 human vaccine trial.PMC12377726CAVDP41 GM103393UM1 AI144462Lin XLu DWilson IAYuan MKalyuzhniy OTingle RKubitz MSchief WRCottrell CAfalseStructural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI G001 human vaccine trial.The development of germline-targeting vaccines represents a potentially transformative strategy to elicit broadly neutralizing antibodies (bnAbs) against HIV and other antigenically diverse pathogens. Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. High-resolution X-ray structures of eOD-GT8 monomer complexed with Fabs of five VRC01-class bnAb precursors with >90% germline identity revealed a conserved mode of binding to the HIV CD4-binding site via IGHV1-2-encoded heavy chains, mirroring mature bnAb interactions. The light-chain V-gene diversity emulated VRC01 bnAbs and stabilized antigen engagement, while their conserved five-residue LCDR3 motifs preven2025-01-01T00:00:00Z2025 Aug2026-07-15T08:58:34.037Z2026-07-03T03:10:42.764ZS-EPMC123777264078902410.1073/pnas.2510163122