C.-H. Yeh, S. R. Walsh, R. J. Parsons, Q. E. Zhang, B. Thakur, K. Song, K. Liu, H. F. Kirshner, E. Van ltallie, M. Clark, W. O. Hahn, S. Song, L. Lin, H.-I. Huang, J. Lugo, A. Quan, Y. Xue, Y. Chen, R. Tuck, K. Mansouri, T. N. Spence, H. A. Laukaitis, R. Parks, M. Barr, E. Schweer, N. Levering, A. Eaton, S. Shen, K. Janowska, V. Ilevbare, G. Johnson, P. Wang, D. W. Cain, A. Arus-Altuz, E. Donahue, I. Zhbannikov, M. Berry, S. Venkatayogi, J. S. Martin Beem, O. Hyrien, P.-C. Yu, L. L. Polakowski, I. Tindale, C. Yurdadon, R. Burnham, J. Andriesen, Wag
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.