Vaccination induces HIV broadly neutralizing antibody precursors in humans
David J. Leggat, Kristen W. Cohen, Jordan R. Willis, William J. Fulp, Allan C. deCamp, Oleksandr Kalyuzhniy, Christopher A. Cottrell, Sergey Menis, Greg Finak, Lamar Ballweber-Fleming, Abhinaya Srikanth, Jason R. Plyler, Torben Schiffner, Alessia Liguori, Farhad Rahaman, Angela Lombardo, Vincent Philiponis, Rachael E. Whaley, Aaron Seese, Joshua Brand, Alexis M. Ruppel, Wesley Hoyland, Nicole L. Yates, LaTonya D. Williams, Kelli Greene, Hongmei Gao, Celia R. Mahoney, Martin Corcoran, Alberto Cagigi, Alison Taylor, David M. Brown, David R. Ambrozak, Troy Sincomb, Xiaozhen Hu, Ryan Tingle, Erik Georgeson, Saman Eskandarzadeh, Nushin Alavi, Danny Lu, Tina-Marie Mullen, Michael Kubitz, Bettina Gröschel, Janine Maenza, Orpheus Kolokythas, Nadia J. Khati, Jeffrey M. Bethony, Shane Crotty, Mario Roederer, Gunilla B. Karlsson Hedestam, Georgia D. Tomaras, David C. Montefiori, David Diemert, Richard A. Koup, Dagna Laufer, M. Juliana McElrath, Adrian B. McDermott, William R. Schief
Abstract
Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine–priming candidate eOD-GT8 60mer adjuvanted with AS01 B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.