Precise targeting of HIV broadly neutralizing antibody precursors in humans
Tom G. Caniels, Madhu Prabhakaran, Gabriel Ozorowski, Kellie J. MacPhee, Weiwei Wu, Karlijn van der Straten, Sashank Agrawal, Ronald Derking, Emma I. M. M. Reiss, Katrina G. Millard, Martina Turroja, Aimee Desrosiers, Jeffrey M. Bethony, Elissa Malkin, Marinus H. Liesdek, Annelou van der Veen, Michelle J. Klouwens, Jonne L. Snitselaar, Joey H. Bouhuijs, Rhianna Bronson, Jalen Jean-Baptiste, Suprabhath Gajjala, Zahra Rikhtegaran Tehrani, Alison Benner, Mukundhan Ramaswami, Michael O. Duff, Yung-Wen Liu, Alicia Sato, J Kim, Isabel J. L. Baken, Catarina Mendes Silva, Tom P. L. Bijl, Jacqueline van Rijswijk, Judith A. Burger, Albert Cupo, Anila Yasmeen, Swastik Phulera, Wen-Hsin Lee, Kipchoge N. Randall, Shiyu Zhang, Martin Corcoran, Isabel Regadas, Alex C. Sullivan, David M. Brown, Jennifer A. Bohl, Kelli Greene, Hongmei Gao, Nicole L. Yates, Sheetal Sawant, Jan M. Prins, Neeltje A. Kootstra, Stephen M. Kaminsky, Burc Barin, Farhad Rahaman, Margaret Meller, Vince Philiponis, Dagna Laufer, Angela Lombardo, Lindsey Mwoga, Solmaz Shotorbani, Drienna Holman, Richard A. Koup, Per Johan Klasse, Gunilla B. Karlsson Hedestam, Georgia D. Tomaras, Marit J. van Gils, David C. Montefiori, Adrian B. McDermott, Ollivier Hyrien, John P. Moore, Ian A. Wilson, Andrew B. Ward, David Diemert, Godelieve J. de Bree, Sarah F. Andrews, Marina Caskey, Rogier W. Sanders
Abstract
A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01 B , induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.