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Steichen, Jon M; Phung, Ivy; Salcedo, Eugenia; Ozorowski, Gabriel; Willis, Jordan R; Baboo, Sabyasachi; Liguori, Alessia; Cottrell, Christopher A; Torres, Jonathan L; Madden, Patrick J; Ma, Krystal M; Sutton, Henry J; Lee, Jeong Hyun; Kalyuzhniy, Oleksandr; Allen, Joel D; Rodriguez, Oscar L; Adachi, Yumiko; Mullen, Tina-Marie; Georgeson, Erik; Kubitz, Michael; Burns, Alison; Barman, Shawn; Mopuri, Rohini; Metz, Amanda; Altheide, Tasha K; Diedrich, Jolene K; Saha, Swati; Shields, Kaitlyn; Schultze, Steven E; Smith, Melissa L; Schiffner, Torben; Burton, Dennis R; Watson, Corey T; Bosinger, Steven E; Crispin, Max; Yates, 3rd, John R; Paulson, James C; Ward, Andrew B; Sok, Devin; Crotty, Shane; Schief, William R
Science (American Association for the Advancement of Science), 2024-May-17, Volume: 384, Issue: 6697Journal Article
Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.
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