Article
Author: Shirreff, Lisa ; Snitselaar, Jonne L. ; Rogers, Kenneth ; Medina-Ramìrez, Max ; Sanders, Rogier W. ; Xian, Yuejiao ; Montefiori, David C. ; Klasse, Per Johan ; Pecetta, Simone ; Baken, Isabel J. L. ; van Gils, Marit J. ; Bouhuijs, Joey H. ; Yuan, Meng ; Wilson, Ian A. ; Torres, Jonathan L. ; Tian, Ming ; Caniels, Tom G. ; Mason, Rosemarie D. ; Ozorowski, Gabriel ; Derking, Ronald ; Koo, Ja-Hyun ; Kratochvil, Sven ; Crispin, Max ; Ketas, Thomas J. ; Silva, Catarina Mendes ; Zhang, Shiyu ; van Schooten, Jelle ; Bijl, Tom P. L. ; Lamperti, Edward ; Alt, Frederick W. ; Gao, Hongmei ; Yasmeen, Anila ; Cupo, Albert ; Carrasco, María Ríos ; Seaman, Michael S. ; Pulendran, Bali ; del Moral Sánchez, Iván ; Allen, Joel D. ; Batista, Facundo D. ; Ward, Andrew B. ; Koup, Richard A. ; Greene, Kelli M. ; Moore, John P. ; Roederer, Mario ; Villinger, François J. ; Martin, Isabel Cuella ; Samsel, Jakob ; McDermott, Adrian B.
Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.