Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site

Tom G. Caniels, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Max Medina-Ramìrez, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Shiyu Zhang, Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
Sven Kratochvil, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA.
Yuejiao Xian, Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
Ja-Hyun Koo, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA.
Ronald Derking, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Jakob Samsel, Vaccine Research Center (VRC), NIAID, NIH, Bethesda, MD, USA.
Jelle van Schooten, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Simone Pecetta, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA.
Edward Lamperti, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA.
Meng Yuan, Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
María Ríos Carrasco, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Iván Del Moral Sánchez, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Joel D. Allen, School of Biological Sciences, University of Southampton, Southampton, UK.
Joey H. Bouhuijs, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Anila Yasmeen, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA.
Thomas J. Ketas, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA.
Jonne L. Snitselaar, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Tom P. Bijl, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Isabel Cuella Martin, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Jonathan L. Torres, Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
Albert Cupo, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA.
Lisa Shirreff, New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
Kenneth Rogers, New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
Rosemarie D. Mason, Vaccine Research Center (VRC), NIAID, NIH, Bethesda, MD, USA.
Mario Roederer, Vaccine Research Center (VRC), NIAID, NIH, Bethesda, MD, USA.
Kelli M. Greene, Duke University Medical Center, Durham, NC, USA.
Hongmei Gao, Duke University Medical Center, Durham, NC, USA.
Catarina Mendes Silva, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Isabel J. Baken, Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Ming Tian, Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Document Type

Journal Article

Publication Date

8-30-2024

Journal

Science immunology

Volume

9

Issue

98

DOI

10.1126/sciimmunol.adk9550

Abstract

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.

Department

Microbiology, Immunology, and Tropical Medicine

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