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

Authors

• 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.

APA Citation

Caniels, Tom G.; Medina-Ramìrez, Max; Zhang, Shiyu; Kratochvil, Sven; Xian, Yuejiao; Koo, Ja-Hyun; Derking, Ronald; Samsel, Jakob; van Schooten, Jelle; Pecetta, Simone; Lamperti, Edward; Yuan, Meng; Carrasco, María Ríos; Del Moral Sánchez, Iván; Allen, Joel D.; Bouhuijs, Joey H.; Yasmeen, Anila; Ketas, Thomas J.; Snitselaar, Jonne L.; Bijl, Tom P.; Martin, Isabel Cuella; Torres, Jonathan L.; Cupo, Albert; Shirreff, Lisa; Rogers, Kenneth; Mason, Rosemarie D.; Roederer, Mario; Greene, Kelli M.; Gao, Hongmei; Silva, Catarina Mendes; Baken, Isabel J.; and Tian, Ming, "Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site" (2024). GW Authored Works. Paper 5410.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/5410

Department

Microbiology, Immunology, and Tropical Medicine