Precise targeting of HIV broadly neutralizing antibody precursors in humans

Tom G. Caniels, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Madhu Prabhakaran, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Gabriel Ozorowski, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Kellie J. MacPhee, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Weiwei Wu, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Karlijn van der Straten, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Sashank Agrawal, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Ronald Derking, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Emma I. Reiss, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Katrina Millard, Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
Martina Turroja, Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
Aimee Desrosiers, Vaccine Research Unit, The George Washington University, Washington, DC, USA.
Jeffrey Bethony, Vaccine Research Unit, The George Washington University, Washington, DC, USA.
Elissa Malkin, Vaccine Research Unit, The George Washington University, Washington, DC, USA.
Marinus H. Liesdek, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Annelou van der Veen, Department of Internal Medicine, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Michelle Klouwens, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, Netherlands.
Jonne L. Snitselaar, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Joey H. Bouhuijs, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Rhianna Bronson, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Jalen Jean-Baptiste, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Suprabhath Gajjala, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Zahra Rikhtegaran Tehrani, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Alison Benner, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Mukundhan Ramaswami, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Michael O. Duff, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Yung-Wen Liu, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Alicia H. Sato, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Ju Yeong Kim, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Isabel J. Baken, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Catarina Mendes Silva, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.
Tom P. Bijl, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, location AMC, Amsterdam, Netherlands.

Document Type

Journal Article

Publication Date

5-15-2025

Journal

Science (New York, N.Y.)

DOI

10.1126/science.adv5572

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, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, that 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.

Department

Microbiology, Immunology, and Tropical Medicine

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