Germline-targeting HIV immunogen induces cross-neutralizing antibodies in outbred macaques

Nitesh Mishra; Bo Liang; Ryan S Roark; Amrit Raj Ghosh; Sean Callaghan; Wen-Hsin Lee; Xuduo Li; Anh L Vo; Gabriel Avillion; Rohan Roy Chowdhury; Rumi Habib; Frederic Bibollet-Ruche; Gabriella Giese; Prabhgun Oberoi; Khaled Amereh; Anjali Somanathan; Yuxin Zhu; Yuexiu Zhang; Muzaffer Kassab; Lifei Tjio; Sharaf Andrabi; Raphael A Reyes; Joel D Allen; Nicole E James; Kipchoge N Randall Jr; Lara van der Maas; Elana Ben-Akiva; Kasia Kacmarek-Michaels; Samantha Plante; Christian L Martella; Ashwin N Skelly; Ajay Singh; Jonathan Hurtado; Katharina Dueker; Tazio Capozzola; Rebecca Nedellec; Gabriel Ozorowski; Mark G Lewis; Samantha Falcone; Andrea Carfi; Sunny Himansu; Lawrence Shapiro; Max Crispin; Beatrice H Hahn; Bryan Briney; Darrell J Irvine; Dennis R Burton; Andrew B Ward; Facundo D Batista; Peter D Kwong; George M Shaw; Raiees Andrabi

doi:10.1016/j.immuni.2026.03.012

Germline-targeting HIV immunogen induces cross-neutralizing antibodies in outbred macaques

Immunity. 2026 Apr 14;59(4):1140-1160.e11. doi: 10.1016/j.immuni.2026.03.012.

Authors

Nitesh Mishra¹, Bo Liang², Ryan S Roark³, Amrit Raj Ghosh⁴, Sean Callaghan¹, Wen-Hsin Lee⁵, Xuduo Li⁶, Anh L Vo⁶, Gabriel Avillion¹, Rohan Roy Chowdhury⁶, Rumi Habib⁶, Frederic Bibollet-Ruche⁶, Gabriella Giese⁶, Prabhgun Oberoi⁶, Khaled Amereh⁶, Anjali Somanathan⁶, Yuxin Zhu⁶, Yuexiu Zhang⁶, Muzaffer Kassab², Lifei Tjio⁶, Sharaf Andrabi⁶, Raphael A Reyes⁴, Joel D Allen⁷, Nicole E James⁷, Kipchoge N Randall Jr⁵, Lara van der Maas⁵, Elana Ben-Akiva⁸, Kasia Kacmarek-Michaels⁸, Samantha Plante⁶, Christian L Martella⁶, Ashwin N Skelly⁶, Ajay Singh⁶, Jonathan Hurtado¹, Katharina Dueker¹, Tazio Capozzola⁹, Rebecca Nedellec⁶, Gabriel Ozorowski⁵, Mark G Lewis¹⁰, Samantha Falcone¹¹, Andrea Carfi¹¹, Sunny Himansu¹¹, Lawrence Shapiro¹², Max Crispin⁷, Beatrice H Hahn⁶, Bryan Briney¹, Darrell J Irvine¹³, Dennis R Burton¹⁴, Andrew B Ward¹⁵, Facundo D Batista¹⁶, Peter D Kwong¹⁷, George M Shaw¹⁸, Raiees Andrabi¹⁹

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
⁴ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Immunology, Harvard Medical School, Harvard University, Cambridge, MA 02114, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.
⁸ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Bioqual, Inc., Rockville, MD, USA.
¹¹ Moderna, Inc., Cambridge, MA 02139, USA.
¹² Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
¹³ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Immunology, Harvard Medical School, Harvard University, Cambridge, MA 02114, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁵ Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁶ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Immunology, Harvard Medical School, Harvard University, Cambridge, MA 02114, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: fbatista1@mgh.harvard.edu.
¹⁷ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA. Electronic address: pdk3@cumc.columbia.edu.
¹⁸ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shawg@pennmedicine.upenn.edu.
¹⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: raiees.andrabi@pennmedicine.upenn.edu.

PMID: 41985438
DOI: 10.1016/j.immuni.2026.03.012

Abstract

Germline targeting (GT) is a promising strategy to activate rare broadly neutralizing antibody (bnAb)-producing B cells against HIV, but induction of such responses in outbred animals has not been achieved. Using antibody-guided structure-based design, we engineered a GT HIV trimer immunogen, Q23-APEX-GT2, which primes diverse V2-apex bnAb precursors. Q23-APEX-GT2 efficiently activated rare V2-apex-specific B cells in humanized knockin mice and consistently elicited immunofocused antibody responses in outbred rhesus macaques, priming multiple long heavy-chain complementarity-determining region 3 (CDRH3)-loop bnAb-B cell lineages. Monoclonal antibodies isolated from immunized macaques showed broad heterologous HIV trimer recognition and modest cross-neutralization of diverse tier-2 viruses. Cryoelectron microscopy (cryo-EM) structural studies confirmed precise epitope targeting and revealed CDRH3-mediated binding modes that mirrored those of human V2-apex bnAbs. Together, these findings establish proof of principle for priming and early maturation of authentic V2-apex bnAb precursors in outbred macaques and highlight the promise of V2-apex-targeted HIV vaccines.

Keywords: HIV-1; Q23-APEX-GT2; V2-apex bnAb epitope; broadly neutralizing antibodies; cryo-EM structure; envelope trimer; germline targeting; long CDRH3 antibodies; tier 2 HIV neutralization; vaccines.

MeSH terms

AIDS Vaccines* / immunology
Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing* / immunology
B-Lymphocytes / immunology
Complementarity Determining Regions / immunology
Cross Reactions / immunology
Cryoelectron Microscopy
Epitopes / immunology
Germ Cells* / immunology
HIV Antibodies* / immunology
HIV Infections* / immunology
HIV-1* / immunology
Humans
Macaca mulatta
Mice

Substances

Antibodies, Neutralizing
HIV Antibodies
Epitopes
Antibodies, Monoclonal
Complementarity Determining Regions
AIDS Vaccines

Abstract

MeSH terms

Substances

Grants and funding