Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans

Jordan R. Willis, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Madhu Prabhakaran, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Michelle Muthui, Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya.
Ansuya Naidoo, IAVI, New York, NY, USA.
Troy Sincomb, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Weiwei Wu, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Christopher A. Cottrell, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Elise Landais, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Allan C. deCamp, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Nahid R. Keshavarzi, IAVI, New York, NY, USA.
Oleksandr Kalyuzhniy, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Jeong Hyun Lee, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Linda M. Murungi, IAVI, Nairobi, Kenya.
Wilfrida A. Ogonda, Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya.
Nicole L. Yates, Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
Martin M. Corcoran, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Swastik Phulera, Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA.
Joel Musando, KAVI - Institute of Clinical Research, University of Nairobi, Nairobi, Kenya.
Amanda Tsai, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Gabrielle Lemire, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Yiakon Sein, Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya.
Michael Muteti, Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya.
Praveen Alamuri, IAVI, New York, NY, USA.
Jennifer A. Bohl, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Drienna Holman, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Sunny Himansu, Moderna, Cambridge, MA, USA.
Brett Leav, Moderna, Cambridge, MA, USA.
Caroline Reuter, Moderna, Cambridge, MA, USA.
Li-An Lin, Moderna, Cambridge, MA, USA.
Baoyu Ding, Moderna, Cambridge, MA, USA.
Chunla He, Moderna, Cambridge, MA, USA.
Walter L. Straus, Moderna, Cambridge, MA, USA.

Document Type

Journal Article

Publication Date

5-15-2025

Journal

Science (New York, N.Y.)

DOI

10.1126/science.adr8382

Abstract

A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI-G002 in the United States and IAVI-G003 in Rwanda and South Africa, we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI-G002). The vaccines were generally safe and well tolerated, except 18% of IAVI-G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM, and heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development. The results establish clinical proof of concept that heterologous boosting can advance bnAb-precursor maturation and demonstrate bnAb priming in Africa where the HIV burden is highest.

Department

Medicine

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