HIV broadly neutralizing antibody precursor maturation induced by mRNA vaccination in nonhuman primates
Year: 2026
Type: preprint
Abstract: The induction of broadly neutralizing antibodies (bnAbs) is a principal goal of prophylactic HIV vaccines. For many bnAbs, priming ultrarare precursors from the naive B cell repertoire is the first major immunological hurdle. Previous studies have shown that the germline-targeting (GT) priming immunogen N332-GT5 delivered as adjuvanted protein to non-human primates (NHPs) activates bnAb precursor B cells for the human bnAb BG18 targeting the V3-glycan supersite on the HIV envelope (Env) glycoprotein. Here, we engineered N332-GT6 to improve binding affinity to diverse BG18-class precursor naive B cells by 9-fold. mRNA-LNP vaccines expressing N332-GT5 or N332-GT6 as membrane-bound (gp151) trimers were evaluated for their ability to prime BG18-class precursor B cells in NHPs across three related studies. Although N332-GT5 gp151 mRNA-LNP priming induced BG18-class precursor B cells in most animals after two vaccinations, the higher-affinity N332-GT6 gp151 induced responses more consistently after only one immunization. Sequential vaccination with two heterologous mRNA-LNP booster immunizations drove affinity maturation and induced BG18-class memory B cells capable of binding wildtype HIV Env. Together, these findings demonstrate that mRNA immunization can achieve GT priming, boosting, and early maturation of ultrarare bnAb-class B cells in NHPs.
Authors: Ivy Phung, Brian L. Freeman, Alessia Liguori, Amber Seymour, Zhenfei Xie, Swastik Phulera, Oleksandr Kalyuzhniy, Patrick J. Madden, Ester Marina-Zarate, Jordan R. Willis, Christopher A. Cottrell, Krystal M. Ma, Sabyasachi Baboo, Claudia T. Flynn, Carolyne Kifude, Danny Lu, Nicole Phelps, Diana Goodwin, Yumiko Adachi, Ryan Tingle, Erik Georgeson, Jenny Tran, Anton Kalyuzhniy, Xiaozhen Hu, Vanessa R. Lewis, Julia T. Ngo, Xiaotie Liu, Jolene K. Diedrich, Usha Nair, Sunny Himansu, Torben Schiffner, Paolo Lusso, James C. Paulson, John R. Yates, Diane G. Carnathan, Dennis R. Burton, Darrell J. Irvine, Guido Silvestri, Andrew B. Ward, Gabriel Ozorowski, Facundo D. Batista, Parham Ramezani-Rad, Jon M. Steichen, Shane Crotty, William R. Schief
Institutions: La Jolla Institute for Immunology, Scripps Research Institute, Ragon Institute of MGH, MIT and Harvard, Mass General Brigham, Massachusetts Institute of Technology, International AIDS Vaccine Initiative, Emory University, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225792016
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