HIV broadly neutralizing antibody precursor maturation induced by mRNA vaccination in nonhuman primates

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.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-11
DOI
https://doi.org/10.64898/2026.11.10.765717
Primary Topic
HIV Research and Treatment
Type
preprint
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preprint

HIV broadly neutralizing antibody precursor maturation induced by mRNA vaccination in nonhuman primates

Xiaozhen Hu, Zhenfei Xie, Brian L. Freeman, Usha Nair et al.
bioRxiv (Cold Spring Harbor Laboratory)
HIV Research and Treatment
preprint

HIV broadly neutralizing antibody precursor maturation induced by mRNA vaccination in nonhuman primates

Xiaozhen Hu, Zhenfei Xie, Brian L. Freeman, Usha Nair, Guido Silvestri, Jon M. Steichen, Parham Ramezani-Rad, Swastik Phulera, Jordan R. Willis, Danny Lu, Ryan D. Tingle, Julia T. Ngo, John R. Yates, Shane Crotty, Jolene K. Diedrich, Sunny Himansu, Xiao Liu, James C. Paulson, Anton Kalyuzhniy, Diane G. Carnathan, Gabriel Ozorowski, Torben Schiffner, Ester Marina-Zárate, Christopher A. Cottrell, Yumiko Adachi, Paolo Lusso, Patrick J. Madden, Alessia Liguori, Ivy Phung, M. Krystal, Dennis R. Burton, Nicole Phelps, Claudia T. Flynn, William R. Schief, Erik Georgeson, Facundo D. Batista, Carolyne Kifude, Sabyasachi Baboo, Darrell J. Irvine, Jenny Tran, Kalyuzhniy Oleksandr, Andrew B. Ward, Vanessa R. Lewis, Diana Goodwin, Amber Seymour
preprint en

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.

bioRxiv (Cold Spring Harbor Laboratory)
Scripps Research Institute (US), National Institutes of Health (US), International AIDS Vaccine Initiative (US), La Jolla Institute for Immunology (US), Emory University (US), Ragon Institute of MGH, MIT and Harvard (US), National Institute of Allergy and Infectious Diseases (US), Mass General Brigham (US), Massachusetts Institute of Technology (US)
HIV Research and Treatment
DOIOpen Access PDFOpenAlex
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