Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models

作者：Parham Ramezani-Rad, Christopher A. Cottrell, Ester Marina-Zárate, Alessia Liguori, Elise Landais, Jonathan L. Torres, Amber Myers, Jeong Hyun Lee, Sabyasachi Baboo, Claudia T. Flynn, Katherine McKenney, Eugenia Salcedo, Xiaoya Zhou, Oleksandr Kalyuzhniy, Erik Georgeson, Nicole Phelps, Danny Lu, Saman Eskandarzadeh, Sergey Menis, Michael Kubitz, Bettina Gröschel, Nushin Alavi, Abigail M. Jackson, Wen-Hsin Lee, Andy S. Tran, Elana Ben‐Akiva, Katarzyna Kaczmarek Michaels, Jolene K. Diedrich, Chiamaka A. Enemuo, Vanessa Lewis, Arpan Pradhan, Sudhir Pai Kasturi, Torben Schiffner, Jon M. Steichen, Diane G. Carnathan, Sunny Himansu, John R. Yates, James C. Paulson, Gabriel Ozorowski, Darrell J. Irvine, Guido Silvestri, Devin Sok, Andrew B. Ward, Shane Crotty, William R. Schief · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adw0721 · 被引用次数：30 · 研究领域：HIV Research and Treatment、RNA Interference and Gene Delivery、vaccines and immunoinformatics approaches

A protective vaccine against human immunodeficiency virus (HIV) will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope glycoprotein (Env) trimer. Nearly all vaccine strategies to induce bnAbs require the use of complex immunization regimens involving a series of different immunogens, most of which are Env trimers. Producing protein-based clinical material to evaluate such relatively complex regimens in humans presents major challenges in cost and time. Furthermore, immunization with HIV trimers as soluble proteins induces strong nonneutralizing responses to the trimer base, which is normally occluded on the virion. These base responses could potentially detract from the elicitation of nAbs and the eventual induction of bnAbs. mRNA vaccine platforms offer potential advantages over protein delivery for HIV vaccine development, including increased production speed, reduced cost, and the ability to deliver membrane-bound trimers that might facilitate improved immuno-focusing to nonbase epitopes. We report the design of mRNA-delivered soluble and membrane-bound forms of a stabilized native-like Env trimer (BG505 MD39.3); initial immunogenicity evaluation in rabbits that triggered clinical evaluation; and more comprehensive evaluation of B cell, T cell, and antibody responses in nonhuman primates. mRNA-encoded membrane-bound Env immunization elicited reduced off-target base-directed Env responses and stronger...