Ramezani-Rad Parham, Cottrell Christopher A, Marina-Zárate Ester, Liguori Alessia, Landais Elise, Torres Jonathan L, Myers Amber, Lee Jeong Hyun, Baboo Sabyasachi, Flynn Claudia, McKenney Katherine, Salcedo Eugenia, Zhou Xiaoya, Kalyuzhniy Oleksandr, Georgeson Erik, Phelps Nicole, Lu Danny, Eskandarzadeh Saman, Menis Sergey, Kubitz Michael, Groschel Bettina, Alavi Nushin, Jackson Abigail M, Lee Wen-Hsin, Tran Andy S, Ben-Akiva Elana, Kaczmarek Michaels Katarzyna, Diedrich Jolene K, Enemuo Chiamaka A, Lewis Vanessa, Pradhan Arpan, Kasturi Sudhir Pai, Schiffner Torben, Steichen Jon M, Carnathan Diane G, Himansu Sunny, Yates John R, Paulson James C, Ozorowski Gabriel, Irvine Darrell J, Silvestri Guido, Sok Devin, Ward Andrew B, Crotty Shane, Schief William R
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.
Sci Transl Med. 2025 Jul 30;17(809):eadw0721. doi: 10.1126/scitranslmed.adw0721.
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 nAb responses compared with mRNA-encoded soluble Env. Overall, mRNA delivery of membrane-bound Env appears promising for enhancing B cell responses to subdominant epitopes and facilitating rapid translation to clinical testing, which should assist HIV vaccine development.
一种针对人类免疫缺陷病毒（HIV）的保护性疫苗可能需要诱导能够结合HIV包膜糖蛋白（Env）三聚体上相对保守表位的广泛中和抗体（bnAbs）。几乎所有诱导bnAbs的疫苗策略都需要使用复杂的免疫方案，包括一系列不同的免疫原，其中大多数是Env三聚体。生产基于蛋白质的临床材料以在人体中评估这种相对复杂的方案在成本和时间方面面临重大挑战。此外，用可溶性蛋白质形式的HIV三聚体进行免疫会诱导对三聚体基部的强烈非中和反应，而该基部在病毒体上通常是被遮蔽的。这些针对基部的反应可能会削弱nAbs的诱导以及最终bnAbs的诱导。mRNA疫苗平台在HIV疫苗开发方面相对于蛋白质递送具有潜在优势，包括提高生产速度、降低成本以及递送膜结合三聚体的能力，这可能有助于更好地将免疫聚焦于非基部表位。我们报告了一种稳定的天然样Env三聚体（BG505 MD39.3）的mRNA递送可溶性和膜结合形式的设计；在兔子中进行的引发临床评估的初始免疫原性评估；以及在非人灵长类动物中对B细胞、T细胞和抗体反应的更全面评估。与mRNA编码的可溶性Env相比，mRNA编码的膜结合Env免疫引发的脱靶基部导向的Env反应减少，nAb反应更强。总体而言，膜结合Env的mRNA递送在增强B细胞对次要表位的反应以及促进快速转化为临床试验方面似乎很有前景，这应该有助于HIV疫苗的开发。
