Pauthner Matthias, Havenar-Daughton Colin, Sok Devin, Nkolola Joseph P, Bastidas Raiza, Boopathy Archana V, Carnathan Diane G, Chandrashekar Abishek, Cirelli Kimberly M, Cottrell Christopher A, Eroshkin Alexey M, Guenaga Javier, Kaushik Kirti, Kulp Daniel W, Liu Jinyan, McCoy Laura E, Oom Aaron L, Ozorowski Gabriel, Post Kai W, Sharma Shailendra K, Steichen Jon M, de Taeye Steven W, Tokatlian Talar, Torrents de la Peña Alba, Butera Salvatore T, LaBranche Celia C, Montefiori David C, Silvestri Guido, Wilson Ian A, Irvine Darrell J, Sanders Rogier W, Schief William R, Ward Andrew B, Wyatt Richard T, Barouch Dan H, Crotty Shane, Burton Dennis R
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Immunity. 2017 Jun 20;46(6):1073-1088.e6. doi: 10.1016/j.immuni.2017.05.007.
The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.
稳定化重组HIV包膜三聚体的研发可模拟病毒体表面分子，这使得人们对基于中和抗体（nAb）的HIV疫苗的热情高涨。然而，将重组三聚体作为免疫原应用于非人灵长类动物（通常用作人类模型）的经验有限。在此，我们对多种免疫原和免疫策略进行了直接比较测试，以确定它们对自体2级nAb产生的数量、质量和动力学的影响。一种双侧、使用佐剂的皮下免疫方案在仅间隔8周的两次免疫后即可诱导出可重复的2级nAb反应，第三次使用BG505 SOSIP三聚体免疫可进一步增强这些反应。我们鉴定出了能将非中和性V3反应降至最低的免疫原，并证明持续给予免疫原可增强nAb反应。通过淋巴结细针穿刺评估发现，nAb反应与生发中心反应密切相关。本研究为旨在诱导nAb的临床前和临床疫苗研究提供了一个框架。
