Gristick Harry B, Hartweger Harald, Nishimura Yoshiaki, Gavor Edem, Nagashima Kaito, Koranda Nicholas S, Gnanapragasam Priyanthi N P, Kakutani Leesa M, Segovia Luisa N, Donau Olivia K, Keeffe Jennifer R, West Anthony P, Martin Malcolm A, Nussenzweig Michel C, Bjorkman Pamela J
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Laboratory of Molecular Immunology, The Rockefeller University , New York, NY, USA.
J Exp Med. 2025 Oct 6;222(10). doi: 10.1084/jem.20250693. Epub 2025 Aug 12.
A primary goal in the development of an AIDS vaccine is the elicitation of broadly neutralizing antibodies (bNAbs) that protect against diverse HIV-1 strains. To this aim, germline-targeting immunogens have been developed to activate bNAb precursors and initiate the induction of bNAbs. While most preclinical germline-targeting HIV-1 vaccine candidates only include a single bNAb precursor epitope, an effective HIV-1 vaccine will likely require bNAbs that target multiple epitopes on Env. Here, we report a newly designed germline-targeting Env SOSIP trimer, named 3nv.2, that presents three bNAb epitopes on Env: the CD4bs, V3, and V2 epitopes. 3nv.2 forms a stable trimeric Env and binds to bNAb precursors from each of the desired epitopes. Immunization experiments in rhesus macaques and mice demonstrate 3nv.2 elicits the combined effects of its parent immunogens. Our results provide proof of concept for using a germline-targeting immunogen presenting three or more bNAb epitopes and a framework to develop improved next-generation HIV-1 vaccine candidates.
开发艾滋病疫苗的一个主要目标是诱导产生能抵御多种HIV-1毒株的广泛中和抗体（bNAb）。为实现这一目标，已开发出靶向胚系的免疫原，以激活bNAb前体并启动bNAb的诱导。虽然大多数临床前靶向胚系的HIV-1疫苗候选物仅包含单个bNAb前体表位，但有效的HIV-1疫苗可能需要能靶向Env上多个表位的bNAb。在此，我们报告一种新设计的靶向胚系的Env SOSIP三聚体，名为3nv.2，它在Env上呈现三个bNAb表位：CD4结合位点（CD4bs）、V3和V2表位。3nv.2形成稳定的三聚体Env，并与来自每个所需表位的bNAb前体结合。在恒河猴和小鼠身上进行的免疫实验表明，3nv.2引发了其亲本免疫原的联合效应。我们的结果为使用呈现三个或更多bNAb表位的靶向胚系免疫原提供了概念验证，并为开发改进的下一代HIV-1疫苗候选物提供了一个框架。
