Jardine Joseph G, Kulp Daniel W, Havenar-Daughton Colin, Sarkar Anita, Briney Bryan, Sok Devin, Sesterhenn Fabian, Ereño-Orbea June, Kalyuzhniy Oleksandr, Deresa Isaiah, Hu Xiaozhen, Spencer Skye, Jones Meaghan, Georgeson Erik, Adachi Yumiko, Kubitz Michael, deCamp Allan C, Julien Jean-Philippe, Wilson Ian A, Burton Dennis R, Crotty Shane, Schief William R
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. IAVI Neutralizing Antibody Center, 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.
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.
Science. 2016 Mar 25;351(6280):1458-63. doi: 10.1126/science.aad9195.
Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. Using deep mutational scanning and multitarget optimization, we developed a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.
诱导广泛中和抗体（bnAbs）是HIV疫苗的一个主要目标。靶向胚系的免疫原旨在通过激活bnAb胚系前体B细胞来启动bnAb的诱导。尚未解决的关键挑战是确定bnAb前体幼稚B细胞是否结合靶向胚系的免疫原，以及在人类中是否以足够高的频率出现以产生可靠的疫苗反应。通过深度突变扫描和多靶点优化，我们开发了一种针对多种VRC01类bnAbs的靶向胚系免疫原（eOD-GT8）。然后，我们使用该免疫原从未感染HIV的供体中分离出VRC01类前体幼稚B细胞。真正的VRC01类前体的频率、它们的结构以及它们与eOD-GT8的亲和力支持将这种免疫原作为人类疫苗初免的候选物。这些方法可应用于针对其他类别的HIV bnAbs以及针对其他病原体的抗体的胚系靶向。
