Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery

描述(由申请人提供)：艾滋病毒/艾滋病疫苗免疫学和免疫原发现中心(CHAVI-ID)将是一个新的联合体，旨在进行免疫学研究，旨在解决阻碍开发有效的艾滋病毒-1疫苗的重大科学问题。在接下来的7年里，CHAVI-ID将在CHAVI联盟取得的进展的基础上，应用最先进的技术以及免疫学和病毒学工具来改进合理的HIV-1疫苗设计。我们的疫苗战略将基于识别和瞄准针对B、T和NK细胞免疫反应的新的艾滋病毒-1脆弱性，然后利用这些信息设计在艾滋病毒-1传播的时间和地点诱导保护性免疫的疫苗。CHAVI-ID的总体目标是设计免疫原，通过诱导HIV-1进入部位的先天性T细胞反应、抗体以及CD4和CD8 T细胞反应来防止HI V-1传播。由于人类免疫系统的各个组成部分协同工作，CHAVI-ID的最终目标是设计一种实用的预防性HIV-1疫苗，其中包括保护性天然免疫原、抗体和T细胞靶向免疫原。CHAVI-ID将由CHAVI-ID首席研究员和科学领导小组领导，以及CHAVI-ID 11个科学研究支持部门的负责人和一个经验丰富的操作人员 和管理支持组件。我们CHAVI-ID研究议程的核心是研究计划，该计划有三个重点：1.诱导保护性抗体反应，2.诱导保护性T细胞反应，3.诱导保护性先天反应--所有这些都直接源自艾滋病毒/艾滋病疫苗免疫学中心(CHAVI)过去6年的发现，共同构成了克服阻碍有效预防性疫苗开发的剩余障碍的明确途径。 CHAVI-ID组织：CHAVI-ID将成为全球HIV-1企业的一个组成部分，由使用最先进技术的杰出调查人员组成，该技术将解决关键问题 通过有重点的、协调的研究，最终以制造成功的HLV-1疫苗为目标，在科学知识方面存在差距。CHAVI-ID最初将通过研究从已完成的人类疫苗效力试验中获得的样本，以及通过实施被动和主动免疫试验来防止恒河猴感染R5shv，从而识别先天、T和B细胞保护性免疫反应。CHAVI-ID研究人员将使用结晶学和单粒子冷冻电子显微镜定义保护性HIV-1包膜(Env)表位的结构，设计用于驱动难以诱导的中和抗体的抗体成熟途径的疫苗策略，以及设计用于扩大诱导的T细胞反应的广度和深度的疫苗策略。CHAVl-ID将有一个管理结构，便于消除不成功的计划，并在需要时获得新的专业知识。CHAVI-ID对接种疫苗的保护性免疫反应的研究将得到长期和持续研究协议的支持，并与艾滋病毒疫苗试验网络(HVTN)、NIH疫苗研究中心(VRC)和军事艾滋病毒研究计划(MHRP)合作。CHAVI-ID将由CHAVI-ID首席研究员和科学领导小组以及CHAV1-LD 12个科学研究支持部门(SRSC)的领导人领导(表1)。CHAVI首席研究员(PI)是杜克大学的巴顿·海恩斯。他选择了五位领导人加入CHAVI科学领导小组(SLG)：杜克大学的加内特·凯尔索、洛斯阿拉莫斯国家实验室的贝特·科伯、哈佛大学的诺曼·莱文、牛津大学的安德鲁·麦克迈克尔和哈佛大学的约瑟夫·索德罗斯基。 相关性：在过去6年中，在克服开发安全有效的艾滋病毒-1疫苗的障碍方面取得了很大进展。然而，仍然存在一些路障。通过研究HIV-1临床试验受试者在一项不太成功的HIV-1疫苗试验(RV144)中做出的免疫反应，以及通过对最终做出所需免疫反应的HIV-1感染者的研究，可以绘制出一条克服最终障碍的路径，并为新的临床试验设计改进的候选疫苗。 总体UM-1中心申请：

DESCRIPTION (provided by applicant): The Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) will be a new consortium established to undertake immunologic research directed at tackling major scientific problems that hinder the development of an effective HIV-1 vaccine. Over the next 7 years, the CHAVI-ID will build on the progress made by the CHAVI consortium and apply state-of-the-art technologies and both immunologic and virologic tools to improve rational HIV-1 vaccine design. Our vaccine strategy will be based on identifying and targeting novel HIV-1 vulnerabilities to B, T and NK cell immune responses and then using this information to design vaccines that will induce protective immunity at the time and location of HIV-1 transmission. The overall CHAVI-ID goals are to design immunogens that prevent HI V-1 transmission by inducing innate, antibody as well as CD4+ and CD8+ T cell responses at the site of HIV-1 entry. Since the components of the human immune system work in concert, the final goal of the CHAVI-ID is to design a practical preventive HIV-1 vaccine that incorporates protective innate, antibody and T cell-targeted immunogens. CHAVI-ID will be led by the CHAVI-ID principal investigator and scientific leadership group along with CHAVI-ID leaders of 11 Scientific Research Support Components and an experienced Operations and Management Support Component. The centerpiece of our CHAVI-ID research agenda is the Research Program which has three Foci: 1. Induction of Protective Antibody Responses, 2. Induction of Protective T Cell Responses and 3. Induction of Protective Innate Responses-all of which are derived directly from discoveries made during the past 6 years of the Center for HIV/AIDS Vaccine Immunology (CHAVI) grant, and together constitute a clear path to overcoming the remaining obstacles preventing development of an effective preventive vaccine. CHAVI-ID Organization: The CHAVI-ID will be a component of the Global HIV-1 Enterprise comprised of outstanding investigators using state-of-the art technology that will address critical gaps in scientific knowledge through focused, coordinated studies ultimately targeted at making a successful HlV-1 vaccine. CHAVI-ID will initially work to identify innate, T, and B cell protectie immune responses by studying samples obtained from completed human vaccine efficacy trials, and by carrying out passive and active immunization trials to prevent infections by R5 SHIVs in rhesus macaques. CHAVI-ID investigators will define structures of protective HIV-1 envelope (Env) epitopes using crystallography and single particle cryoelectron microscopy, design vaccine strategies for driving antibody maturation pathways of difficult-to-induce neutralizing antibodies, as well as.design vaccine strategies for expanding the breadth and depth of induced T cell responses. CHAVl-ID will have an administrative structure that facilitates eliminating unsuccessful programs and acquiring new expertise as they are needed. CHAVI-ID studies of protective immune responses in vaccinees will be supported by long-term and ongoing research agreements and collaborations with the HIV Vaccine Trials Network (HVTN), the NIH Vaccine Research Center (VRC) and the Military HIV Research Program (MHRP). CHAVI-ID will be led by the CHAVI-ID principal investigator and scientific leadership group along with CHAVl-lD leaders of 12 Scientific Research Support Components (SRSCs) (Table 1). The CHAVI Principal Investigator (PI) is Barton Haynes at Duke University. He has chosen five leaders to join the CHAVI Scientific Leadership Group (SLG): Garnett Kelsoe from Duke University, Bette Korber from Los Alamos National Laboratory, Norman Letvin from Harvard University, Andrew McMichael from Oxford University and Joseph Sodroski from Harvard University. RELEVANCE: Much progress has been made over the past 6 years in overcoming roadblocks to development of a safe and effective HIV-1 vaccine. However, a number of roadblocks remain. By study of immune responses made by HIV-1 clinical trial vaccinees in a modestly successful HIV-1 vaccine trial (RV144), and by study of HIV-1-infected people who eventually make the desired immune responses, a path to overcoming the final roadblocks can be charted, and improved vaccine candidates designed for new clinical trials. OVERALL UM-1 CENTER APPLICATION: