Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery

HIV/AIDS疫苗免疫学和免疫原发现中心（CHAVI-ID）将是一个新的联盟，旨在开展免疫学研究，以解决阻碍有效HIV-1疫苗开发的主要科学问题。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靶向新的HIV-1对B、T和NK细胞免疫应答的脆弱性，然后利用这些信息设计疫苗，在HIV-1传播的时间和地点诱导保护性免疫。CHAVI-ID的总体目标是设计通过在HIV-1进入位点诱导先天性抗体以及CD 4+和CD 8 + T细胞应答来预防HIV-1传播的免疫原。由于人体免疫系统的组成部分协同工作，CHAVI-ID的最终目标是设计一种实用的预防性HIV-1疫苗，该疫苗包含保护性先天性、抗体和T细胞靶向免疫原。CHAVI-ID将由CHAVI-ID主要研究者和科学领导小组沿着，以及11个科学研究支持部门的CHAVI-ID领导人和一个经验丰富的运营部门领导。 和管理支助部分。我们的CHAVI-ID研究议程的核心是研究计划，其中有三个焦点：1。保护性抗体应答的诱导，2.保护性T细胞应答的诱导和3.保护性先天反应的诱导-所有这些都直接来自于过去6年中HIV/AIDS疫苗免疫学中心（CHAVI）资助的发现，共同构成了克服阻碍有效预防疫苗开发的剩余障碍的明确途径。 Registrant Organization：CHAVI-ID将成为全球HIV-1企业的一个组成部分，由杰出的研究人员组成，他们使用最先进的技术， 通过集中的、协调的研究来消除科学知识的差距，最终目标是制造成功的HIV-1疫苗。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品，并通过进行被动和主动免疫试验以预防恒河猴中R5 SHIV感染，来鉴定先天性、T和B细胞保护性免疫应答。CHAVI-ID研究人员将使用晶体学和单粒子冷冻电子显微镜来定义保护性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，as.design用于扩大诱导T细胞应答的广度和深度的疫苗策略。CHAVl-ID将有一个行政结构，以促进消除不成功的计划，并获得新的专业知识，因为他们需要。CHAVI-ID疫苗接种者保护性免疫反应的研究将得到长期和正在进行的研究协议以及与HIV疫苗试验网络（HVTN），NIH疫苗研究中心（VRC）和军事HIV研究计划（MHRP）的合作的支持。 CHAVI-ID将由CHAVI-ID主要研究者和科学领导小组沿着以及12个科学研究支持组件（SRSC）的CHAVI-ID领导人领导（表1）。CHAVI的主要研究者（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）：来自杜克大学的Garnett Kelsoe，来自洛斯阿拉莫斯国家实验室的Bette Korber，来自哈佛大学的Norman Letvin，来自牛津大学的Andrew McMichael和来自哈佛大学的Joseph Sodroski。 相关性：过去6年来，在克服开发安全有效的HIV-1疫苗的障碍方面取得了很大进展。然而，仍然存在一些障碍。通过研究HIV-1临床试验疫苗接种者在一项适度成功的HIV-1疫苗试验（RV 144）中产生的免疫应答，以及通过研究最终产生所需免疫应答的HIV-1感染者，可以绘制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。 UM-1中心总体应用：

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: