Protective immunity following dengue virus natural infections and vaccination

登革热自然感染和疫苗接种后保护性免疫机制的研究 整体P01 摘要 登革热病毒的四种血清型(DENV1-4)会导致人类最重要的蚊媒病毒疾病， 每年有1亿个病例。宿主对DENV的免疫反应提供以下两种机制 对不同DENV血清型的后续感染的保护或增强并不完全 理解，这一直是疫苗开发和实施中的一个主要关切。糟糕的结果 首次登记的登革热减毒活疫苗凸显了更好地了解免疫的迫切需要 对自然DENV感染和候选疫苗的反应，并确定强有力的保护相关性。我们的 当前计划项目非常成功，在3.5年内出版了50篇高水平出版物， 产生及时的、有针对性的和有影响力的关键发现。在这里，我们建议将免疫 全面探索影响DENV感染和疫苗接种效果的机制 抗体的抗原特异性和Fc功能以及T细胞应答的质量 在对自然DENV感染和感染进行长期临床和流行病学研究的背景下 疫苗。我们集成了经典的尖端分子遗传学和系统血清学方法来 系统检测抗体的抗原特异性、Fc特性和效应器功能 以及T细胞属性，预测保护或致病机制。我们提出了一个协调的P01计划， 包括四个项目：1)B细胞的质量和对自然登革病毒感染的抗体反应；2) 登革热疫苗：将疫苗诱导的抗体反应与保护性或疾病增强性免疫联系起来； 3)登革病毒自然感染和减毒活病毒后T细胞反应的质量 疫苗接种，以及4)人类抗体抑制登革病毒的遗传和结构基础。《P01》 是高度协同作用，因为来自相同个体的样品以及特定的分析、试剂和 方法论在项目之间共享，这些项目由管理核心计算支持 生物学和统计建模核心，以及临床和数据管理核心。我们将利用独特的 来自尼加拉瓜最长的登革热连续队列研究以及队列研究的样本集 跟踪菲律宾登革热®疫苗的接受者和NIH LIVE的人类挑战研究 减毒疫苗。我们已经扩大了我们现有的P01世界知名调查人员联盟 在登革热临床、免疫学和病毒学研究以及 疫苗开发--从而确保持续高质量的成功研究计划。所有的合作伙伴 有长期的合作记录和许多联合出版物(&gt；225)。具体目标 是：1)确定抗体的抗原库和Fc特征，以预测随后的结果 DENV感染与长期体液免疫应答；2)LINK疫苗诱导抗体应答 针对特定结果，如保护、疫苗失效和疫苗引发的严重疾病；3)展示 T细胞反应的质量影响感染和疫苗接种的临床结果，并调节 B细胞应答的数量和质量；4)全面定义保护性抗原谱 DENV1-3型特异性以及DENV交叉反应的单抗和多克隆抗体。这个 首要前提是来自自然DENV感染的免疫学数据的积累，疫苗 队列，人类挑战研究，加上最先进的计算模型和数据 整合，将使识别预测保护性免疫或免疫的新免疫关联成为可能 改进，为评估现有和第二代DENV疫苗提供关键指标。

Mechanisms of Protective!Immunity after Dengue Natural Infections and Vaccination OVERALL P01 SUMMARY The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with 100 million cases annually. The mechanisms by which the host immune response to DENV provides either protection against or enhancement of a subsequent infection with a different DENV serotype are not fully understood, and this has been a major concern in vaccine development and implementation. The poor results of the first registered dengue live attenuated vaccine highlight the critical need to better understand the immune response to natural DENV infections and vaccine candidates and to identify robust correlates of protection. Our current Program Project has been very successful, generating >50 high-level publications in 3.5 years and producing key findings that are timely, topical, and impactful. Here, we propose to identify immune mechanisms responsible for outcomes of DENV infection and vaccination, comprehensively exploring both the antigenic specificity and Fc functionality of antibodies as well as the quality of T cell responses in the context of long-term ongoing clinical and epidemiological studies of natural DENV infections and vaccines. We integrate classical cutting-edge molecular genetic and systems serology approaches to systematically examine both antigen specificity and Fc characteristics and effector functions of antibodies, as well as T cell attributes, that predict protection or pathogenesis. We propose a coordinated P01 Program that includes four projects: 1) Quality of B Cell and Antibody Responses to Natural Dengue Virus Infections; 2) Dengue Vaccines: Linking Vaccine-Induced Antibody Responses to Protective or Disease-Enhancing Immunity; 3) Quality of T Cell Responses Following Dengue Virus Natural Infections and Live-Attenuated Dengue Virus Vaccination, and 4) Genetic and Structural Basis for Human Antibody Inhibition of Dengue Viruses. The P01 is highly synergistic in that samples from the same individuals, as well as specific assays, reagents and methodologies, are shared among the Projects, which are supported by an Administrative Core, Computational Biology and Statistical Modeling Core, and Clinical and Data Management Core. We will leverage unique sample sets from the longest continuous cohort study of dengue, in Nicaragua, as well as a cohort study following recipients of the Dengvaxia® vaccine in the Philippines and human challenge studies of the NIH live attenuated vaccine. We have have expanded our existing P01 Consortium of world-renowned investigators with extensive experience and on-going programs in dengue clinical, immunological, and virological research and vaccine development – thus ensuring a continued high-quality successful research program. All the partners have a long-standing record of collaboration and numerous joint publications (>225). The Specific Aims are: 1) Define the antigenic repertoire and Fc characteristics of antibodies that predict outcome of subsequent DENV infection as well as the long-term humoral immune response; 2) Link vaccine-induced antibody responses to specific outcomes such as protection, vaccine failure and vaccine-primed severe disease; 3) Demonstrate that quality of T cell responses influences the clinical outcomes of infection and vaccination and modulates the quantity and quality of B cell responses; 4) Comprehensively define the protective antigenic landscape of DENV1-3 type-specific as well as DENV cross-reactive monoclonal and polyclonal antibodies. The overarching premise is that the accumulation of immunologic data from natural DENV infections, vaccine cohorts, and human challenge studies, coupled with state-of-the-art computational modeling and data integration, will enable identification of new immune correlates that predict protective immunity or immune enhancement, providing critical metrics for evaluating existing and second-generation DENV vaccines.