Protective immunity following dengue virus natural infections and vaccination

保护机制!登革热自然感染后的免疫和疫苗接种 总体P01 总结 四种登革热病毒血清型（DENV 1 - 4）引起人类最重要的蚊媒病毒性疾病， 每年有1亿个病例宿主对DENV的免疫应答提供以下机制： 针对不同DENV血清型的后续感染的保护或增强并不完全 这是疫苗开发和实施中的一个主要问题。业绩不佳 第一个注册的登革减毒活疫苗的使用突出表明，迫切需要更好地了解免疫 本发明的目的是提供针对天然DENV感染和候选疫苗的免疫应答，并鉴定保护的强有力的相关性。我们 目前的计划项目非常成功，在3.5年内产生了50多个高水平的出版物， 产生及时、专题和有影响力的关键发现。在这里，我们建议识别免疫 负责DENV感染和疫苗接种结果的机制，全面探索 抗体的抗原特异性和Fc功能性以及T细胞应答的质量 在天然DENV感染的长期持续临床和流行病学研究的背景下， 疫苗。我们整合了经典的尖端分子遗传学和系统血清学方法， 系统地检查抗体的抗原特异性和Fc特性以及效应器功能， 以及T细胞属性，预测保护或发病机制。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） 登革疫苗：疫苗诱导的抗体应答与保护性或疾病增强性免疫的联系; 3)登革病毒自然感染和减毒活登革病毒后T细胞应答的质量 疫苗接种，以及4）人抗体抑制登革病毒的遗传和结构基础。P01 在来自相同个体的样品以及特定的测定、试剂和 这些方法在项目之间共享，由一个行政核心、计算核心和管理核心支持。 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 来自尼加拉瓜登革热最长连续队列研究的样本集，以及一项队列研究 在菲律宾接受Dengvaxia®疫苗和NIH现场人体挑战研究后， 减毒疫苗我们已经扩大了我们现有的P01世界知名的研究者联盟， 在登革热临床、免疫学和病毒学研究方面的丰富经验和正在进行的项目， 疫苗开发-从而确保持续的高质量成功的研究计划。全体合伙人 有着长期的合作记录和众多的联合出版物（> 225）。具体目标 是：1）定义预测后续免疫治疗结果的抗体的抗原库和Fc特征， 登革病毒感染以及长期体液免疫反应; 2）链接疫苗诱导的抗体反应 具体结果，如保护，疫苗失败和疫苗引发的严重疾病; 3）证明 T细胞应答的质量影响感染和疫苗接种的临床结果，并调节免疫应答。 B细胞应答的数量和质量; 4）全面定义 DENV 1 - 3型特异性以及DENV交叉反应性单克隆和多克隆抗体。的 首要前提是，来自天然DENV感染、疫苗和免疫学数据的积累， 队列和人类挑战研究，加上最先进的计算模型和数据 整合，将能够鉴定新的免疫相关物， 增强，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.