Protective immunity following dengue virus natural infections and vaccination

描述（由申请方提供）：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，每年约有4亿例感染。宿主对DENV的免疫应答在随后的不同DENV血清型感染中提供保护或增强的机制知之甚少，这一直是疫苗开发的主要障碍。第一次概念验证登革热疫苗有效性试验的次优结果强调了更好地了解对天然DENV感染和候选疫苗的免疫反应以及确定保护的强大相关性的迫切需要。该P01计划在尼加拉瓜天然登革病毒感染的长期持续临床和流行病学研究以及武田四价登革减毒活疫苗（TV-LAV）的2期和3期疫苗试验的背景下应用最先进的免疫学方法。我们计划在协调的P01计划下研究人类B和T细胞免疫应答的定性和定量特征，包括三个项目：1）天然登革病毒感染的B细胞和抗体应答; 2）活登革减毒病毒疫苗接种后的B细胞和抗体应答; 3）登革病毒天然感染和活登革减毒病毒疫苗接种后的T细胞应答。总体假设是，DENV初治和DENV暴露个体在暴露于新的DENV感染或活疫苗后产生根本不同的保护性B和T细胞应答。此外，我们认为，中和抗体的质量和数量决定了保护效力。P01具有高度的协同作用，因为来自相同个体和/或样本集的样本以及特定的测定和方法在项目之间共享，这些项目由行政核心，免疫学核心和临床与数据管理核心支持。P01还利用了一些现有的赠款和合同，支持登革热研究、疫苗试验和表位作图计划。我们已经成立了一个由世界知名的研究人员组成的联盟，他们在登革热临床，免疫学和病毒学研究以及疫苗开发方面拥有丰富的经验和正在进行的项目-从而确保高质量的成功研究项目，特别是因为研究人员有着长期的富有成效的合作历史（超过190份联合出版物）。P01应导致：1）提高对在1°和2° DENV感染中以及在登革TVLAV的幼稚和先前DENV暴露的接受者中构成保护性适应性免疫的理解，这可以为未来的疫苗制剂提供信息; 2）鉴定天然和疫苗诱导的B细胞/抗体和CD 4 +/CD 8 + T细胞的保护相关性，其可以用于评估现有和未来的疫苗; 3）鉴定潜在的治疗性单克隆抗体和T细胞肽疫苗;和4）定位新表位和产生可用作新表位特异性诊断工具的重组病毒。

DESCRIPTION (provided by applicant): The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with ~400 million infections annually. The mechanisms by which the host immune response to DENV provides either protection or enhancement in a subsequent infection with a different DENV serotype are poorly understood, and this has been a major hindrance in vaccine development. The suboptimal results from the first proof-of-concept dengue vaccine efficacy trial highlight the critical need t better understand the immune response to natural DENV infections and vaccine candidates and to identify robust correlates of protection. This P01 Program applies state-of-the-art immunological methods in the context of long-term ongoing clinical and epidemiological studies of natural DENV infections in Nicaragua as well as Phase 2 and 3 vaccine trials of the Takeda tetravalent live-attenuated dengue vaccine (TV-LAV). We propose to study qualitative and quantitative features of B and T cell immune responses in humans under a coordinated P01 Program including three projects: 1) B cell and antibody responses to natural dengue virus infections; 2) B cell and antibody responses following live attenuated dengue virus vaccination; 3) T cell responses following DENV natural infections and live-attenuated dengue virus vaccination. The overall hypothesis is that DENV-naïve and DENV-exposed individuals develop fundamentally different protective B and T cell responses upon exposure to a new DENV infection or live vaccine. Moreover, we posit that it is the quality as well as the quantity of neutralizing antibodies that determines protective efficacy. The P01 is highly synergistic in that samples from the same individuals and/or sample sets, as well as specific assays and methodologies, are being shared among the Projects, which are supported by an Administrative Core, Immunology Core, and Clinical & Data Management Core. The P01 also leverages a number of existing grants and contracts supporting dengue studies, vaccine trials, and epitope mapping programs. We have formed a 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 high-quality successful research program, especially since the investigators have a long history of productive collaboration (>190 joint publications). The P01 should result in: 1) Improved understanding of what constitutes protective adaptive immunity in 1° and 2° DENV infections and in naïve and previously DENV-exposed recipients of a dengue TVLAV, which can inform future vaccine formulations; 2) Identification of natural and vaccine-induced B cell/antibody and CD4+/CD8+ T cell correlates of protection that can be used to assess existing and future vaccines; 3) Identification of potential therapeutic monoclonal antibodies and T cell peptide vaccines; and 4) Mapping of novel epitopes and generation of recombinant viruses that can serve as new epitope-specific diagnostic tools.