PROJECT 2: Linking Vaccine-Induced Antibody Responses to Protective or Disease Enhancing Immunity

项目2：将疫苗诱导的抗体反应与保护性或疾病增强免疫联系起来 (北卡罗来纳大学教堂山分校)。 摘要 疫苗接种是最有希望和最具成本效益的战略，以控制由 四种登革热病毒(DENV)血清型。基于四价减毒活疫苗(TV-DLAV)的DENV疫苗 配方处于临床开发的不同阶段。最近，DENV疫苗面临着重大挑战 临床研究中的挫折，例如四种DENV血清型之间免疫反应不平衡， 疫苗效力取决于儿童的基线免疫状态，疫苗反应更多 对与疫苗株非常匹配的菌株有效，最重要的是，疫苗引发的严重 接触野生型登革热病毒引起的登革热。理解和解决这些问题一直是一个挑战 问题，因为我们仍然缺乏强大的免疫相关性来预测DENV疫苗的有效性和安全性。这个 项目2的总体方法是对接受TV-DLAV的人的抗体(Ab)反应进行表征。要链接 疫苗诱导的抗体对特定结果的反应，如保护、疫苗失败和疫苗启动 严重疾病，我们的研究利用了接种疫苗的人的样本，这些人在暴露在野生环境中时，结果已知- 键入DENVS。我们将测试这一假设，即在接种了DENV疫苗的先前对DENV没有免疫力的人中， 持久的保护将需要抗体诱导类型特定(TS)的三级和四级结构表位 针对每个DENV血清型(特异性目标1.1)。在基线血清阴性的儿童中，我们将测试是否低- 接种疫苗诱导的亲和力交叉反应(XR)抗体增加严重登革病(特异性)的风险 目标1.2)。在先前对DENV有免疫力的人中，我们将探索疫苗效力是否与 激活DENV特异性记忆B细胞并诱导交叉保护性抗体反应，类似于 自然2°DENV感染的保护性反应(特定目标2)。我们亦会进行研究，以界定 每种DENV血清型内的基因变异对疫苗效力的影响(具体目标3)。这个项目将 明确免疫相关因素和疫苗在不同水平人群中的有效性和安全性机制 对DENV的基线免疫力。项目2与本P01中的其他项目和核心具有高度的协同性。我们 将产生试剂(嵌合表位移植黄病毒和重组抗原)，供其他人使用 项目(项目1和4)，共享临床样本(核心C，项目1和3)，比较抗体对疫苗的反应 和自然DENV感染(项目1和4)，并整合抗体和T细胞反应的分析(核心B) 到DENV疫苗(项目3)。

PROJECT 2: Linking Vaccine Induced Antibody Responses to Protective or Disease Enhancing Immunity (University of North Carolina, Chapel Hill). SUMMARY Vaccination is the most promising and cost-effective strategy for controlling the global pandemic caused by the four dengue virus (DENV) serotypes. DENV vaccines based on tetravalent live attenuated (TV-DLAV) formulations are at different stages of clinical development. Recently, DENV vaccines have faced major setbacks in clinical studies, such as poorly balanced immune responses across the four DENV serotypes, variable vaccine efficacy depending on the baseline immune status of children, vaccine responses that are more effective against strains that closely match the vaccine strain and, most significantly, vaccine-primed severe dengue disease upon exposure to wild-type DENVs. It has been challenging to understand and solve these problems because we still lack robust immune correlates that predict DENV vaccine efficacy and safety. The overall approach of Project 2 is to characterize antibody (Ab) responses in people who receive TV-DLAV. To link vaccine-induced Ab responses to specific outcomes such as protection, vaccine failure and vaccine-primed severe disease, our studies utilize samples from vaccinated people with known outcomes upon exposure to wild- type DENVs. We will test the hypothesis that in people with no prior immunity to DENVs who are vaccinated, durable protection will require the induction of Abs to type-specific (TS) tertiary and quaternary structure epitopes on each DENV serotype (Specific Aim 1.1). In children who are seronegative at baseline, we will test if low- avidity cross-reactive (XR) Abs induced by vaccination increase the risk of severe dengue disease (Specific Aim 1.2). In people with pre-existing immunity to DENV, we will explore if vaccine efficacy is linked to the activation of DENV-specific memory B cells and the induction of cross-protective Ab responses, similar to protective responses in natural 2° DENV infections (Specific Aim 2). We will also conduct studies to define the impact of genotypic variation within each DENV serotype on vaccine efficacy (Specific Aim 3). This project will define immune correlates and mechanisms of vaccine efficacy and safety in people with different levels of baseline immunity to DENV. Project 2 is highly synergistic with the other Projects and Cores in this P01. We will generate reagents (chimeric epitope transplant flaviviruses and recombinant antigens) for use by other Projects (Projects 1 & 4), share clinical samples (Core C, Projects 1 & 3), compare Ab responses to vaccines and natural DENV infections (Projects 1 and 4) and integrate the analysis (Core B) of the Ab and T cell response to DENV vaccines (Project 3).