Identification of serological markers of protection and risk for dengue vaccines and natural infection

项目摘要 登革热在许多国家仍然顽固地流行。疫苗开发工作一直受到以下因素的阻碍 对免疫反应的理解很差。我们知道预先存在的免疫接种疫苗或 既往感染是推动疾病风险的关键，然而，缺乏准确的风险标记或保护， 包括它们在多年来是如何变化的。对非中和抗体的作用知之甚少 驾驶疾病中的功能，如抗体依赖细胞细胞毒性和抗体依赖增强 风险。中和性和非中和性抗体反应并不像细胞一样具有特征。 已被确认与疾病风险相关的免疫反应。在这里，我们将扩展到 以前关于中和反应的多样性的工作专门增加了非中和的特征 采集样本进行自然感染和疫苗接种的抗体反应和细胞免疫反应 来自同一个人的多个时间点。这些样本来自于有规律的 收集血清和PBMC，并跟踪观察感染和疾病的情况，其中许多情况很严重。这 包括一组接种了唯一获得许可的登革热疫苗的个人，随后是 13年。我们还可以获得接种了另一种候选疫苗的个人的样本 五年多了。最后，我们将重新招募队列参与者，在他们参与23年后提供样本 调查感染后的长期反应。我们将测量多个非中和和中和 对一组不同的登革热病毒的反应、广泛的抗体检测以及有限的一组 细胞免疫反应，提供体液和细胞的多维系统特征 免疫反应。我们将使用这种多维测量和数学模型来重建完整的 感染史和免疫动力学。这些努力将提供一套保护/疾病风险的相关因素 以及可用于在疫苗试验和流行病学研究中评估风险的感染。这些机械式的 模型一般可用于推断对抗原可变病原体的免疫反应动力学和 可用于协助设计和分析疫苗试验和流行病学研究。 与公共卫生的相关性 然而，多种候选登革热疫苗目前正在开发中，它们可能在短期内有效 由于缺乏良好的保护或风险标志，很长一段时间仍不得而知。确定这样的 标记物及其随时间的变化对其最佳使用、持续效力和种群安全至关重要。 更广泛地说，非中和抗体的特征和对不同类型的 登革热病毒与人类的中和反应一起跟踪了多年，他们经历了 登革热感染和/或接种疫苗将增加我们对登革热免疫反应的了解。

Project Summary Dengue remains stubbornly endemic in many countries. Vaccine development efforts have been hampered by a poor understanding of the immune response. We do know that pre-existing immunity from vaccination or historic infections is key to driving disease risk, however, accurate markers of risk or protection are lacking, including how they change over multiple years. Less is known about the role of non-neutralizing antibody functions, such as antibody-dependent cell cytotoxicity, and antibody-dependent enhancement in driving disease risk. Neutralizing and non-neutralizing antibody responses have not been characterized alongside cellular immune responses that have been identified to be associated with risk of illness. Here, we will expand upon previous work on the diversity of neutralization responses to specifically add characterization of non-neutralizing antibody responses and cellular immune responses from natural infection and vaccination using samples taken from the same individuals over numerous time points. These samples come from cohorts that had regular collection of sera and PBMC and were followed for instances of infection and illness, many of which severe. This includes a cohort of individuals that were vaccinated by the only licensed dengue vaccine, a cohort followed for 13 years. We also have access to samples from individuals vaccinated with another candidate vaccine followed over five years. Finally, we will re-recruit cohort participants to provide samples 23 years after their participation to investigate long term responses after infections. We will measure multiple non-neutralizing and neutralizing responses to a diverse set of dengue viruses a wide range of antibody measures as well as a limited set of cellular immune responses, providing a multi-dimensional, systems characterization of humoral and cellular immune responses. We will use this multi-dimensional measure and mathematical models to reconstruct full infection histories and immune dynamics. These efforts will provide a set of correlates of protection/risk of illness and infection that can be used to assess risk in vaccine trials and epidemiological studies. These mechanistic models will be generally useful to infer dynamics of immune responses to antigenically variable pathogens and can be used to assist in the design and analysis of vaccine trials and epidemiological studies. Relevance to Public Health Multiple candidate dengue vaccines are currently in development, however, their likely effectiveness over short and long time periods remain unknown due to a lack of good markers of protection or risk. Identifying such markers, and how they change over time is critical to their optimal use, continued efficacy and population safety. More broadly, characterization of non-neutralizing antibody and cellular immune responses to a diverse set of dengue viruses alongside neutralizing responses in humans followed over many years who have experienced dengue infection and/or vaccination will increase our understanding of immune responses to dengue.