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

鉴定登革热疫苗和自然感染的保护和风险的血清学标记

• 批准号: 10638037
• 负责人: Derek A Cummings
• 金额: $ 69.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638037
• 关键词: Acute; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antigenic Specificity; Antigenic Variation; Attenuated; Automobile Driving; B-Lymphocytes; Biological; Biological Assay; Collection; Complement Activation; Country; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Dimensions; Disease; Effectiveness; Evaluation; Failure; Grant; Human; Immune; Immune response; Immunity; Immunologic Markers; Immunological Models; Immunologics; Immunology procedure; Individual; Infection; Label; Licensing; Licensure; Life Cycle Stages; Link; Longterm Follow-up; Measures; Mediating; Memory; Memory B-Lymphocyte; Modeling; Outcome; Participant; Performance; Peripheral Blood Mononuclear Cell; Philippines; Population; Public Health; Recording of previous events; Risk; Risk Assessment; Risk Marker; Role; Safety; Sampling; Severities; Severity of illness; System; T cell response; T-Lymphocyte; Thailand; Time; United States National Institutes of Health; Vaccinated; Vaccination; Vaccinee; Vaccines; Work; antibody-dependent cell cytotoxicity; cohort; design; disorder risk; epidemiology study; experience; follow-up; immunological diversity; improved; infection risk; mathematical model; pathogen; phase 3 testing; recruit; response; serological marker; unvaccinated; vaccine candidate; vaccine development; vaccine evaluation; vaccine trial

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.

项目概要 登革热在许多国家仍然顽固地流行。疫苗研发工作受到阻碍 对免疫反应了解甚少。我们确实知道，预先存在的疫苗接种免疫力或 历史感染是推动疾病风险的关键，然而，缺乏准确的风险或保护标记， 包括它们多年来如何变化。关于非中和抗体的作用知之甚少 功能，例如抗体依赖性细胞毒性和驱动疾病的抗体依赖性增强 风险。中和性和非中和性抗体反应尚未与细胞反应一起表征 已确定与疾病风险相关的免疫反应。在这里，我们将展开 之前关于中​​和反应多样性的工作，专门添加了非中和反应的特征 使用采集的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 来自同一个人在多个时间点上的信息。这些样本来自定期进行 收集血清和 PBMC，并跟踪感染和疾病的情况，其中许多是严重的。这 包括一组接种了唯一获得许可的登革热疫苗的个体，一组随后接受了 13年。我们还可以获得接种另一种候选疫苗的个体的样本 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 研究感染后的长期反应。我们将测量多个非中和和中和 对多种登革热病毒的反应 广泛的抗体测量以及有限的一组 细胞免疫反应，提供体液和细胞的多维系统表征 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 感染史和免疫动态。这些努力将提供一系列保护/疾病风险的相关性 和感染，可用于评估疫苗试验和流行病学研究中的风险。这些机制 模型通常可用于推断对抗原变异病原体的免疫反应动态， 可用于协助疫苗试验和流行病学研究的设计和分析。 与公共卫生的相关性 目前正在开发多种候选登革热疫苗，但是它们可能在短期内有效 由于缺乏良好的保护或风险标记，很长一段时间仍然未知。识别此类 标记物及其随时间的变化对于其最佳使用、持续疗效和人群安全至关重要。 更广泛地说，非中和抗体和细胞免疫反应对多种不同的反应的表征 登革热病毒与人类的中和反应一起跟踪了多年 登革热感染和/或疫苗接种将增加我们对登革热免疫反应的了解。