Immune phenotyping of human immune responses to dengue vaccination and challenge

人类对登革热疫苗接种和攻击的免疫反应的免疫表型

基本信息

批准号：
10595650
负责人：
Ana Fernandez-Sesma
金额：
$ 14.1万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-22 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595650
关键词：
Admixture Aftercare Architecture Area Attenuated Biological Assay Biology Cells Cellular Assay Cellular Immunity Clinical Clinical Trials Data Analyses Dengue Dengue Infection Dengue Vaccine Dengue Virus Development Disease Dissociation Elements Exanthema Flow Cytometry Formulation Generations Genetic Genomics Homo Human Humoral Immunities Immune Immune response Immunity Immunologics Immunology Individual Infection Innate Immune Response Knowledge Lead Modeling Peripheral Blood Mononuclear Cell Phenotype Population Sampling Serology Serotyping Structure of germinal center of lymph node Suspensions Time Tissue imaging Tonsil United States National Institutes of Health Vaccination Vaccinee Vaccines Viral Viremia Virus Visualization adaptive immune response data management genetic approach imaging approach immunogenicity mosquito-borne protective efficacy response transcriptomics vaccine development vaccine efficacy vaccine formulation vaccine trial virology

项目摘要

PROJECT 3: PROJECT SUMMARY Dengue virus (DENV) is the most prevalent mosquito–borne virus infecting humans in tropical and subtropical areas of the world. There are 4 DENV serotypes, namely DENV1, DENV2, DENV3 and DENV4 circulating in humans. Understanding the immunoprotective and immunopathogenic responses to dengue vaccines and responses to dengue virus (DENV) infection are critical to the development of a safe and effective dengue vaccine. To assess the innate and adaptive immune responses contributing to homo- and heterotypic immune responses to dengue vaccination and infection, we will analyze samples obtained from two clinical trials which evaluated the live attenuated dengue vaccine TV003 (LATV) or a trivalent admixture missing the DENV-2 component of TV003 (CIR287 and CIR300 respectively), against DENV-2 challenge. TV003 induced 100% protection against viremia and rash following DENV-2 challenge, the trivalent formulation induced only 20% protection against DENV-2 viremia. Using available samples from vaccine trials described above that are fully characterized serologically, we will analyze the cellular immune responses in PBMCs generated in those individuals over time, provided by the clinical core (Core B). With multiparametric immunological and genetic approaches performed by the immune phenotyping core (Core C) and genetic core (Core D), we will profile the innate and adaptive immune responses to tetra- and trivalent vaccine formulations (Aim 1) and to challenge with rDEN230, a live attenuated DENV-2 discarded as vaccine component (Aim 2). Additionally, we will use human tonsillar histocultures (HC) provided by core B to analyze the immune responses induced by different admixtures of the dengue vaccines (Aim 3). Tonsils have a well-defined spatial architecture and cellular microenvironments and can be readily dissociated for single cell assays. They also show important features to understand the generation of innate and adaptive immune responses, like the formation of germinal centers. These facts make them ideal for comparing cell suspension profiling assays such as Aurora flow cytometry with tissue imaging approaches like spatial transcriptomics (Core D). The understanding of the elements in the different vaccine formulations that confer immunogenicity and the contribution of the different serotypes to vaccine efficacy will be crucial for the development of efficacious vaccines. Our approach will provide important information on the generation of immune responses to vaccination and infections and the immune signatures induced by protective vaccines versus less protective ones as determined by the data management and analysis core (Core E). The analyses of the different cell populations present in PBMCs and in the tonsil HC will expand our knowledge on generation of innate and adaptive immune responses and will allow for the visualization of germinal center formation and other features important for the generation of protective immune responses. The team assembled in this project has the right expertise in DENV biology, immunology, and vaccine development.

项目 3：项目摘要登革热病毒（DENV）是热带和亚热带地区最流行的蚊媒病毒，感染人类世界各地有 4 种 DENV 血清型，即 DENV1、DENV2、DENV3 和 DENV4。了解登革热疫苗的免疫保护性和免疫致病性反应对登革热病毒（DENV）感染的反应对于开发安全有效的登革热病毒至关重要评估促进同型和异型免疫的先天性和适应性免疫反应。对登革热疫苗接种和感染的反应，我们将分析从两项临床试验中获得的样本评估了登革热减毒活疫苗 TV003 (LATV) 或缺少 DENV-2 的三价混合物 TV003 的组成部分（分别为 CIR287 和 CIR300），对抗 TV003 诱导的 100% 攻击。预防 DENV-2 攻击后的病毒血症和皮疹，三价制剂仅诱导 20% 使用上述疫苗试验中的可用样本来预防 DENV-2 病毒血症。通过血清学表征，我们将分析这些细胞中产生的 PBMC 中的细胞免疫反应随着时间的推移，由临床核心（核心 B）提供的多参数免疫学和遗传学。免疫表型核心（核心 C）和遗传核心（核心 D）执行的方法，我们将分析对四价和三价疫苗制剂的先天性和适应性免疫反应（目标 1）使用 rDEN230 进行攻击，这是一种作为疫苗成分丢弃的减毒活 DENV-2（目标 2）。我们将使用Core B提供的人类扁桃体组织培养物（HC）来分析诱导的免疫反应由登革热疫苗的不同混合物组成（目标 3）。扁桃体具有明确的空间结构和它们也显示出重要的作用，可以在细胞微环境中轻松分离。了解先天性和适应性免疫反应的产生的特征，例如生发细胞的形成这些事实使它们成为比较细胞悬浮液分析测定（例如 Aurora 流）的理想选择。细胞计数与组织成像方法，如空间转录组学（核心 D）。不同疫苗配方中赋予免疫原性的成分以及不同成分的贡献疫苗功效的血清型对于开发有效的疫苗至关重要。提供关于疫苗接种和感染的免疫反应的产生以及由数据确定的保护性疫苗与保护性较低的疫苗诱导的免疫特征管理和分析核心（核心 E）对 PBMC 中存在的不同细胞群进行分析。扁桃体 HC 将扩大我们对先天性和适应性免疫反应产生的认识，并将允许生发中心形成和其他对生成重要的特征的可视化该项目中组建的团队拥有 DENV 生物学方面的专业知识，免疫学和疫苗开发。