Maternal Antibody-Mediated Enhancement of Dengue Pathogenesis

母体抗体介导的登革热发病机制增强

基本信息

批准号：
10366012
负责人：
Sujan Shresta
金额：
$ 72.54万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-05 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366012
关键词：
9 year old Adult Affect Age Antibodies Antibody Response Antibody-Dependent Enhancement Antigen-Antibody Complex Antigens Automobile Driving Avidity Binding Biological Assay Blood Circulation CD4 Positive T Lymphocytes Cell Count Cells Child Country Data Dengue Dengue Infection Dengue Vaccine Dengue Virus Dengvaxia Development Disease Dose Epidemiology Exhibits Female Flavivirus Flavivirus Infections Flow Cytometry Frequencies Genomics Geography Health Priorities Helper-Inducer T-Lymphocyte Human Human Development Immune Immune response Immune system Immunity Immunization Immunize Immunoglobulin G Immunology Individual Infant Infection Japanese encephalitis virus Knowledge Maternal antibody Mediating Modeling Molecular Morbidity - disease rate Mothers Mus OX40 Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Persons Phylogenetic Analysis Play Population Predisposition Production Publishing RNA Regulatory Pathway Regulatory T-Lymphocyte Replicon Risk Role Serotyping System T cell response T-Lymphocyte Testing Tumor Necrosis Factor Receptor Vaccination Vaccines Viral Envelope Proteins Viral Load result Viral Pathogenesis Virus Vulnerable Populations Work ZIKV disease Zika Virus base epigenomics genomic RNA global health insight maternal vaccination mortality mosquito-borne mouse model neutralizing antibody novel novel vaccines offspring prevent prospective pup receptor response severe dengue transcriptome sequencing transcriptomics vaccination strategy vaccine candidate vaccine platform vaccine strategy vaccine-induced antibodies

项目摘要

ABSTRACT Dengue virus (DENV) represents a major threat to global health. However, the precise role of the immune system in protecting against and pathogenesis of the four DENV serotypes, which share antigenic similarities and geographic ranges with each other and other closely related flaviviruses are poorly understood. In particular, antibodies can contribute to DENV pathogenesis by mediating antibody (Ab)-dependent enhancement of infection (ADE). This project focuses on defining the features of the anti-flavivirus Ab response that contributes to ADE vs protection using epidemiologically relevant mouse models in which DENV infection of mouse pups is enhanced by maternally acquired flavivirus Abs. Our published and new data demonstrate that flavivirus vaccination-infection combinations can promote either pathogenesis or protection. Our preliminary data also show that mice lacking T follicular helper (Tfh) cell responses are unable to induce DENV IgG response, and that mice treated with an agonistic Ab that stimulates OX40, a T cell costimulatory molecule belonging to the TNF receptor superfamily, exhibit a boosted DENV IgG response, suggesting that the magnitude of the Tfh response correlates with the level of Ab response to DENV. Therefore, we hypothesize that promoting Tfh responses will increase the production of broadly-neutralizing Ab (bnAb) responses that mediate protection and minimize ADE during DENV infection. We will test this hypothesis by using an RNA replicon-based vaccine platform that induces robust T cell and Ab responses in the following Specific Aims: (1) Determine how vaccination with different flavivirus antigens affects Tfh cell and Ab responses in maternal mice and susceptibility to DENV ADE in their offspring. (2) Test whether manipulation of immunization variables and candidate T cell costimulatory pathways boosts maternal Tfh cell and Ab responses and induces a protective response to DENV2 infection in offspring. These studies will provide critical insights into the factors and mechanisms that regulate ADE vs protective immunity to DENV2 infection. This knowledge is urgently needed to inform development of DENV vaccines that protect infants and young children, the highly vulnerable populations, and other flaviviral vaccines that are safe and effective worldwide, including in countries with co-circulation of 2 or more flaviviruses. The proposed work is based on our strong track record in investigating humoral and cellular immune mechanisms during flavivirus infections using state-of-the-art mouse models. The project will also benefit from our collaborators’ expertise in Tfh cells, T cell costimulatory molecules, flaviviral Ab response in humans, development of novel vaccine platforms, and genomics assays.

抽象的登革热病毒 (DENV) 对全球健康构成重大威胁，但免疫系统的确切作用却不容忽视。具有抗原相似性的四种 DENV 血清型的防御系统和发病机制特别是，人们对黄病毒之间以及其他密切相关的黄病毒之间的地理范围知之甚少。抗体可通过介导抗体 (Ab) 依赖性增强，从而促进 DENV 发病机制该项目的重点是定义有助于抗黄病毒抗体反应的特征。使用流行病学相关的小鼠模型来比较 ADE 与保护，其中小鼠幼崽的 DENV 感染是母体获得的黄病毒抗体增强了我们发布的和新的数据表明黄病毒。我们的初步数据还表明，疫苗-感染组合可以促进发病机制或保护作用。表明缺乏滤泡辅助 T (Tfh) 细胞反应的小鼠无法诱导 DENV IgG 反应，并且用激动性抗体治疗的小鼠可以刺激 OX40，一种 T 细胞共刺激分子，属于 TNF 受体超家族，表现出增强的 DENV IgG 反应，表明 Tfh 的强度反应与对 DENV 的抗体反应水平相关，因此，我们致力于促进 Tfh。反应将增加广泛中和抗体（bnAb）反应的产生，从而介导保护和我们将通过使用基于 RNA 复制子的疫苗来检验这一假设。在以下具体目标中诱导强大的 T 细胞和抗体反应的平台：(1) 确定如何不同黄病毒抗原疫苗接种会影响母鼠 Tfh 细胞和抗体反应以及易感性 (2) 测试免疫变量和候选 T 细胞的操作。共刺激途径增强母体 Tfh 细胞和 Ab 反应并诱导对 DENV2 的保护性反应这些研究将为调节后代感染的因素和机制提供重要的见解。 ADE 与 DENV2 感染的保护性免疫的比较迫切需要这些知识来为疾病的发展提供信息。保护婴儿和幼儿、高度脆弱人群和其他黄病毒的 DENV 疫苗在全世界范围内（包括在同时流行 2 种或更多黄病毒的国家）安全有效的疫苗。拟议的工作基于我们在研究体液和细胞免疫机制方面的良好记录在使用最先进的小鼠模型进行黄病毒感染期间，该项目也将从我们的研究中受益。合作者在 Tfh 细胞、T 细胞共刺激分子、人类黄病毒抗体反应方面的专业知识，开发新型疫苗平台和基因组学检测。