Maternal Antibody-Mediated Enhancement of Dengue Pathogenesis

母体抗体介导的登革热发病机制增强

• 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
• 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

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）代表了对全球健康的主要威胁。但是，免疫的确切作用 四种DENV血清型的保护和发病机理的系统，它们具有抗原相似性 彼此之间的地理范围和其他密切相关的黄病毒的理解很少。尤其， 抗体可以通过介导抗体（AB）依赖性增强来促进DENV发病机理 感染（ADE）。该项目着重于定义有助于抗流血病病毒AB反应的特征 使用流行病学相关的小鼠模型来保护小鼠幼崽的DENV感染是 通过主要获得的黄病毒ABS增强。我们已发布的新数据表明了Flavivivirus 疫苗接种感染组合可以促进发病机理或保护。我们的初步数据 表明缺乏T卵泡辅助器（TFH）细胞反应的小鼠无法诱导DENV IgG反应，并且 用刺激OX40的激动AB处理的小鼠，T细胞属于属于该的T细胞 TNF受体超家族，暴露了增强的DENV IgG响应，表明TFH的大小 响应与AB对DENV的响应水平相关。因此，我们假设促进TFH 响应将增加介导保护和 在DENV感染期间最小化ADE。我们将通过使用基于RNA复制品的疫苗来检验该假设 在以下特定目的中影响强大的T细胞和AB响应的平台：（1）确定如何 使用不同黄病毒抗原的疫苗接种会影响母亲小鼠的TFH细胞和AB反应 要在他们的后代。 （2）测试是否操纵免疫变量和候选T细胞 共刺激途径增强材料TFH细胞和AB反应，并引起对DENV2的受保护响应 后代感染。这些研究将为调节的因素和机制提供关键的见解 ADE与DENV2感染的保护性免疫。迫切需要这些知识来告知开发 保护婴儿和幼儿，高度脆弱人群和其他黄素的DENV疫苗 在全球范围内安全有效的疫苗，包括在2个或更多黄病毒的共同循环的国家中。 拟议的工作是基于我们在研究体液和细胞免疫组机制方面的强大记录 在黄病毒感染期间，使用最先进的小鼠模型。该项目也将从我们的 合作者在TFH细胞，T细胞共刺激分子，人类黄素AB反应方面的专业知识， 开发新型疫苗平台和基因组学测定法。