Integrating innate and adaptive pathways in vaccine responses

将先天和适应性途径整合到疫苗反应中

• 批准号: 10265794
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 150万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265794
• 关键词: Acute; Affinity; Antibodies; Antigens; Antiviral Agents; B-Lymphocytes; Cell Line; Cells; Characteristics; Clinical; Communicable Diseases; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Development; Disease; Disease susceptibility; Engineering; Exhibits; Fc domain; Flavivirus; Flavivirus Infections; Follow-Up Studies; Gene Expression Profile; Goals; Hepatitis B Virus; Heterogeneity; Human; Human Activities; IgG1; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologic Memory; Immunologics; Immunology; In Vitro; Individual; Infection; Inflammatory; Influenza; Leukocytes; Mediating; Medical; Memory B-Lymphocyte; Molecular; Monoclonal Antibodies; Mouse Strains; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Polysaccharides; Population; Predisposition; Process; Research; Rice; Risk Factors; Role; Series; Severity of illness; Shapes; Structure; Transgenic Mice; Vaccinated; Vaccination; Variant; Viral; Viral Antigens; Virus Diseases; ZIKA; ZIKV infection; cross reactivity; epidemiologic data; glycosylation; humanized mouse; immunological status; immunoregulation; in vivo; individual response; insight; novel; novel strategies; novel vaccines; pathogen; pathogenic virus; response; severe dengue; vaccination strategy; vaccine response

ABSTRACT – Overall Significant progress in basic immunology research over the last three decades has resulted in numerous medical advances and dissected the general mechanisms by which the human immune system responds to foreign antigens. However, a much more substantial understanding of the coordinated molecular mechanisms involved in eliciting immunity will be required, as each viral pathogen poses unique challenges to the immune system and the elicited immune responses are characterized by substantial heterogeneity that impacts disease susceptibility and pathogenesis. Indeed, it is expected that B-cell responses against diverse viral pathogens are uniquely evolved during infection to shape the functional activity of IgG antibodies. Studies from viral infectious diseases have shown that antiviral IgG antibodies have the capacity to mediate a wide spectrum of opposing functions: (i) protective functions, including neutralization, viral opsonization, and clearance of infected cells and (ii) pathogenic activities, which enhance viral infectivity, disease susceptibility and severity; a phenomenon termed as antibody-mediated enhancement (ADE) of disease. ADE mechanisms have been previously suggested to account for susceptibility to dengue disease, as epidemiological data support that prior flavivirus infection is the major risk factor for dengue disease, implicating the presence of cross-reactive, non-neutralizing IgG antibodies to this process. Understanding the heterogeneity of IgG responses elicited upon infection or vaccination with diverse viral antigens is therefore critical for characterizing the immunological mechanisms that drive human immunity and determine the protective vs. pathogenic activity of IgG antibodies. Our Center will feature three Projects directed by Drs. Ravetch (Project 1: Fc domain effector activity in dengue disease), Nussenzweig and Rice (Project 2: Understanding B cell memory in response to diverse virus infections), and Wang (Project 3: Immunity to dengue viruses), supported by a scientific core (Core A: Transgenic mouse core) and the administrative core (Core B). Through a series of collaborative studies between the three Projects, our Center aims to study human antiviral immune responses during infection and vaccination and characterize the immune mechanisms that regulate the function of IgG antibodies in humans. More specifically, we aim to characterize the heterogeneity of IgG responses elicited upon vaccination or infection with diverse viral pathogens, including HBV and flaviviruses, like Zika and dengue. Additionally, we will dissect the ADE mechanisms by which IgG antibodies mediate disease-enhancing activities and contribute to dengue disease susceptibility and pathogenesis. These studies will provide novel insights into the mechanisms that drive protective immunity and modulate antibody function, having a broader impact on the development of vaccination strategies against infectious pathogens.

摘要-总体 在过去的三十年中，基础免疫学研究的重大进展导致了许多医学研究。 进步和解剖的一般机制，其中人类免疫系统响应外来 抗原然而，对所涉及的协调分子机制的更实质性的理解， 需要激发免疫力，因为每种病毒病原体都会对免疫系统构成独特的挑战， 引发的免疫应答的特征在于影响疾病易感性的实质性异质性 和发病机制。事实上，预计B细胞对不同病毒病原体的反应是独特的， 在感染过程中进化形成IgG抗体的功能活性。病毒性传染病的研究 已经显示抗病毒IgG抗体具有介导广谱相反功能的能力：（i） 保护功能，包括中和、病毒调理作用和感染细胞的清除，和（ii） 致病活性，增强病毒感染性、疾病易感性和严重性;这种现象称为 抗体介导的疾病增强（ADE）。ADE机制先前已被提出， 流行病学数据支持先前的黄病毒感染是登革热的易感性， 登革热的主要危险因素，涉及交叉反应性非中和IgG抗体的存在 这个过程。了解感染或接种后引起的IgG应答的异质性 因此，不同的病毒抗原对于表征驱动人类免疫的免疫机制是至关重要的。 免疫力和确定IgG抗体的保护性与致病性活性。我们的中心将提供三个 Ravetch博士指导的项目（项目1：登革热病中的Fc结构域效应物活性），Nussenzweig和 Rice（项目2：了解应对不同病毒感染的B细胞记忆）和Wang（项目3： 免疫登革热病毒），由科学核心（核心A：转基因小鼠核心）和 核心B。通过三个项目之间的一系列合作研究，我们的中心 目的是研究感染和疫苗接种过程中人类的抗病毒免疫应答，并表征免疫应答的特征。 调节人体IgG抗体功能的机制。更具体地说，我们的目标是描述 接种疫苗或感染不同病毒病原体后引起的IgG应答的异质性，包括 HBV和黄病毒，如寨卡病毒和登革热。此外，我们还将分析IgG 抗体介导疾病增强活性并有助于登革热疾病易感性， 发病机制这些研究将为驱动保护性免疫的机制提供新的见解， 调节抗体功能，对疫苗接种策略的发展产生更广泛的影响， 传染性病原体