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，基本免疫学研究的重大进展导致了许多医学 进步并阐述了人类免疫系统对外国反应的一般机制 抗原。但是，对所涉及的协调分子机制的更为实质性理解 在引起免疫力时，每种病毒病原体都对免疫系统面临独特的挑战，并且 引起的免疫反应的特征是实质性异质性，影响疾病的易感性 和发病机理。确实，可以预期，针对潜水病毒病原体的B细胞反应是独特的 在感染过程中进化以塑造IgG抗体的功能活性。病毒传染病的研究 已经表明，抗病毒IgG抗体具有介导广泛相反功能的能力：（i） 保护功能，包括中和，病毒调子化和被感染细胞的清除率和（ii） 致病活性，增强病毒感染，疾病易感性和严重程度；称为现象 作为抗体介导的疾病增强（ADE）。以前已经提出了ADE机制 考虑到登革热疾病的易感性，因为流行病学数据支持先前的黄病毒感染是 风扇的主要危险因素，暗示存在交叉反应性，非中和IgG抗体 到这个过程。了解感染或疫苗接种后引起的IgG反应的异质性 因此，潜水病毒抗原对于表征驱动人类的免疫机制至关重要 免疫并确定IgG抗体的受保护与致病活性。我们的中心将有三个 由Drs执导的项目。 Ravetch（项目1：FC域效应子在登革热中的活性），Nussenzweig和 大米（项目2：了解B细胞记忆以响应潜水病毒感染）和Wang（项目3： 受到科学核心（核心A：转基因鼠标核心）和粉丝的免疫力）和 行政核心（核心B）。通过三个项目之间的一系列协作研究，我们的中心 旨在研究感染和疫苗接种期间人类抗病毒药免疫复杂并表征免疫。 调节人类IgG抗体功能的机制。更具体地说，我们的目的是表征 IgG反应的异质性在疫苗接种或感染带有多种病毒病原体的感染后引起，包括 HBV和Flaviviruses，例如Zika和Dengue。此外，我们将剖析IgG的ADE机制 抗体介导了增强疾病的活动，并为疾病易感性和 发病。这些研究将提供有关推动保护性免疫学和的机制的新见解。 调节抗体功能，对疫苗接种策略的发展具有更大的影响 感染性病原体。