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: 10595522
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 208.74万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595522
• 关键词: Acute; Affinity; Antibodies; Antigens; 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; Vaccinee; 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; vaccine strategy

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 过去三十年来基础免疫学研究取得了重大进展，产生了许多医学成果 进步并剖析了人类免疫系统对外来反应的一般机制 抗原。然而，对所涉及的协调分子机制有更深入的了解 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， 引发的免疫反应具有显着的异质性，影响疾病易感性 及发病机制。事实上，预计 B 细胞针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。病毒感染性疾病的研究 研究表明，抗病毒 IgG 抗体能够介导广泛的相反功能：(i) 保护功能，包括中和、病毒调理作用和感染细胞的清除；(ii) 致病活性，增强病毒传染性、疾病易感性和严重程度；一种现象称为 作为抗体介导的疾病增强（ADE）。 ADE 机制之前已被建议 解释了对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 登革热的主要危险因素，涉及交叉反应性、非中和性 IgG 抗体的存在 到这个过程。了解感染或接种疫苗后引起的 IgG 反应的异质性 因此，不同的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 抗体的保护活性与致病活性。我们的中心将设有三个 博士指导的项目。 Ravetch（项目 1：登革热病中的 Fc 结构域效应子活性）、Nussenzweig 和 Rice（项目 2：了解 B 细胞记忆对不同病毒感染的反应）和 Wang（项目 3： 对登革热病毒的免疫力），由科学核心（核心 A：转基因小鼠核心）和 行政核心（核心B）。通过这三个项目之间的一系列合作研究，我们的中心 旨在研究感染和疫苗接种过程中人类抗病毒免疫反应并表征免疫 调节人类 IgG 抗体功能的机制。更具体地说，我们的目标是表征 疫苗接种或感染不同病毒病原体时引起的 IgG 反应的异质性，包括 乙型肝炎病毒和黄病毒，如寨卡病毒和登革热。此外，我们将剖析 IgG 的 ADE 机制 抗体介导疾病增强活动并导致登革热病易感性和 发病。这些研究将为驱动保护性免疫和保护性免疫的机制提供新的见解。 调节抗体功能，对疫苗接种策略的制定产生更广泛的影响 传染性病原体。

项目成果

High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape.

• DOI: 10.1038/s41586-021-04005-0
• 发表时间: 2021-12
• 期刊: Nature
• 影响因子: 64.8

Antibody fucosylation predicts disease severity in secondary dengue infection.

• DOI: 10.1126/science.abc7303
• 发表时间: 2021-06-04
• 期刊: Science (New York, N.Y.)
• 作者: Bournazos S;Vo HTM;Duong V;Auerswald H;Ly S;Sakuntabhai A;Dussart P;Cantaert T;Ravetch JV
• 通讯作者: Ravetch JV

Single-Cell Sorting of HBsAg-Binding Memory B Cells from Human Peripheral Blood Mononuclear Cells and Antibody Cloning.

人外周血单核细胞中 HBsAg 结合记忆 B 细胞的单细胞分选和抗体克隆

• DOI: 10.1016/j.xpro.2020.100129
• 发表时间: 2020-12-18
• 期刊: STAR protocols
• 作者: Zhou Y;Liu Z;Wang Z;Zhang Q;Mayer CT;Schoofs T;Nussenzweig MC;de Jong YP;Wang Q
• 通讯作者: Wang Q

Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination.

• DOI: 10.1038/s41586-021-04060-7
• 发表时间: 2021-12
• 期刊: Nature
• 影响因子: 64.8
• 作者: Cho A;Muecksch F;Schaefer-Babajew D;Wang Z;Finkin S;Gaebler C;Ramos V;Cipolla M;Mendoza P;Agudelo M;Bednarski E;DaSilva J;Shimeliovich I;Dizon J;Daga M;Millard KG;Turroja M;Schmidt F;Zhang F;Tanfous TB;Jankovic M;Oliveria TY;Gazumyan A;Caskey M;Bieniasz PD;Hatziioannou T;Nussenzweig MC
• 通讯作者: Nussenzweig MC

Human dendritic cells (DCs) are derived from distinct circulating precursors that are precommitted to become CD1c+ or CD141+ DCs.

• DOI: 10.1084/jem.20161135
• 发表时间: 2016-12-12
• 期刊: The Journal of experimental medicine
• 作者: Breton G;Zheng S;Valieris R;Tojal da Silva I;Satija R;Nussenzweig MC
• 通讯作者: Nussenzweig MC