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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

基本信息

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
项目类别：
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

项目摘要

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