Immunity to dengue viruses

对登革热病毒的免疫力

• 批准号: 10595530
• 负责人: Taia Wang
• 金额: $ 54.46万
• 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/10595530
• 关键词: 5 year old; Address; Affinity; Age; Antibodies; Antibody Repertoire; Antibody Response; Antibody-Dependent Enhancement; Asian Americans; Attenuated; Binding; Biological Assay; Cell Line; Cells; Childhood; Clinical; Clinical Trials; Cohort Studies; Collaborations; Country; Data; Data Analyses; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Disease; Endemic Diseases; Fc Receptor; Fc domain; Flavivirus; Goals; Hospitals; Human; Immune; Immunity; Immunoglobulin G; In Vitro; Individual; Infant; Infection; Inflammatory; Latin American; Light; Mediating; Modification; Molecular; Outcome; Outpatients; Pathogenesis; Pathway interactions; Phase; Phase III Clinical Trials; Polysaccharides; Predisposition; Preparation; Production; Public Health; Recombinants; Regulation; Research Personnel; Risk; Role; Sampling Studies; Serotyping; Specificity; Testing; Vaccination; Vaccinee; Vaccines; Virus; Work; acute infection; cytokine; design; disorder risk; efficacy trial; experimental study; follow-up; monocyte; mortality; mosquito-borne; novel; patient subsets; phase III trial; predict clinical outcome; rational design; risk prediction; severe dengue; vaccine efficacy; vaccine response

PROJECT SUMMARY ! Dengue viruses are mosquito-borne flaviviruses of immense public health impact that cause a spectrum of disease in humans ranging from mild to fatal. Progression to severe dengue disease is promoted by the presence of non-neutralizing anti-dengue IgGs that modulate virus and cytokine production in Fc receptor- bearing cells. We have shown that progression to severe dengue disease is promoted by the presence of anti- dengue antibodies with abundant afucosylated Fc glycoforms, a modification that enhances affinity of the Fc for a specific activating Fc receptor, FcγRIIIa. Thus, our data point to a role for FcγRIIIa in the pathogenesis of dengue disease. In this proposal we will study samples from Phase III trials of a live, attenuated tetravalent dengue virus vaccine, CYD-TDV (Dengvaxia, Sanofi Pasteur), to define mechanism involved in human immunity to dengue viruses. Recent analyses of data from the Phase III trials of CYD-TDV showed that risk for disease was increased in some study cohorts by vaccination. This finding highlights the importance of understanding how antibody responses to dengue vaccination are regulated and molecular mechanisms by which antibodies can enhance dengue infections. Aims in this proposal will: a) define regulators of Fc fucosylation on antibodies elicited by CYD-TDV vaccination or by natural dengue infection in humans; b) define associations between post- vaccination/pre-infection anti-dengue antibody repertoires and susceptibility to dengue disease during a 5-year follow-up period after vaccination; c) define mechanisms by which FcγRIIIa impacts dengue infections and disease pathogenesis. Collectively, these aims will advance our fundamental understanding of mechanisms regulating human immunity to dengue viruses and guide the design of safe, effective dengue virus vaccines.

项目总结