Elimination of flavivirus infected target cells by ADCC

通过 ADCC 消除黄病毒感染的靶细胞

• 批准号: 10057300
• 负责人: Alan L Rothman
• 金额: $ 23.36万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057300
• 关键词: Antibodies; Antibody Specificity; Antibody titer measurement; Antigens; Biological Assay; Cell Line; Cells; Cellular Assay; Cessation of life; Child; Clinical; Cohort Studies; Cytolysis; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Development; Disease; Disease Outcome; Effector Cell; Flavivirus; Flavivirus Infections; Flow Cytometry; Goals; Image Cytometry; Immune; Immune Sera; Immunity; Immunoglobulin Constant Region; Immunoglobulin G; Individual; Infection; Measures; Mediating; Membrane Proteins; Monoclonal Antibodies; NK Cell Activation; Natural Killer Cells; Outcome; Peripheral Blood Mononuclear Cell; Phase; Phase III Clinical Trials; Pilot Projects; Play; Prospective Studies; Prospective cohort; Proteins; Refractory; Reporting; Reproducibility; Role; Sampling; Serotyping; Source; Surface; Thailand; Vaccines; Viral; Viremia; Virus Diseases; ZIKA; Zika Virus; Zika virus vaccine; antibody-dependent cell cytotoxicity; cohort; density; env Gene Products; immunogenic; improved; in vitro Assay; in vivo; mosquito-borne; neutralizing antibody; next generation; novel; pathogenic virus; prospective; vaccine development; vaccine trial

SUMMARY The development and widespread use of a dengue vaccine is required to significantly reduce the global dengue burden. A major goal of vaccine developers is to elicit robust immunity to each of the four antigenically distinct serotypes of dengue since all four serotypes can cause disease and death. It is likely that a zika virus vaccine will be available in the coming years. Pre-existing dengue virus immunity may impact the ability to generate an immunogenic zika vaccine. An improved understanding of the quality of Abs elicited during flavivirus infection is necessary as it is becoming clear that antibody function beyond neutralization is important. For this proposal, we will assess antibody dependent cell mediated cytotoxicity (ADCC) activity of antibodies present in well-defined zika immune sera (with and without previous dengue exposure). We have novel cell lines that enable us to assess the protein specificity of ADCC antibodies and also evaluate both target cell and effector cell activation. We will determine the relationship between antigen density and ADCC antibody titers in the sera. Finally, using pre-infection sera in individuals from Thailand who subsequently developed a subclinical or clinical dengue infection, we will correlate ADCC activity of antibodies with clinical outcome. The studies proposed are important to guide the development of an effective flavivirus vaccine.

摘要 登革热疫苗的开发和广泛使用需要 显著减轻全球登革热负担。疫苗研发人员的一个主要目标是 诱导对四种不同的登革热血清型的强大免疫力 所有四种血清型都可以导致疾病和死亡。寨卡病毒疫苗很可能会 将在未来几年推出。先前存在的登革热病毒免疫力可能会影响 产生免疫原性寨卡病毒疫苗的能力。更好地理解 黄病毒感染期间产生的抗体的质量是必要的，因为越来越明显的是 中和之外的抗体功能很重要。 对于这项建议，我们将评估抗体依赖细胞介导的细胞毒性。 (ADCC)明确定义的寨卡病毒免疫血清中存在的抗体的活性(有和没有 以前接触过登革热)。我们有新的细胞系，使我们能够评估 ADCC抗体的蛋白特异性及靶细胞和效应物的评价 细胞激活。我们将确定抗原密度与ADCC的关系 血清中的抗体滴度。最后，使用泰国人感染前的血清 谁随后发展为亚临床或临床登革热感染，我们将相互关联 抗体ADCC活性与临床结局的关系。建议的研究是重要的。 指导研制有效的黄病毒疫苗。