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.

总结 需要开发和广泛使用登革热疫苗， 大大减轻全球登革热负担。疫苗开发者的主要目标是 引起对登革热的四种抗原性不同血清型中的每一种的强大免疫， 所有四种血清型都可导致疾病和死亡。寨卡病毒疫苗很可能 在未来几年内可用。先前存在的登革热病毒免疫力可能会影响 产生免疫原性寨卡疫苗的能力。更好地理解 在黄病毒感染期间引起的抗体的质量是必要的，因为越来越清楚的是， 除了中和作用之外，抗体的功能也很重要。 对于本提案，我们将评估抗体依赖性细胞介导的细胞毒性 明确定义的寨卡病毒免疫血清中存在的抗体的ADCC活性（有和没有 先前的登革热暴露）。我们有新的细胞系，使我们能够评估 ADCC抗体的蛋白特异性，并评估靶细胞和效应细胞 细胞激活我们将确定抗原密度和ADCC之间的关系 血清中的抗体滴度。最后，使用来自泰国的个体的感染前血清， 随后发生亚临床或临床登革热感染的患者，我们将 抗体的ADCC活性与临床结局。建议的研究是重要的 以指导有效的黄病毒疫苗的开发。