Elimination of flavivirus infected target cells by ADCC

通过 ADCC 消除黄病毒感染的靶细胞

基本信息

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
项目类别：
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

项目摘要

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.

概括需要开发和广泛使用登革热疫苗大大减轻了全球登革热负担。疫苗开发人员的主要目标是自以来对登革热的四种抗原不同的血清型中的每一种都具有强大的免疫力所有四种血清型都会引起疾病和死亡。寨卡病毒疫苗可能会未来几年可用。现有的登革热病毒免疫可能会影响能够产生免疫原性寨卡疫苗。对在黄病毒感染期间引起的ABS的质量是必要的，因为很明显超出中和的抗体功能很重要。对于此建议，我们将评估抗体依赖性细胞介导的细胞毒性（ADCC）在定义明确的Zika Immune Sera中存在的抗体活性（有和没有以前的登革热暴露）。我们有新的细胞系，使我们能够评估 ADCC抗体的蛋白质特异性，还评估靶细胞和效应子细胞激活。我们将确定抗原密度与ADCC之间的关系血清中的抗体滴度。最后，在泰国的个体中使用感染前血清后来发展了亚临床或临床登革热感染的人，我们将相关具有临床结果的抗体的ADCC活性。提出的研究很重要指导有效的黄病毒疫苗的开发。