HUMAN IMMUNE RESPONSES TO YELLOW FEVER VIRUS

人类对黄热病病毒的免疫反应

• 批准号: 6719605
• 负责人: Sharone Green
• 金额: $ 11.77万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719605
• 关键词: cellular immunity; clinical research; cytotoxic T lymphocyte; dengue virus; human subject; immunologic memory; neutralizing antibody; recombinant virus; viral vaccines; virus antigen; virus load; yellow fever; yellow fever virus

DESCRIPTION (adapted from application abstract): Yellow fever virus (YF) infections are an important and emerging health problem in Africa and South America, despite the availability of the licensed, safe and immunogenic YF 17D strain vaccine. Little is known about the cellular immune responses to YF or the mechanism of pathogenesis in humans. T lymphocyte studies in a related human flavivirus, dengue, have demonstrated that CD4+ and CD8+ memory T cells are generated with the nonstructural NS3 protein as an immunodominant protein. Recently chimaeric flaviviruses have been developed with a YF nonstructural gene as a backbone for Japanese encephalitis (JE) structural genes. These new vaccines will soon enter Phase I clinical trials and further emphasize the importance of learning more about human immune responses to YF. There are two major goals presented training and research in human immune responses to yellow fever virus. To achieve the first goal training a two-year curriculum involving didactic training in biochemistry, molecular biology, cellular and molecular immunology, biostatistics and epidemiology. Laboratory rotations will complement didactic studies in the area of molecular biology. The candidate will learn (1) to construct a vaccines/YF NS3 recombinant virus; (2) to design primers to develop a qualitative nested RT-PCR for the detection of YF RNA in human primate specimens; (3) to create a competitor for the development of a quantitative competitor RT-PCR for the titration of YF RNA; (4) to engineer a YF/dengue chimaeric virus. The molecular reagents developed above will be utilized in the Research Plan. The specific aims are: (1) to define the immunodominant proteins recognized by T lymphocytes in TF- vaccinated individuals; (2) To examine viral replication by quantitative RT- PCR during primary infection/vaccination and its relationship to clinical and/or immunological outcome; (3) To determine if a correlation exists between the pre-existing level of memory cytotoxic T lymphocyte response or neutralizing antibody responses and the development of subsequent viremia, neutralizing antibody responses and/or cellular immune responses following administration of a second dose of YF or chimaeric YF/JE vaccine.

描述（根据应用摘要改编）：黄热病病毒（YF） 感染是非洲和南方的重要且新兴的健康问题 尽管有许可，安全和免疫原性的YF 17d有效期 应变疫苗。 关于YF或YF的细胞免疫反应知之甚少 人类发病机理的机制。 相关的T淋巴细胞研究 登革热的人类黄病毒已经证明了CD4+和CD8+记忆T细胞 由非结构性NS3蛋白作为免疫主导蛋白产生。 最近已经开发了Chimaeric Flavivirus 基因作为日本脑炎（JE）结构基因的骨干。 这些新 疫苗将很快进入I期临床试验，并进一步强调 了解更多有关人类免疫反应的重要性。 有两个 主要目标是针对人类免疫反应的培训和研究 黄热病病毒。 为了实现第一个目标训练两年 课程涉及生物化学中的教学培训，分子生物学， 细胞和分子免疫学，生物统计学和流行病学。 实验室 旋转将补充分子生物学领域的教学研究。 候选人将学习（1）以构建疫苗/YF NS3重组病毒； （2）设计底漆以开发定性嵌套的RT-PCR进行检测 人类灵长类动物标本中的YF RNA； （3）为 开发用于滴定YF RNA的定量竞争者RT-PCR； （4）设计YF/Dengue Chimaeric病毒。 分子试剂开发了 以上将用于研究计划。具体目的是：（1） 定义TF-中T淋巴细胞识别的免疫主导蛋白 疫苗接种的人； （2）通过定量RT-检查病毒复制 原发性感染/疫苗接种期间的PCR及其与临床的关系 和/或免疫学结果； （3）确定是否存在相关性 记忆细胞毒性T淋巴细胞反应的预先存在水平或 中和抗体反应和随后病毒血症的发展， 中和抗体反应和/或细胞免疫反应之后 给予第二剂YF或Chimaeric YF/JE疫苗。