YELLOW FEVER 17D-BASED CHIMERIC FLAVIVIRUS VACCINES

登革热和日本脑炎病毒是人类 全球范围的疾病和针对这两种病毒的疫苗开发 仍然是公共卫生的优先事项。基于活体的功效- 黄热病病毒减毒活疫苗的潜力 登革热和流行性乙型脑炎结构蛋白的表达 嵌合黄花病毒背景下的病毒正在 调查过了。目标1将确定一种工程嵌合病毒 可提供保护性免疫力，抵御神经致病原的攻击 乙型脑炎病毒在成年小鼠体内的感染及其亲缘关系的比较 流行性乙型脑炎的免疫原性及保护作用 疫苗产品。目标2将完全描述一种嵌合黄热病 表达登革2型病毒包膜蛋白的病毒，以及 确定这种新型病毒是否能在小鼠身上产生保护作用 模特。AIM 3将使用嵌合黄热病病毒系统来定义 流行性乙型脑炎病毒包膜内的遗传决定因素 蛋白质，它区分了高度神经毒力克隆和 无毒克隆。目标4将确定一种深刻的衰减 YS/JE-SA，4-14-2嵌合病毒 病毒复制不同阶段的包膜蛋白。这个 这项提案的总体目标是评估这种嵌合病毒 技术为人类生活的发展提供了进一步的思考 登革热、日本脑炎和其他疾病的减毒疫苗 具有重要医学意义的黄病毒，并提供更好的知识 这些病毒的分子发病机制。

Dengue and Japanese encephalitis viruses are important causes of human disease on a global scale and vaccine development against both viruses remains a public health priority. Based on the efficacy of the live- attenuated viral vaccine against yellow fever virus, the potential of expressing the structural proteins of Dengue and Japanese encephalitis viruses in the context of chimeric yellow fiver viruses is being investigated. Aim 1 will determine whether an engineered chimeric virus can provide protective immunity against challenge with neuropathogenic Japanese encephalitis virus in adult mice, and to compare relative immunogenicity and protection with available Japanese encephalitis vaccine products. Aim 2 will fully characterize a chimeric yellow fever virus expressing the envelope protein of a dengue type 2 strain, and determine whether this novel virus can elicit protection in the mouse model. Aim 3 will use the chimeric yellow fever virus system to define the genetic determinants within the Japanese encephalitis virus envelope protein, which differentiate a highly neurovirulent clone from a nonvirulent clone. Aim 4 will determine whether a profound attenuation of the YS/JE-SA, 4-14-2 chimeric virus by investigating the effects of the envelope protein on different stages of viral replication. The overall goal of this proposal is to evaluate whether this chimeric virus technology warrants further consideration for development of human live- attenuated vaccines for dengue, Japanese encephalitis, and perhaps other medically important flaviviruses and to provide better knowledge of the molecular pathogenesis of these viruses.