DEVELOPMENT OF A YELLOW FEVER VACCINE FOR VULNERABLE POPULATIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 黄热病病毒(YFV)疫苗接种已被发现在相当数量的60岁患者中导致严重的内脏疾病(发病率约为1：50,000剂量)，这些病例导致约50%的死亡。加强监测工作还记录了几例与疫苗相关的死亡病例，这些病例发生在没有已知免疫缺陷的健康成年人的年轻人群中。到目前为止，还没有替代YFV活疫苗接种的方法。在这项提案中，我们将使用一项专有的新技术来开发一种灭活疫苗配方，除了用于其他健康人群外，还可用于为婴儿和老年人等脆弱人群接种疫苗。我们的初步研究表明，这种疫苗方法是可行的，具有很高的免疫原性。在这个项目中，我们将评估候选疫苗配方，进行规模化开发，并测试体内对致命YFV感染的有效性。 到目前为止，我们已经开发了一种新的方法来定量黄热病病毒的非斑块株，使用基于流式细胞术的限制稀释法。有了这项检测，我们现在已经培育和滴定了新的致病株达喀尔1279株黄热病，并启动了恒河猴体内挑战研究。此外，我们已经用过氧化氢灭活的YFV疫苗接种了几组动物，在接下来的几周/几个月里，我们将用致死剂量达喀尔1279挑战这些动物，并确定我们的第二代YFV疫苗是否对致命挑战具有保护作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Yellow fever virus (YFV) vaccination has been found to cause severe viscerotropic disease in a substantial number of patients 60 years of age (incidence rate is approximately 1:50,000 doses administered) and these cases result in approximately 50% mortality. Increased monitoring efforts have also documented several cases of vaccine-related fatalities in young, otherwise healthy adults with no known pre-existing immune deficiencies. To date, there is no alternative to live YFV vaccination. In this proposal, we will use a proprietary new technology to develop an inactivated vaccine formulation that can be used to immunize vulnerable populations such as infants and elderly, in addition to other healthy populations. Our preliminary studies demonstrate that this vaccine approach is feasible and highly immunogenic. In this project, we will evaluate candidate vaccine formulations, perform scale-up development, and test in vivo efficacy against lethal YFV infection. To date, we have developed a novel approach to quantitating non-plaqueable strains of yellow fever virus using a flow cytometry-based limiting dilution assay. With this assay in hand, we have now grown and titrated new stocks of the virulent Dakar 1279 strain of yellow fever and initiated in vivo challenge studies in rhesus macaques. In addition, we have vaccinated groups of animals with an H2O2-inactivated YFV vaccine and in the coming weeks/months, we will challenge the animals with a lethal dose of Dakar 1279 and determine if our 2nd generation YFV vaccine is protective against lethal challenge.