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)曾一度在美国流行，是一种新出现/重新出现的人类病原体，可导致高达20%的死亡。目前的YFV减毒活疫苗是在1936年开发的，随着病毒种子批次制度的发展，它在50多年里没有进行过修改或其他方面的改进。最近，接种YFV疫苗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。这表明接种YFV疫苗不仅是婴儿的禁忌，而且可能很快也会在老年人中禁忌，因为严重和危及生命的疾病的风险增加。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。

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) was at one time endemic in the United States and represents an emerging/re-emerging human pathogen that causes up to 20% mortality. The current live attenuated YFV vaccine was developed in 1936 and following the development of a virus seed lot system, it has not been modified or otherwise improved in over 50 years. More recently, 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. This indicates that YFV vaccination is not only contraindicated in infants, but may soon be contraindicated in the elderly as well due to the increased risk of severe and life-threatening disease. 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.