Development of a Yellow Fever Vaccine for Vulnerable Populations

描述（由申请人提供）：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%的死亡率。虽然YFV通常通过埃及伊蚊叮咬传播，但它也代表了一种病毒性脑炎，具有用作生物恐怖剂的潜力，因为：1）YFV的临床分离株在自然爆发期间可用和/或容易获得，2）YFV在体外用相对简单的设备生长至高滴度，以及3）当通过气溶胶途径施用时，YFV可引起致命脑炎。目前的YFV减毒活疫苗是在1936年开发的，在病毒种子批系统开发之后，50多年来没有进行过修改或其他改进。这种疫苗每百万剂可导致4例脑炎。YFV疫苗接种后的总体死亡率估计为每百万剂1至2人死亡，表明该疫苗与活天花疫苗Dryvax一样危险。自20世纪60年代以来，由于在这个年龄组中发现了高的疫苗相关性脑炎率，因此禁止对小于9个月的婴儿接种YFV疫苗。最近，已经发现YFV疫苗接种在相当数量的>60岁的患者中引起严重的内脏嗜性疾病（发病率约为1：50，000施用剂量），并且这些病例导致约50%的死亡率。这表明YFV疫苗接种不仅在婴儿中禁忌，而且由于严重和危及生命的疾病风险增加，可能很快也会在老年人中禁忌。加强监测工作还记录了几起与疫苗有关的死亡病例，这些病例发生在年轻、健康的成年人中，他们没有已知的预先存在的免疫缺陷。到目前为止，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，除了其他健康人群外，还可用于免疫婴儿和老年人等脆弱人群。我们的初步研究表明，这种疫苗的方法是可行的和高度免疫原性。在这个项目中，我们将评估候选疫苗配方，进行规模化开发，并测试对致死性YFV感染的体内功效。 公共卫生相关性：在这份可行性I期提案中，我们提供了强有力的初步数据，证明了一种专有的新疫苗平台的抗原性、免疫原性和保护效力，可用于开发更安全、更有效的YFV疫苗。

DESCRIPTION (provided by applicant): 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. Although YFV is typically spread by the bite of Aedes aegypti mosquitoes, it also represents a viral encephalitide with potential for use as a bioterrorism agent because; 1) clinical isolates of YFV are available and/or easily obtained during natural outbreaks, 2) YFV grows to high titers in vitro with relatively simple equipment, and 3) YFV can cause lethal encephalitis when administered by an aerosol route. 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. This vaccine causes 4 cases of encephalitis per million doses administered. The overall mortality rate following YFV vaccination is estimated at 1 to 2 deaths per million doses, indicating that this vaccine is as dangerous as the live smallpox vaccine, Dryvax. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to the discovery of high rates of vaccine-associated encephalitis in this age group. 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. PUBLIC HEALTH RELEVANCE: In this feasibility Phase I proposal, we provide strong preliminary data demonstrating the antigenicity, immunogenicity, and protective efficacy of a proprietary new vaccine platform that can be used to develop a safer and more effective YFV vaccine.