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/再出现的人类病原体，可导致高达20%的死亡率。虽然YFV通常通过埃及伊蚊的叮咬传播，但它也代表了一种可能用作生物恐怖主义剂的病毒性脑肽，因为；1) YFV的临床分离株在自然暴发期间是可用的和/或容易获得的，2)YFV在体外用相对简单的设备就能生长到高滴度，3)通过气溶胶途径给药时，YFV可引起致命的脑炎。目前的YFV减毒活疫苗是在1936年开发的，在病毒种子批次系统开发之后，50多年来没有对其进行修改或以其他方式进行改进。这种疫苗每注射100万剂就会导致4例脑炎。接种YFV疫苗后的总死亡率估计为每百万剂量1至2例死亡，表明这种疫苗与天花活疫苗Dryvax一样危险。自20世纪60年代以来，由于在9个月以下的婴儿中发现疫苗相关脑炎的高发率，禁止对9个月以下的婴儿接种YFV疫苗。最近发现，在60岁至60岁的大量患者中，接种YFV疫苗可导致严重的嗜内脏疾病（发病率约为1:50 000剂），这些病例导致约50%的死亡率。这表明，YFV疫苗接种不仅是婴儿的禁忌症，而且由于严重和危及生命的疾病的风险增加，可能很快也会在老年人中成为禁忌症。加强监测工作还记录了几例与疫苗有关的死亡病例，这些病例发生在没有已知免疫缺陷的年轻健康成年人中。迄今为止，除了活的YFV疫苗接种，没有其他选择。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，还可用于对婴儿和老年人等弱势群体进行免疫。我们的初步研究表明，这种疫苗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，进行大规模开发，并测试针对致命YFV感染的体内功效。

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.