Development of a Yellow Fever Vaccine for Vulnerable Populations

描述(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。虽然YFV通常通过埃及伊蚊的叮咬传播，但它也代表着一种有可能被用作生物恐怖分子的病毒脑肽，因为1)YFV的临床分离株可以在自然暴发期间获得和/或很容易获得，2)YFV在体外用相对简单的设备生长到高滴度，以及3)YFV通过气雾剂途径感染可以引起致命的脑炎。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。这种疫苗每注射一百万剂就会导致4例脑炎。接种YFV疫苗后的总死亡率估计为每百万剂1至2人死亡，这表明该疫苗与天花活疫苗Dryvax一样危险。自20世纪60年代S以来，由于疫苗相关性脑炎在该年龄段的高发病率，婴儿和9个月龄婴儿一直被禁止接种YFV疫苗。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剂量接种)，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。 公共卫生相关性：在这项可行性第一阶段的提案中，我们提供了强有力的初步数据，证明了专利新疫苗平台的抗原性、免疫原性和保护效力，该平台可用于开发更安全和更有效的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.