Development of a Yellow Fever Vaccine for Vulnerable Population

描述（由申请人提供）：黄热病病毒（YFV）曾一度在美国流行，是一种蚊媒新发/再发人类病原体，可导致高达20%的死亡率。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。根据美国疾病控制与预防中心的数据，每100万次接种这种疫苗会导致47次严重不良事件（定义为导致住院、长期残疾或死亡）。最近的报告表明，与疫苗有关的神经系统疾病的发生率约为每10,000例疫苗接种1例。自20世纪60年代以来，由于9个月以下婴儿的疫苗相关脑炎高发率，禁止接种YFV疫苗。接种YFV疫苗后的总体（所有年龄）死亡率估计为每百万剂1至2例死亡。最近，已发现在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疫苗接种不仅在婴儿中是禁忌的，而且也不建议在老年人中接种，因为这增加了严重和危及生命的疾病的风险。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。目前，除了活的YFV疫苗接种，没有其他选择。在该提案中，我们将在GMP条件下制备灭活YFV疫苗，并进行必要的安全性、效力和稳定性研究，以便将来向FDA提交IND。这种疫苗基于专有的新技术，用于开发灭活疫苗配方，可用于免疫易感人群，如婴儿和老年人，以及其他健康人群。提供的初步数据表明，H2O2-YFV疫苗是可行的，具有高度免疫原性，并对致死性嗜内脏型黄热病提供充分的保护性免疫。本项目将在cGMP条件下制备临床级疫苗，进行体外和体内安全性/毒性试验，确定疫苗效力和长期稳定性。这些目标的成功完成将产生适合未来启动I期临床试验的cgmp级疫苗材料。

DESCRIPTION (provided by applicant): Yellow fever virus (YFV) was at one time endemic in the United States and represents a mosquito-borne 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. According to the CDC, this vaccine causes 47 severe adverse events (defined as resulting in hospitalization, long-term disability, or death) per million vaccinations. More recent reports indicate that vaccine-associated neurological disease occurs at an approximate rate of 1 case per 10,000 vaccinations. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to high rates of vaccine-associated encephalitis in this age group. The overall (all ages) mortality rate following YFV vaccination is estimated at 1 to 2 deaths per million doses. More recently, YFV vaccination has been found to cause severe viscerotropic disease in a substantial number of patients >60 years of age (an incidence rate of 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 is also not recommended in the elderly 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. There is currently no alternative to live YFV vaccination. In this proposal, we will prepare an inactivated YFV vaccine under GMP conditions and perform the necessary safety, potency, and stability studies required for a future IND submission to the FDA. This vaccine is based on proprietary new technology used to develop inactivated vaccine formulations that can be used to immunize vulnerable populations such as infants and the elderly, in addition to other healthy populations. Preliminary data is provided demonstrating that an H2O2-YFV vaccine is feasible to manufacture, highly immunogenic, and provides full protective immunity against lethal viscerotropic yellow fever. In this project, we will prepare clinical grade vaccine under cGMP conditions, perform in vitro and in vivo safety/toxicity tests, and determine vaccine potency and long-term stability. The successful completion of these objectives will result in cGMP-grade vaccine material suitable for future initiation of a Phase I clinical trial. PUBLIC HEALTH RELEVANCE: In this Phase II proposal, we provide strong preliminary data from our Phase I application demonstrating the antigenicity, immunogenicity, and protective efficacy of a proprietary new vaccine platform that can be used to develop a safer and highly effective YFV vaccine.