Development of a Yellow Fever Vaccine for Vulnerable Population

为弱势群体开发黄热病疫苗

• 批准号: 8056918
• 负责人: Ian James Amanna
• 金额: $ 99.99万
• 依托单位: NAJIT TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056918
• 关键词: Adult; Age; Age-Months; Age-Years; Attenuated; Attenuated Vaccines; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Collaborations; Communities; Consultations; Culicidae; Cyclic GMP; Data; Developing Countries; Development; Disease; Dose; Drug Formulations; Elderly; Emerging Communicable Diseases; Encephalitis; Future; Generations; Growth; Human; Hydrogen Peroxide; Immune; Immunity; In Vitro; Inactivated Vaccines; Incidence; Industry; Infant; Investigation; Life; Military Personnel; Monitor; Morbidity - disease rate; Mus; Nigeria; Oral; Oral Poliovirus Vaccine; Oryctolagus cuniculus; Outcome; Paralysed; Patients; Peru; Phase; Phase I Clinical Trials; Poliomyelitis; Population; Population Heterogeneity; Price; Proteins; Recommendation; Reporting; Resources; Risk; Safety; Schedule; Seeds; Serious Adverse Event; Severe Adverse Event; Small Business Innovation Research Grant; Smallpox; Soldier; System; Technology; Testing; Time; Toxicity Tests; Toxicology; United States; Vaccination; Vaccines; Virus; Vulnerable Populations; Work; World Health Organization; Yellow Fever; Yellow Fever Vaccine; Yellow fever virus; age group; base; design; disability; immunogenic; immunogenicity; improved; in vivo; long term hospitalization; meetings; mortality; nervous system disorder; neurotropic; new technology; nonhuman primate; novel strategies; novel vaccines; pathogen; potency testing; protective efficacy; safety testing; stability testing; vaccine candidate

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.

描述（由申请人提供）：黄热病病毒 (YFV) 曾在美国流行，是一种由蚊子传播的新出现/重新出现的人类病原体，可导致高达 20% 的死亡率。目前的 YFV 减毒活疫苗于 1936 年开发出来，随着病毒种子批系统的开发，它在 50 多年来没有经过修改或其他改进。据 CDC 称，每百万次接种该疫苗会导致 47 起严重不良事件（定义为导致住院、长期残疾或死亡）。最近的报告表明，与疫苗相关的神经系统疾病的发生率约为每 10,000 次疫苗接种中 1 例。自 20 世纪 60 年代以来，9 个月以下的婴儿就被禁止接种 YFV 疫苗，因为该年龄段的疫苗相关脑炎发病率很高。黄热病疫苗接种后的总体（所有年龄段）死亡率估计为每百万剂 1 至 2 人死亡。最近，人们发现，YFV 疫苗接种会在大量 60 岁以上的患者中引起严重的内脏疾病（发病率约为 1:50,000 剂注射剂量），这些病例导致大约 50% 的死亡率。这表明黄热病疫苗不仅禁止婴儿接种，而且也不建议老年人接种，因为这会增加患严重和危及生命疾病的风险。加强监测工作还记录了几起与疫苗相关的死亡病例，这些死亡病例都是健康的年轻人，没有已知的预先存在的免疫缺陷。目前没有其他方法可以替代 YFV 活疫苗接种。在此提案中，我们将在 GMP 条件下制备灭活 YFV 疫苗，并进行未来向 FDA 提交 IND 所需的必要安全性、效力和稳定性研究。该疫苗基于用于开发灭活疫苗配方的专有新技术，除了其他健康人群外，还可用于对婴儿和老年人等易感人群进行免疫。提供的初步数据表明，H2O2-YFV 疫苗的生产可行，具有高免疫原性，并提供针对致命性内脏黄热病的全面保护性免疫力。在该项目中，我们将在cGMP条件下制备临床级疫苗，进行体外和体内安全/毒性测试，并确定疫苗的效力和长期稳定性。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。 公共健康相关性：在这一第二阶段提案中，我们提供了来自第一阶段申请的强有力的初步数据，证明了专有新疫苗平台的抗原性、免疫原性和保护功效，该平台可用于开发更安全、高效的 YFV 疫苗。