Development of a Safe and Effective Vaccine Against West Nile Virus

描述(由申请人提供)：西尼罗河病毒(WNV)对美国的公共卫生构成重大威胁，特别是在老年人和免疫功能受损的脆弱人群中。这种由蚊子传播的病原体已经在整个北美传播到包括加拿大和墨西哥在内的国家以及中美洲、南美洲和加勒比海地区。虽然大多数西尼罗河病毒感染都是轻微或无症状的，但神经侵袭性疾病伴随着高死亡率(住院老年人高达35%)。此外，从急性西尼罗河病毒脑炎康复的幸存者中，高达77%的人在感染后遭受长期的神经后遗症，导致步态受损、肌肉无力、听力丧失和震颤等问题超过或等于3年。西尼罗河病毒是一种新发传染病，被列为NIAID B类优先病原体。虽然有一种有效的针对西尼罗河病毒的兽医疫苗，但目前还没有FDA批准的疫苗来预防人类感染西尼罗河病毒。在这项提案中，我们将使用一种专有的新平台技术来开发一种灭活疫苗配方，该配方可用于为包括老年人等免疫脆弱群体在内的不同人群接种疫苗。我们的初步研究表明，这种疫苗方法是可行的，具有高度的免疫原性(激发CD8+T细胞和中和抗体反应)，并保护小鼠免受致死性西尼罗河病毒的感染。在这个项目中，我们将在两个动物模型中评估候选疫苗配方，进行主要候选疫苗的扩大开发和cGMP制造，并进行必要的基准临床前研究，以准备IND申请和启动未来的第一阶段临床试验。

DESCRIPTION (provided by applicant): West Nile Virus (WNV) represents a significant threat to public health in the United States, particularly in vulnerable populations such as the elderly and the immunocompromised. This mosquito-borne pathogen has spread throughout North America to countries including Canada and Mexico as well as to Central America, South America, and the Caribbean. Although most WNV infections are either mild or asymptomatic, neuroinvasive disease is accompanied by a high mortality rate (up to 35% in the hospitalized elderly). Moreover, up to 77% of survivors who recover from acute WNV encephalitis endure long-term neurological sequelae resulting in problems such as impaired gait, muscle weakness, hearing loss, and tremors for more than or equal to 3 years after infection. WNV is an emerging infectious disease and is listed as an NIAID Category B Priority Pathogen. Although there is an effective veterinary vaccine against WNV, there are currently no FDA-approved vaccines available for preventing human WNV infection. In this proposal, we will use a proprietary new platform technology for developing an inactivated vaccine formulation that can be used to immunize a diverse population including immunologically vulnerable groups such as the elderly. Our preliminary studies demonstrate that this vaccine approach is feasible, highly immunogenic (eliciting CD8+ T cell and neutralizing antibody responses) and protects mice against lethal WNV infection. In this project, we will evaluate candidate vaccine formulations in two animal models, perform scale-up development and cGMP manufacturing of the lead candidate vaccine, and perform benchmark preclinical studies necessary for preparing an IND application and initiating future Phase I clinical trials.