Rift Valley Fever Vaccine Development of Animal Models and Optimize Production

描述（由申请人提供）：裂谷热是撒哈拉以南非洲地区的一种地方性病毒性疾病，是埃及最近发生的几起动物流行病和流行病的原因。它是一种蚊子传播的包膜RNA病毒，通过气溶胶途径传播。经过2-6天的潜伏期后，通常会引起急性发热性疾病，约10%的感染者发展为视网膜炎，约1%的感染者发展为暴发性病程，死亡率高达50%。它有可能扩大并通过广泛的物种传播，包括在美国发现的家畜和蚊子。先前的人类疫苗接种工作包括IND福尔马林灭活疫苗。它产生中和抗体，但需要三次初级系列和反复加强。为了增强免疫原性，USAMRIID创建了一种名为MP12的减毒活疫苗，这种疫苗在20世纪80年代初制备的IND下生长并进行了有限数量的志愿者免疫，这种冻干疫苗在近20年后被发现保持了完全的效力。共有62名志愿人员接种了疫苗，最新一批19名受试者从2006年9月开始接种疫苗（由赠款AI-062636支持）。结果是有希望的，保护性抗体在一次注射后形成，所有患者都有反应，许多患者的抗体升得很高，以前从未见过。在最初的研究中，抗体在一年后出现，在最近的试验中，抗体在6个月后保持在理想水平。所有患者的副作用都很小。结果表明，疫苗株MP-12具有稳定的逆转录能力，基因组遗传分析显示，在34个连续传代中，减弱区没有突变。从疫苗接种者身上恢复MP-12病毒的尝试被证明是困难的，这再次证明了控制个人接种疫苗的能力。这种疫苗长期以来一直被认为是获得许可的裂谷热疫苗的主要候选疫苗。该项目将通过将优化的生产条件转移到cGMP， FDA注册的合同设施并验证过程来继续疫苗开发。将生产三批适合临床前毒理学试验的疫苗，以支持新的新药开发，并在以后用于新的临床试验。我们将开发一种小型动物替代模型，以支持在FDA动物规则下对难以进行对照临床试验的疾病进行功效测试，并证明在非人类灵长类动物中对MP-12的人类抗体的保护功效，这些抗体来自最近免疫的志愿者，并根据他们的协议从NIH获得，以收集研究兴趣的人类样本。该提案中没有临床试验。

DESCRIPTION (provided by applicant): Rift-Valley fever is a viral disease endemic to sub-Saharan Africa and has been the cause of several recent epizootics and epidemics in Egypt. It is a mosquito borne enveloped RNA virus that is infectious via the aerosol route. Following a 2-6 day incubation, it typically causes acute febrile illness, and about 10% of those develop a retinitis, and about 1% of those infected develop a fulminant course with up to 50% mortality. It has the potential to amplify and be transmitted by a wide species range, including domestic livestock and mosquito species found in the United States. Prior vaccination efforts in humans have included an IND formalin inactivated vaccine. It produced neutralizing antibodies but it required a three-shot primary series and repeated boosters. To enhance immunogenicity, USAMRIID created a live, attenuated vaccine designated MP12 This was grown and a limited number of volunteers immunized under an IND prepared in the early 1980s, and this lyophilized vaccine was found to retain full potency nearly 20 years later. A total of 62 volunteers have received the vaccine, with the latest cohort of 19 subjects being vaccinated beginning in September, 2006 (supported by grant AI-062636). Results are promising in that protective antibodies were formed following one injection, and all patients responded, many with high liters not seen previous. In the initial studies, antibodies were present after one year and remain at desired levels after 6 months in the recent trial. There were minimal side effects observed in all patients. The vaccine strain MP-12 was demonstrated to be stable to reversion and genetic analysis of the genome during 34 serial passages showed no mutations in the attenuating regions. Attempts to recover MP-12 virus from vaccinees proved difficult, again demonstrating the ability to control the administration of the vaccine to an individual. This vaccine has long been considered a prime candidate for a licensed Rift Valley Fever vaccine. This project will continue vaccine development by transferring the optimized manufacturing conditions to a cGMP, FDA registered contract facility and validating the process. Three vaccine lots suitable for pre-clinical toxicology testing in support of a new IND and later usable for a new clinical trial will be produced. We will develop a small animal surrogate model necessary to support efficacy tests under the FDA Animal Rule for diseases where controlled clinical trials are difficult, and to demonstrate protective efficacy in a non-human primate of human antibody to MP-12 from volunteers recently immunized and obtained from NIH under their protocol to collect human samples of research interest. No clinical trials are in this proposal.