Rift Valley Fever Vaccine Development of Animal Models and Optimize Production

描述(申请人提供)：裂谷热是一种撒哈拉以南非洲的地方性病毒性疾病，是埃及最近几次家禽流行性疾病和流行病的原因。它是一种由蚊子传播的包膜RNA病毒，通过气溶胶途径传播。在2-6天的潜伏期后，它通常会引起急性发热性疾病，大约10%的人会患上视网膜炎，大约1%的感染者会出现暴发性病程，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物种。此前在人类身上的疫苗接种努力包括一种IND福尔马林灭活疫苗。它产生了中和抗体，但它需要三针初级系列和重复的增强剂。为了提高免疫原性，USAMRIID创造了一种名为MP12的减毒活疫苗，这种疫苗是在20世纪80年代初制备的IND下培养的，并让有限数量的志愿者免疫，这种冻干疫苗在近20年后被发现保持完全效力。共有62名志愿者接种了疫苗，最新的19名受试者从2006年9月开始接种(由赠款AI-062636支持)。结果是很有希望的，因为一次注射就形成了保护性抗体，所有患者都有反应，其中许多人的滴度是以前从未见过的。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。在所有患者中观察到的副作用都很小。疫苗株MP-12被证明对逆转是稳定的，在34代连续传代的基因组分析中，弱化区没有突变。从接种疫苗的人身上恢复MP-12病毒的尝试被证明是困难的，再次证明了控制对个人的疫苗接种的能力。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首选候选疫苗。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工艺来继续疫苗开发。将生产三批适合临床前毒理学测试的疫苗，以支持新的IND，并在以后可用于新的临床试验。我们将开发一个必要的小动物代理模型，以支持FDA动物规则下对难以进行临床控制试验的疾病的疗效测试，并在非人类灵长类动物中展示MP-12人类抗体的保护效果，这些抗体来自最近免疫的志愿者，并根据他们的方案从NIH获得，以收集有研究意义的人类样本。这项提案中没有进行临床试验。

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.