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的一种病毒性地方病，是埃及最近几次动物流行病和流行病的原因。它是一种蚊子携带的包膜RNA病毒，通过气溶胶途径传染。在2-6天的潜伏期后，它通常会引起急性发热性疾病，约10%的人会发展为视网膜炎，约1%的感染者会发展为暴发性病程，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物种。先前的人类疫苗接种工作包括IND福尔马林灭活疫苗。它产生了中和抗体，但它需要一个三针的初级系列和重复的助推器。为了增强免疫原性，USAMRIID创造了一种称为MP 12的减毒活疫苗，该疫苗在20世纪80年代初制备的IND下生长并对有限数量的志愿者进行免疫接种，并且发现这种冻干疫苗在近20年后保留了全部效力。共有62名志愿者接种了疫苗，最新的一批19名受试者于2006年9月开始接种疫苗（由AI-062636资助）。结果是有希望的，因为在一次注射后形成了保护性抗体，所有患者都有反应，许多人的抗体升得很高，以前没有见过。在最初的研究中，抗体在一年后出现，并在最近的试验中在6个月后保持在所需的水平。在所有患者中观察到最小的副作用。证明了疫苗株MP-12对回复突变稳定，并且在34次连续传代期间对基因组进行的遗传分析显示在减毒区域中没有突变。从接种者身上回收MP-12病毒的尝试证明是困难的，这再次证明了控制对个体接种疫苗的能力。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者。该项目将通过将优化的生产条件转移到cGMP、FDA注册的合同机构并验证工艺来继续疫苗开发。将生产三个适合用于临床前毒理学试验的疫苗批次，以支持新的IND，随后可用于新的临床试验。我们将开发一种小动物替代模型，以支持FDA动物规则下针对难以进行对照临床试验的疾病的有效性试验，并证明最近免疫的志愿者的MP-12人抗体在非人灵长类动物中的保护性有效性，并根据其方案从NIH获得以收集研究兴趣的人类样本。本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.