Rift Valley Fever Vaccine Development of Animal Models and Optimize Production

裂谷热疫苗动物模型开发和优化生产

• 批准号: 7860454
• 负责人: Clarence J. Peters
• 金额: $ 43.11万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2012-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860454
• 关键词: Acute; Adopted; Adverse effects; Aerosols; Africa South of the Sahara; Animal Model; Animal Testing; Animals; Antibodies; Attenuated; Attenuated Live Virus Vaccine; Biological Assay; Biological Models; Cells; Clinical; Clinical Trials; Contracts; Controlled Clinical Trials; Culicidae; Culture Media; Cyclic GMP; Disease Outbreaks; Dose; Egypt; Epidemic; Evaluation; Fever; Formalin; Freezing; Future; Genome; Grant; Growth; Harvest; Human; Immune Sera; Inactivated Vaccines; Individual; Infection; Injection of therapeutic agent; Investigation; Knowledge; Licensing; Livestock; Macaca mulatta; Modeling; Monitor; Mus; Mutation; Onset of illness; Outcome; Pathogenesis; Pathology; Patients; Plasma; Process; Production; Protocols documentation; Qualifying; RNA Viruses; Rattus; Reporting; Research; Research Personnel; Retinitis; Rift Valley Fever; Rift Valley fever virus; Rodent; Route; Running; Sampling; Seeds; Serial Passage; Series; Serological; Serum Albumin; Site; System; Testing; Time; Toxic effect; Training; Translating; United States; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Production; Vaccines; Viral; Virus; Virus Diseases; Work; animal model development; animal rule; cell growth; clinical toxicology; cohort; design; disorder control; efficacy testing; efficacy trial; epizootic; flasks; genetic analysis; human disease; human subject; immunogenicity; interest; mortality; neurovirulence; neutralizing antibody; nonhuman primate; pre-clinical; protective efficacy; quality assurance; research study; safety testing; scale up; text searching; tissue culture; vaccine development; volunteer

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.

描述（由申请人提供）：Rift-Valley Fever是撒哈拉以南非洲特有的病毒疾病，是埃及最近几种Epizootics和流行病的原因。这是一种通过气溶胶路线传染的蚊子传播的RNA病毒。 2-6天的孵育后，它通常会导致急性发热疾病，约有10％的人出现视网膜炎，而大约1％的感染者会发展出高达50％死亡率的暴发性病程。它有可能通过广泛的物种范围进行扩增和传播，包括在美国发现的家用牲畜和蚊子物种。人类的事先疫苗接种工作包括IND福尔马林灭活疫苗。它产生了中和抗体，但需要三弹性的初级系列和重复的助推器。为了增强免疫原性，USAMRIID创建了一种活的，衰减的疫苗，指定为MP12，并且在1980年代初制备的IND下进行了有限的志愿者免疫，并且发现这种冻干的疫苗在将近20年后保留了全部势力。共有62名志愿者接收了疫苗，最新的19名受试者队列从2006年9月开始接种疫苗（由Grant AI-062636支持）。结果是有希望的，因为在一次注射后形成了保护性抗体，并且所有患者都反应，许多患者较高升高。在最初的研究中，抗体在一年后存在，在最近的试验中6个月后保持所需水平。在所有患者中观察到最小的副作用。证明疫苗菌株MP-12在34个串行通道期间对基因组的遗传分析稳定，在衰减区域没有突变。事实证明，从疫苗中回收MP-12病毒的尝试再次证明了控制疫苗对个体的施用的能力。长期以来，这种疫苗一直被认为是持牌裂谷发烧疫苗的主要候选人。该项目将通过将优化的制造条件转移到CGMP，FDA注册合同设施并验证该过程来继续开发疫苗。三个疫苗批次适用于临床前毒理学测试，以支持新的IND，后来可用于新的临床试验。我们将开发一个小动物替代模型，以支持FDA动物规则下的疗效测试对受控临床试验很困难的疾病，并在非人类抗体对MP-12的非人类抗体灵长类动物的志愿者中从NIH中免疫和从NIH中获得的人类抗体，以收集研究感兴趣的人类的MP-12。该提案中没有临床试验。