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: 7455452
• 负责人: Clarence J. Peters
• 金额: $ 84万
• 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 2010-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455452
• 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; Condition; Contracts; Controlled Clinical Trials; Culicidae; Culture Media; Cyclic GMP; Disease Outbreaks; Dose; Egypt; Epidemic; Evaluation; Fever; Formalin; Freezing; Future; Genome; Grant; Growth; Guanosine Monophosphate; Harvest; Human; Immune Sera; Inactivated Vaccines; Individual; Infection; Injection of therapeutic agent; Investigation; Knowledge; Licensing; Livestock; MCC protocol; Macaca mulatta; Modeling; Monitor; Mus; Mutation; Numbers; Onset of illness; Outcome; Pathogenesis; Pathology; Patients; Plasma; Process; Production; Protocols documentation; Purpose; Qualifying; RNA Viruses; Range; Rattus; Reporting; Research; Research Personnel; Retinitis; Rift Valley Fever; Rift Valley fever virus; Rodent; Route; Running; Safety; Sampling; Seeds; Serial Passage; Series; Serological; Serum Albumin; Site; System; Testing; Time; Toxic effect; Toxicology; Training; Translating; United States; United States Food and Drug Administration; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Production; Vaccines; Viral; Virus; Virus Diseases; Work; cell growth; cohort; day; design; desire; disorder control; efficacy trial; epizootic; flasks; genetic analysis; human disease; human subject; immunogenicity; interest; model development; mortality; neurovirulence; neutralizing antibody; nonhuman primate; pre-clinical; quality assurance; research study; 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）：裂谷热是撒哈拉以南非洲地区流行的一种病毒性疾病，也是埃及最近几起动物流行病和流行病的原因。它是一种由蚊子传播的有包膜 RNA 病毒，通过气溶胶途径传染。经过 2-6 天的潜伏期后，它通常会引起急性发热性疾病，其中约 10% 的感染者会出现视网膜炎，约 1% 的感染者会出现暴发性病程，死亡率高达 50%。它有可能放大并通过广泛的物种传播，包括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。它产生中和抗体，但需要三针初级系列和重复加强剂。为了增强免疫原性，USAMRIID 创造了一种名为 MP12 的活减毒疫苗。这种疫苗是在 20 世纪 80 年代初准备的 IND 下培育的，并对有限数量的志愿者进行了免疫，这种冻干疫苗在近 20 年后被发现保留了全部效力。共有 62 名志愿者接种了疫苗，最新一批 19 名受试者于 2006 年 9 月开始接种（由 AI-062636 拨款支持）。结果令人鼓舞，因为一次注射后就形成了保护性抗体，所有患者都有反应，其中许多患者的升数很高，这是以前从未见过的。在最初的研究中，抗体在一年后出现，并且在最近的试验中 6 个月后仍保持在所需水平。在所有患者中观察到的副作用极小。疫苗株 MP-12 被证明对回复稳定，并且在 34 次连续传代期间对基因组的遗传分析显示减毒区域没有突变。从疫苗接种者身上回收 MP-12 病毒的尝试被证明是困难的，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疫苗。该项目将通过将优化的生产条件转移到 FDA 注册的 cGMP 合同工厂并验证流程来继续疫苗开发。将生产三批适合临床前毒理学测试的疫苗批次，以支持新的 IND，并随后用于新的临床试验。我们将开发一种必要的小动物替代模型，以支持根据 FDA 动物规则对难以进行对照临床试验的疾病进行功效测试，并证明来自最近免疫的志愿者的 MP-12 人类抗体对非人类灵长类动物的保护功效根据 NIH 的协议从 NIH 获得，用于收集研究兴趣的人类样本。该提案中没有临床试验。