Safety and immunogenicity of a novel Rift Valley fever candidate vaccine, RVax-1

新型裂谷热候选疫苗 RVax-1 的安全性和免疫原性

• 批准号: 10353404
• 负责人: Tetsuro Ikegami
• 金额: $ 38.61万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353404
• 关键词: Abortion Rates; Affect; Africa South of the Sahara; Animal Experiments; Animal Model; Animals; Area; Attenuated; Attenuated Vaccines; Blindness; Callithrix; Callithrix jacchus jacchus; Category A pathogen; Cattle; Cells; Characteristics; Clinical; Containment; Country; Culicidae; Disease; Disease Outbreaks; Dose; Egypt; Encephalitis; Ensure; Enzymes; Fetus; Generations; Genes; Genetic Markers; Goals; Goat; Health; Hemorrhage; Human; Immunity; Infant; Intramuscular; Investigational Drugs; Knowledge; Liver; Madagascar; Medical; Midgut; Military Personnel; Modeling; Mus; National Institute of Allergy and Infectious Disease; Neonatal Mortality; Open Reading Frames; Phase I/II Trial; Phenotype; Placenta; Play; Predisposition; Pregnancy; Pregnant sheep; Production; Public Health; Quantitative Evaluations; Rattus; Recombinants; Rift Valley Fever; Rift Valley fever virus; Role; Route; Ruminants; Safety; Saudi Arabia; Silent Mutation; Sprague-Dawley Rats; Syndrome; Testing; Texas; Tissues; United States National Institutes of Health; Universities; Vaccinated; Vaccination; Vaccines; Vero Cells; Vertical Disease Transmission; Viral; Viremia; Virus; Virus Diseases; World Health Organization; Yemen; Zoonoses; attenuation; experimental study; fetal; immunogenic; immunogenicity; malformation; mosquito-borne; mouse model; mutant; neutralizing antibody; novel; pre-clinical; preclinical evaluation; pregnant; professional atmosphere; protective efficacy; prototype; research clinical testing; reverse genetics; vaccine candidate; vector mosquito

Specific Aims Rift Valley fever (RVF), a mosquito-borne zoonotic viral disease affecting ruminants and humans endemic to sub-Saharan Africa, Egypt, Saudi Arabia and Yemen, is classified as Category A Priority Pathogen by the NIH/NIAID and the Blueprint priority disease by the World Health Organization. With One Health approach, a control of infected animals and mosquitoes are important to eradicate RVF from specific areas, whereas vaccinated humans will support overall activities including the handling of infected animals. There are, however, no licensed RVF vaccines for human use. Live-attenuated MP-12 vaccine, which was conditionally licensed in 2013 as a veterinary RVF vaccine in the U.S., had Investigational New Drug (IND) vaccine status, it has now been replaced with weakly immunogenic inactivated RVF candidate vaccine under IND. To develop a highly immunogenic and safe RVF candidate vaccine for human use, we have generated a novel live-attenuated candidate vaccine for RVF, termed “RVax-1”, which encodes more than 500 silent mutations throughout the open reading frame and a truncation of 78kD/NSm genes. Our central hypothesis is that the RVax-1 candidate vaccine is highly immunogenic in mice and marmosets via the intramuscular route with a single dose, highly attenuated in pregnant rat placenta and in infant mice, and disseminate poorly in mosquito vectors. The overall objective is characterize the immunogenicity, safety, and efficacy of the RVax-1 candidate vaccine in mice, rats, and marmosets, and to determine the level of viral dissemination in mosquitoes, in order to fill the gaps in knowledge regarding this candidate vaccine and move forward into IND-enabling preclinical and, subsequently, clinical evaluation. The work environment is ideal because the high containment facilities at the University of Texas Medical Branch are suitable for animal experiments, and SUNY Upstate Medical University supports mosquito experiments. The long-term goal of our study is to move the RVax-1 vaccine forward into preclinical evaluation, production under Good Manufacturing Practice, and Phase 1/2 trials. Specific Aim 1: To characterize the attenuation, immunogenicity, and protective efficacy of RVax-1 in a mouse model. Specific Aim 2: To characterize the mosquito dissemination of RVax-1. Specific Aim 3: To characterize the attenuation, immunogenicity, and protective efficacy of RVax-1 in a marmoset model. Specific Aim 4: To characterize the attenuation of RVax-1 in rat placenta. Successful completion of proposed project will qualify RVax-1 for further characterization in preclinical and clinical evaluation.

具体目标 裂谷谷热（RVF），一种蚊子传播的人畜共患病毒病，影响反刍动物和人类内在 撒哈拉以南非洲，埃及，沙特阿拉伯和也门，被归类为一种优先病原体 世界卫生组织的NIH/NIAID和蓝图优先疾病。采用一种健康方法， 控制感染的动物和蚊子对从特定区域的放射性RVF很重要，而 接种疫苗的人将支持整体活动，包括处理感染动物。但是，有 没有许可的RVF疫苗用于人类使用。有条件许可的实时衰减的MP-12疫苗 2013年作为美国的兽医RVF疫苗，具有调查新药（IND）疫苗状况，现在已有 被IND下的弱免疫原性的RVF候选疫苗代替。发展高度 免疫原性和安全的RVF候选疫苗用于人类使用 RVF的候选疫苗，称为“ RVAX-1”，该疫苗在整个过程中编码500多个无声突变 开放式阅读框架和78KD/NSM基因的截断。我们的中心假设是RVAX-1候选人 疫苗在小鼠和摩尔果中通过肌肉内路线具有高度免疫原性 在怀孕的大鼠plapeta和婴儿小鼠中减弱，并在蚊子载体中传播较差。总体 目的是特征是小鼠，大鼠RVAX-1候选疫苗的免疫原性，安全性和效率 和马尔莫群岛，并确定蚊子中的病毒传播水平，以填补空白 有关这种候选疫苗的知识，并继续进行临床前，随后， 临床评估。工作环境是理想的，因为大学的高遏制设施 德克萨斯医疗部门适用于动物实验，纽约州立大学医科大学支持 蚊子实验。我们研究的长期目标是将RVAX-1疫苗前进到临床前 评估，良好的制造实践下的生产以及1​​/2阶段的试验。特定目标1： 表征小鼠模型中RVAX-1的衰减，免疫原性和受保护的效率。具体目标 2：表征RVAX-1的蚊子传播。特定目标3：要表征衰减， 免疫原性和在Marmoset模型中RVAX-1的保护效率。特定目标4：表征 RVAX-1在大鼠plapeta中的衰减。成功完成拟议项目将使RVAX-1有资格进一步 临床前和临床评估的表征。