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

具体目标 裂谷热（RVF）是一种影响反刍动物和人类的蚊媒人畜共患病毒性疾病， 撒哈拉以南非洲、埃及、沙特阿拉伯和也门被列为A类优先病原体。 NIH/NIAID和世界卫生组织的蓝图优先疾病。通过“一个健康”方法， 控制受感染的动物和蚊子对于在特定地区根除裂谷热十分重要， 接种疫苗的人将支持包括处理受感染动物在内的整体活动。然而， 没有获得许可的裂谷热疫苗供人使用。MP-12减毒活疫苗，于2009年获得有条件许可。 2013年在美国作为兽用裂谷热疫苗，研究性新药（IND）疫苗状态，现在 在IND下已被弱免疫原性灭活裂谷热候选疫苗取代。 为了获得免疫原性和安全的人用裂谷热候选疫苗，我们产生了一种新的减毒活疫苗， 裂谷热候选疫苗，称为“RVax-1”，它编码500多个沉默突变， 开放阅读框和78 kD/NSm基因的截短。我们的中心假设是RVax-1候选者 疫苗在小鼠和绒猴中通过单剂量肌肉注射途径具有高度免疫原性， 在孕鼠胎盘和幼鼠中减毒，在蚊媒中传播较差。整体 目的是表征RVax-1候选疫苗在小鼠、大鼠 和绒猴，并确定病毒在蚊子中传播的水平，以填补 关于这种候选疫苗的知识，并进入IND使能的临床前阶段，随后， 临床评价工作环境是理想的，因为在大学的高遏制设施， 德州医学分支适合动物实验，SUNY上州医科大学支持 蚊子实验我们研究的长期目标是将RVax-1疫苗推进到临床前阶段。 评价、根据药品生产质量管理规范生产和1/2期试验。具体目标1： 在一个实施方案中，本发明提供了表征RVax-1在小鼠模型中的减毒、免疫原性和保护功效的方法。具体目标 2：表征RVax-1的蚊子传播。具体目标3：为了表征衰减， 在绒猴模型中RVax-1的免疫原性和保护功效。具体目标4： RVax-1在大鼠胎盘中的衰减。成功完成拟议项目将使RVax-1有资格进一步 临床前和临床评价中的表征。

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.