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: 10578688
• 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/10578688
• 关键词: Abortion Rates; Affect; Africa South of the Sahara; Animal Experiments; Animal Model; Animals; Area; Attenuated; Attenuated Vaccines; Blindness; C57BL/6 Mouse; Category A pathogen; Cattle; Cells; Characteristics; Child; Classification; Clinical; Containment; Country; Culicidae; Disease; Disease Outbreaks; Dose; Egypt; Encephalitis; Ensure; Enzymes; Fetus; Generations; Genes; Genetic Markers; Goals; Goat; Good Manufacturing Process; Health; Hemorrhage; Human; Immunity; Infant; Intramuscular; Investigational Drugs; Kansas; Knowledge; Licensing; Liver; Madagascar; Medical; Midgut; Military Personnel; 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; Qualifying; Quantitative Evaluations; Rattus; Recombinants; Rift Valley Fever; Rift Valley fever virus; Rodent; Rodent Model; Role; Route; Ruminants; Safety; Saudi Arabia; Sheep; Silent Mutation; Sprague-Dawley Rats; Syndrome; Testing; Texas; Tissues; United States National Institutes of Health; Universities; Update; Vaccinated; Vaccination; Vaccines; Vero Cells; Vertical 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; sheep model; transmission process; vaccine candidate; vector mosquito

Summary / Abstract (Updated) Project Summary/Abstract. 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 sheep 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 to characterize the immunogenicity, safety, and efficacy of the RVax-1 candidate vaccine in mice, rats, and sheep, 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, while SUNY Upstate Medical University and Kansas State University support mosquito and sheep experiments, respectively. 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 sheep model. Specific Aim 4: To characterize the attenuation of RVax-1 in rodent placenta. Successful completion of proposed project will qualify RVax-1 for further characterization in preclinical and clinical evaluation.

摘要/摘要(更新) 项目摘要/摘要。裂谷热(RVF)是一种由蚊子传播的人畜共患病，在撒哈拉以南非洲、埃及、沙特阿拉伯和也门流行，NIH/NIAID将其列为A类优先病原体，世界卫生组织将其列为蓝图优先疾病。通过One Health Approach，控制受感染的动物和蚊子对于从特定地区根除裂谷热很重要，而接种疫苗的人将支持包括处理受感染动物在内的所有活动。然而，目前还没有获得许可的人用裂谷热疫苗。MP-12减毒活疫苗于2013年在美国获得有条件许可的兽用RVF疫苗，具有研究新药(IND)疫苗地位，现已被IND规定的弱免疫原性灭活RVF候选疫苗取代。为了开发一种高免疫原性和安全的RVF候选疫苗供人类使用，我们开发了一种新型的RVF减毒候选疫苗，命名为“RVax-1”，它编码500多个沉默突变和78kD/NSM基因的截断。我们的中心假设是，RVax-1候选疫苗通过单剂肌肉注射途径在小鼠和绵羊体内具有高度的免疫原性，在怀孕大鼠胎盘和幼鼠体内高度减毒，在蚊子媒介中传播较差。总体目标是确定RVax-1候选疫苗在小鼠、大鼠和绵羊中的免疫原性、安全性和有效性，并确定病毒在蚊子中的传播水平，以填补关于该候选疫苗的知识空白，并进入IND启用的临床前和随后的临床评估。工作环境非常理想，因为德克萨斯大学医学分校的高密封性设施适合进行动物实验，而纽约州立大学北部医科大学和堪萨斯州立大学分别支持蚊子和绵羊的实验。我们研究的长期目标是将RVax-1疫苗推进到临床前评估、在良好的制造规范下生产和1/2阶段试验。具体目的1：在小鼠模型中研究RVax-1的减毒作用、免疫原性和保护作用。具体目标2：确定RVAX-1病毒在蚊子中的传播特征。具体目标3：在绵羊模型中表征RVax-1的减毒作用、免疫原性和保护作用。具体目的4：研究RVax-1在啮齿动物胎盘中的衰减特性。拟议项目的成功完成将使RVAX-1有资格在临床前和临床评估中进一步表征。