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

基本信息

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
项目类别：
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

项目摘要

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) 是一种影响反刍动物和人类的蚊媒人畜共患病毒性疾病，在撒哈拉以南非洲、埃及、沙特阿拉伯和也门流行，被 NIH/NIAID 列为 A 类重点病原体，世界卫生组织制定的蓝图优先疾病。通过“同一个健康”方法，控制受感染的动物和蚊子对于根除特定地区的裂谷热非常重要，而西方人类将支持包括处理受感染动物在内的整体活动。然而，尚未获得批准用于人类使用的减毒活疫苗 MP-12，该疫苗于 2013 年在美国获得有条件许可作为兽用 RVF 疫苗，具有研究性新药 (IND) 疫苗状态，现已被替换。 IND 下的弱免疫原性灭活 RVF 候选疫苗为了开发供人类使用的高免疫原性且安全的 RVF 候选疫苗，我们开发了一种新型的 RVF 减毒活候选疫苗，称为 RVF。 “RVax-1”，在整个开放阅读框中编码 500 多个沉默突变和 78kD/NSm 基因的截短。我们的中心假设是，RVax-1 候选疫苗通过肌肉注射途径在小鼠和绵羊中具有高度免疫原性。单剂量，在怀孕大鼠胎盘和幼年小鼠中高度减毒，并且在蚊子媒介中传播不良。总体目标是表征 RVax-1 的免疫原性、安全性和有效性。小鼠、大鼠和羊中的候选疫苗，并确定蚊子中的病毒传播水平，以便填补该候选疫苗的知识空白，并进入支持 IND 的临床前和随后的临床评估环境。非常理想，因为德克萨斯大学医学分校的高密闭设施适合动物实验，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实验。我们研究的长期目标是移动 RVax-。 1 疫苗转发至临床前评估、良好生产规范下的生产和 1/2 期试验具体目标 1：表征 RVax-1 在小鼠模型中的减毒、免疫原性和保护功效。具体目标 2：表征 RVax 的蚊子传播。 -1. 具体目标 3：表征 RVax-1 在绵羊模型中的减毒、免疫原性和保护功效。具体目标 4：表征 RVax-1 在绵羊模型中的减毒作用。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行进一步表征。