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：
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
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/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

项目摘要

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.

具体目标裂谷热 (RVF) 是一种由蚊子传播的人畜共患病毒性疾病，影响反刍动物和人类，是一种流行病撒哈拉以南非洲地区、埃及、沙特阿拉伯和也门被世界卫生组织列为 A 类优先病原体 NIH/NIAID 和世界卫生组织的蓝图重点疾病方法，一种健康方法。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，而接种疫苗的人类将支持包括处理受感染动物在内的整体活动。没有获得批准用于人类使用的 RVF 疫苗 MP-12 减毒活疫苗，该疫苗在 2019 年有条件获得许可。 2013年作为兽用裂谷热疫苗在美国获得试验性新药（IND）疫苗地位，现已获得 IND 下被弱免疫原性灭活 RVF 候选疫苗取代。作为具有免疫原性且安全的人用裂谷热候选疫苗，我们开发了一种新型减毒活疫苗 RVF 候选疫苗称为“RVax-1”，在整个过程中编码 500 多个沉默突变我们的中心假设是 RVax-1 候选基因。疫苗通过单剂量肌肉注射途径对小鼠和狨猴具有高度免疫原性，在怀孕大鼠胎盘和幼年小鼠中减弱，并且在蚊媒中传播不良。目标是表征 RVax-1 候选疫苗在小鼠、大鼠、和狨猴，并确定蚊子中的病毒传播水平，以填补在有关该候选疫苗的知识，并进入支持 IND 的临床前阶段，随后，临床评估的工作环境非常理想，因为大学的隔离设施很高。德州医学分院适合动物实验，SUNY Upstate医科大学支持我们研究的长期目标是将 RVax-1 疫苗推进到临床前阶段。评估、良好生产规范下的生产以及第 1/2 阶段试验：具体目标 1：描述 RVax-1 在特定目标小鼠模型中的减毒、免疫原性和保护功效。 2：表征 RVax-1 的蚊子传播。具体目标 3：表征衰减。 RVax-1 在狨猴模型中的免疫原性和保护功效。具体目标 4：表征 RVax-1 在大鼠胎盘中的减弱作用将使 RVax-1 能够进一步发挥作用。临床前和临床评估的表征。