A VSV vectored vaccine for emergent tick-born phleboviruses

针对蜱传白斑病毒的 VSV 载体疫苗

基本信息

批准号：
9903829
负责人：
Paul Bates
金额：
$ 24.3万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-03-02 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903829
关键词：
Andes Virus Animal Model Animals Antibodies Antibody Response Antigens Antiviral Agents Asia Attenuated Award Body Weight decreased Bunyaviridae Case Fatality Rates Cell Line China Clinical Data Development Disease Disease Outbreaks Distant Dose Ebola Vaccines Ebola virus Epidemic Evaluation Fever Foundations Future Generations Genes Genetic Transcription Genome Genus Phlebovirus Geographic Distribution Glycoproteins Goals Heartland virus Hemorrhage Human IFNAR1 gene Immune response Immunize Immunocompromised Host Infection Influenza Interferons Intervention Japan Korea Leukopenia Membrane Proteins Mus National Institute of Allergy and Infectious Disease Pathogenesis Pathogenicity Pathology Plasmids Polymerase Production RNA Processing RNA Viruses Recombinants Recommendation Reporting Research Research Proposals Respiratory syncytial virus Ribosomes Safety Severe Fever with Thrombocytopenia Syndrome Virus Surface Symptoms System T cell response Testing Therapeutic Thrombocytopenia Ticks Transcript Treatment Efficacy United States Vaccinated Vaccination Vaccine Production Vaccines Vesicular stomatitis Indiana virus Viral Viral Genome Viral Vaccines Virion Virus Virus Diseases base clinical development design gastrointestinal symptom human pathogen immunogenicity improved mortality mouse model neutralizing antibody next generation novel strategies pathogen pathogenic virus prevent prophylactic research and development response reverse genetics success tick-borne vaccine development vector vector vaccine

项目摘要

Vesicular stomatitis virus (VSV) is a cytopathic virus that has been developed as a vaccine vector due to its ability to induce strong, protective antibody and T cell responses to encoded foreign antigens after a single dose. VSV efficiently incorporates glycoproteins ( GP) from a different virus on virion surface allowing production of replication-competent recombinant vectors in which the cognate VSV G gene is replaced by a foreign GP gene. Recombinant VSVs (rVSVs) expressing foreign GPs have been studied as vaccine vectors for a number of pathogens including the recent successful deployment of a rVSV-Ebola vaccine. Despite this success, studies in animal models demonstrate significant pathogenic effects when some rVSV are injected intracerebrally or when used to infect animals with defective interferon responses. Concerns raised by these studies support development of more attenuated rVSV vectors with better safety profiles. Specific Aim 1 will utilize a novel strategy for attenuating rVSV vaccine vectors by joining adjacent VSV transcripts using a P2A ribosomal skipping sequence between adjacent genes in the VSV genome. rVSV with single or multiple fused transcripts will be tested for pathogenesis in immunocompromised mouse models or in the CNS. In Specific Aim 2 these next generation, low pathogenicity vectors expressing the glycoproteins of Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) will be analyzed for their ability to induce neutralizing responses. SFTSV is a pathogenic, tick-transmitted bunyaviruses that causes a severe febrile hemorrhagic-like disease with case fatality rates of up to 30%. Initially discovered during a 2009 outbreak of febrile illness in China, the geographic distribution of SFTSV extends into Korea and Japan. There are currently no vaccine or therapeutics for SFTSV. Because of its potential threat the WHO included SFTSV in its 2017 recommendation “A research and development Blueprint for action to prevent epidemics” and identified SFTSV as one of 11 pathogens most likely to cause severe outbreaks in the near future and proposed development of vaccines. Included in this revised application are preliminary data demonstrating induction of strong neutralizing antibody responses that correlate with protection from SFTSV challenge in mice vaccinated with a 1st generation rVSV-SFTSV. Additionally, vaccination of IFNAR-/- mice with the 1st generation rVSV-SFTSV demonstrated significant pathology (weight loss) supporting the premise for Aim 1. This short IDEA proposal is designed to produce attenuated rVSV vectors useful for vaccine development for many pathogens and will generate proof-of-principle data that will permit further development of a vaccine for SFTSV.

囊泡气孔病毒（VSV）是一种细胞病毒，已作为疫苗开发矢量由于其能够诱导强，受保护的抗体和对编码的T细胞反应的能力单剂量后外抗原。 VSV有效地掺入了糖蛋白（ GP）来自病毒表面上的不同病毒，允许产生具有复制能力的重组同源VSV G基因的载体被外gp基因取代。重组VSV （RVSVS）表达外gp已被研究为多种病原体的疫苗向量包括最近成功部署RVSV-EBOLA疫苗。尽管取得了成功，动物模型中的研究表明，当一些RVSV注入时，会有显着的致病作用脑内或用于感染具有干扰素反应不良的动物。关注通过这些研究提出的支持更安全的RVSV载体的开发概况。具体目标1将利用一种新的策略来减弱RVSV疫苗向量使用相邻的P2A核糖体跳过序列连接相邻的VSV转录本 VSV基因组中的基因。将测试带有单个或多个Fused成绩单的RVSV的RVSV。免疫功能低下的小鼠模型或中枢神经系统中的发病机理。在特定的目标2中下一代，表达严重发烧的糖蛋白的低致病载体与将分析血小板减少综合征病毒（SFTSV）的诱导能力中和反应。 SFTSV是一种致病性的，tick虫的bunyaviruse，导致严重的高温出血样疾病，病例死亡率高达30％。最初发现在2009年中国发热疾病的爆发中，SFTSV的地理分布扩展进入韩国和日本。目前没有SFTSV的疫苗或治疗。因为它潜在的威胁WHO在其2017年建议中包括SFTSV的“研究和开发蓝图，以防止发作”并确定SFTSV为11个病原体之一最有可能在不久的将来引起严重爆发，并提议开发疫苗。此修订的应用程序包括初步数据，证明了强大的诱导中和抗体反应与小鼠侵害SFTSV挑战相关的抗体反应用第一代RVSV-SFTSV接种疫苗。此外，IFNAR - / - 小鼠的疫苗接种第一代RVSV-SFTSV表现出明显的病理（减肥） AIM 1的前提。这个简短的想法提案旨在产生衰减的RVSV载体对于许多病原体的疫苗开发有用，将产生原则数据证明这将允许进一步开发用于SFTSV的疫苗。