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Development of a novel replicating viral RNA vaccine platform

新型复制病毒RNA疫苗平台的开发

基本信息

批准号：
10161283
负责人：
Jesse Hong-Sae Erasmus
金额：
$ 4.43万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161283
关键词：
Alphavirus Animals Antigens Astroviridae Astrovirus Bacterial Antigens Bacterial Infections Biological Biology CD8-Positive T-Lymphocytes Capsid Cell Nucleus Cells Clinical Codon Nucleotides Comparative Study Complementarity Determining Regions Complex Development Elements Emerging Communicable Diseases Engineering Enzymes Expression Profiling Family Family Picornaviridae Flavivirus Fluorescence-Activated Cell Sorting Foundations Frequencies Gene Expression Genes Genetic Genetic Transcription Genome Goals Immune Immune Evasion Immune response Immunity Infection Interferons Libraries Literature Malignant Neoplasms Mediating Methodology Modification Mutation Natural Immunity Nucleic Acid Vaccines Pathway interactions Phenotype Procedures Public Health RNA RNA Viruses RNA delivery RNA vaccine Recombinant DNA Replicon Shapes Structural Genes Structure Synthetic Vaccines System Technology Testing Therapeutic Transcript Translations Tuberculosis Vaccine Design Vaccines Viral Viral Antigens Viral Genome Virion Virus Virus Diseases Work ZIKA adaptive immune response base comparative deep sequencing design genetic element genomic RNA immunogenic in vivo interest mouse model mutant mutation screening novel novel vaccines nucleic acid delivery particle pathogen plasmid DNA response tool vaccine development vector viral RNA

项目摘要

PROJECT SUMMARY Viral replicons, or self-replicating RNA elements incapable of initiating a spreading infection, are traditionally packaged into virus particles, termed viral replicon particles (VRPs), for in vivo delivery. Alternatively, they can be encoded on a plasmid DNA and transfected for host cell nucleus-mediated launch of replicating RNA. However, concerns of anti-vector immunity with respect to the former, or genome integration in the latter approach has limited the clinical use of such technologies. Furthermore, the development of VRPs has been restricted to larger viruses that are capable of harboring additional genetic cargo. With improvements in the delivery of naked RNA, there are now opportunities to develop new viral replicons without the constraints provided by traditional delivery paradigms. By utilizing replicons derived from diverse positive- strand RNA virus families, we can exploit the various mechanisms used by the host to detect replicating viral RNA as well as the differential mechanisms of immune evasion utilized by the parental virus, to rationally design vaccines. We propose studies that will elucidate the minimal genetic elements derived from a small positive-stranded RNA animal virus that are required to replicate and express a heterologous gene from a subgenomic transcript. We will then demonstrate the translational applications towards vaccine development for Zika and tuberculosis, viral and bacterial diseases with significant public health consequences. Furthermore, we will perform comparative studies between this platform with existing platform technologies derived from other positive-strand RNA virus families with the hypothesis that each will elicit distinct innate and adaptive immune responses due to evolutionary differences of the parental viruses.

项目概要病毒复制子或自我复制的 RNA 元件无法引发传播感染，传统上包装成病毒颗粒，称为病毒复制子颗粒（VRP），用于体内送货。或者，它们可以编码在质粒 DNA 上并转染宿主细胞核介导的复制RNA启动。然而，人们对抗媒介免疫的担忧就前者而言，或后一种方法中的基因组整合限制了临床使用此类技术。此外，VRP的开发仅限于较大的病毒能够携带额外的基因货物。随着交付的改进裸RNA，现在有机会不受限制地开发新的病毒复制子由传统的交付模式提供。通过利用来自不同阳性的复制子链RNA病毒家族，我们可以利用宿主使用的各种机制来检测复制病毒RNA以及病毒利用的免疫逃避的差异机制亲本病毒，合理设计疫苗。我们提出的研究将阐明最小的源自小型正链RNA动物病毒的遗传元件，这些元件是从亚基因组转录物中复制并表达异源基因。我们随后将展示寨卡病毒疫苗开发的转化应用结核病、病毒性和细菌性疾病，对公共卫生造成重大影响。此外，我们还将对该平台与现有平台进行比较研究源自其他正链 RNA 病毒家族的技术，假设每个由于进化差异，将引发不同的先天性和适应性免疫反应亲本病毒。