Development of a novel replicating viral RNA vaccine platform

新型复制病毒RNA疫苗平台的开发

• 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
• 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

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。

项目成果

A Nanostructured Lipid Carrier for Delivery of a Replicating Viral RNA Provides Single, Low-Dose Protection against Zika.

用于传递复制病毒 RNA 的纳米结构脂质载体可提供单一、低剂量的寨卡病毒保护。

• DOI: 10.1016/j.ymthe.2018.07.010
• 发表时间: 2018-10-01
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Jesse H. Erasmus;A. Kh;har;har;J. Guderian;B. Granger;Jacob Archer;Michelle C. Archer;E. Gage;Jasmine Fuerte;Elise Larson;Susan Lin;R. Kramer;R. Coler;C. Fox;D. Stinchcomb;S. Reed;N. Van Hoeven
• 通讯作者: N. Van Hoeven