Rapid deployment DNA vaccine for pandemic influenza

快速部署大流行性流感 DNA 疫苗

• 批准号: 7264425
• 负责人: James Williams
• 金额: $ 20.7万
• 依托单位: NATURE TECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264425
• 关键词: Adjuvant; Animal Model; Animals; Antibody Formation; Antigen Targeting; Antigens; Area; Arts; Autoimmunity; Biological Products; Cell Line; Cells; Clinical; DNA Vaccines; Development; Double-Stranded RNA; Down-Regulation; Electroporation; Elements; Ferrets; Gene Targeting; Genes; Goals; Hemagglutinin; Human; Immune response; Immunity; Inflammatory Response Pathway; Influenza; Influenza A Virus, H5N1 Subtype; Influenza Hemagglutinin; Interferons; Intramuscular Injections; Lead; Licensing; Mediating; Membrane; Memory; MicroRNAs; Modification; Molecular Conformation; Mus; Natural Immunity; Pathway interactions; Phase; Plasmid Cloning Vector; Plasmids; Primates; Proteins; RNA; RNA Interference Pathway; Regulatory Element; Research; Safety; Signal Pathway; System; Technology; Testing; Time; Translating; Translations; Tretinoin; Vaccination; Vaccine Production; Vaccines; Vertebral column; Vietnam; Viral Vector; Virus Diseases; base; concept; eIF-2 Kinase; egg; expression vector; improved; in vivo; influenza virus vaccine; inhibitor/antagonist; mouse model; neutralizing antibody; nonhuman primate; novel; pandemic disease; pandemic influenza; pre-clinical; prevent; receptor; response; small hairpin RNA; vector; vector control; vector vaccine

DESCRIPTION (provided by applicant): DNA-only vaccination would significantly enhance the rapid deployment utility of DNA vaccines for pandemic application (development times for DNA vaccines are significantly shorter than those for protein or viral vector systems). The overall goal of this project is to develop a rapid deployment DNA vaccine platform protective against pandemic influenza H5N1. The hypothesis is that influenza DNA vaccine potency can be increased through activation of cytoplasmic double stranded RNA (dsRNA) signaling pathways by vector encoded immunostimulatory RNA. This will be accomplished through the use of various immunostimulatory "RNA elements" (RNAe). This Phase I proof of concept study will investigate the potential benefit of inclusion of vector-mediated RNAe on immune responses to an vector encoded target antigen. Influenza Hemagglutinin (HA) will be used as an example antigen requiring antibody responses for protection. Novel HA DNA vaccine plasmid vectors that produce immunostimulatory dsRNA will be created and screened for immune response in vivo after delivery by electroporation-enhanced intramuscular injection. The optimal backbone that improves neutralizing antibody response to HA will be selected. Then, building upon this RNAe vector, 'inhibiting-the-inhibitor' DNA vaccines will be created and tested in a subordinate study. The secondary hypothesis is that immune responses induced by the dsRNA activating DNA vaccines can be further improved by preventing target cell downregulation of immune responses mediated by vector activation of innate immunity. The vectors defined above will be further modified to incorporate RNAe which knockdown expression of various attenuators of these cytoplasmic dsRNA signaling pathways. Antibody responses to HA induced by the 'inhibiting-the- inhibitor' DNA vaccines will then be determined in an animal model. In Phase II the resulting optimal vector backbone (i.e., specific immunostimulatory RNAe alone, or potentially in combination with 'inhibiting the inhibitor' shRNA as determined herein) will be developed as a novel, rapid deployment DNA-only vaccine platform for influenza H5N1. The rapid deployment DNA vaccine platform developed herein will have general utility with a variety of other emerging biological agents; NTC will license the platform for such applications. This proposal is aimed at developing novel influenza vaccines to replace egg based vaccine production technologies and as such is responsive to NIAID's high priority influenza research areas, as outlined in NOT-AI-06-011.

描述（由申请人提供）：仅DNA疫苗接种将显着增强DNA疫苗在大流行应用中的快速部署效用（DNA疫苗的发育时间比蛋白质或病毒载体系统的疫苗的发育时间明显短）。该项目的总体目标是开发针对大流行性流感H5N1的快速部署DNA疫苗平台。假设是，通过载体编码的免疫刺激性RNA激活细胞质双链RNA（DSRNA）信号通路，可以通过激活细胞质双链RNA（DSRNA）信号通路来提高流感DNA疫苗的效力。这将通过使用各种免疫刺激性的“ RNA元素”（RNAE）来实现。本阶段I概念证明将研究纳入载体介导的RNAE对载体编码靶抗原的免疫反应的潜在益处。流感血凝素（HA）将用作需要保护的抗体反应的示例抗原。通过电穿孔增强的肌内注射递送后，将创建并筛选产生免疫刺激性dsRNA的新型HA DNA疫苗质粒载体，并筛选在体内免疫反应。将选择改善对HA的中和抗体反应的最佳主链。然后，在该RNAE载体的基础上，将在下属研究中创建和测试“抑制抑制剂” DNA疫苗。次要假设是，通过防止靶细胞下调介导的先天免疫激活介导的免疫反应的靶细胞下调，可以进一步改善DSRNA激活DNA疫苗引起的免疫反应。上面定义的向量将进一步修改，以结合RNAE，从而敲低这些细胞质DSRNA信号通路的各种衰减器的表达。然后将在动物模型中确定“抑制剂” DNA疫苗对HA的抗体反应。在第二阶段中，所得的最佳载体主链（即单独使用特定的免疫刺激RNAE，或者可能与“抑制抑制剂” SHRNA相结合）作为一种新型，快速部署DNA唯一的DNA疫苗平台，用于流感H5N1。此处开发的快速部署DNA疫苗平台将具有多种其他新兴的生物剂的通用效用。 NTC将为此类应用程序许可该平台。该提案旨在开发新型的流感疫苗来替代基于鸡蛋的疫苗生产技术，因此对NOT-06-011中概述的NIAID高优先级流感研究领域有反应。