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（由申请方提供）：仅DNA疫苗接种将显著增强DNA疫苗在大流行应用中的快速部署效用（DNA疫苗的开发时间显著短于蛋白质或病毒载体系统的开发时间）。该项目的总体目标是开发一种快速部署的DNA疫苗平台，以预防大流行性流感H5 N1。假设流感DNA疫苗效力可以通过载体编码的免疫刺激RNA激活细胞质双链RNA（dsRNA）信号传导途径来增加。这将通过使用各种免疫刺激性“RNA元件”（RNAe）来实现。该I期概念验证研究将研究包含载体介导的RNAe对载体编码的靶抗原的免疫应答的潜在益处。流感血凝素（HA）将用作需要抗体应答以进行保护的示例抗原。将产生产生免疫刺激性dsRNA的新型HA DNA疫苗质粒载体，并在通过电穿孔增强的肌内注射递送后筛选体内免疫应答。将选择改善对HA的中和抗体应答的最佳骨架。然后，基于这种RNAe载体，“抑制剂抑制”DNA疫苗将被创建并在从属研究中进行测试。第二个假设是，由dsRNA活化DNA疫苗诱导的免疫应答可以通过防止由先天免疫的载体活化介导的免疫应答的靶细胞下调来进一步改善。上述定义的载体将被进一步修饰以掺入RNAe，其敲低这些细胞质dsRNA信号传导途径的各种衰减剂的表达。然后将在动物模型中确定由“抑制剂抑制”DNA疫苗诱导的对HA的抗体应答。在阶段II中，得到的最佳载体骨架（即，单独的特异性免疫刺激性RNAe，或潜在地与如本文所确定的"抑制抑制剂“shRNA组合）将被开发为用于流感H5 N1的新的快速部署的仅DNA疫苗平台。本文开发的快速部署DNA疫苗平台将具有与各种其他新兴生物制剂的通用性; NTC将许可该平台用于此类应用。该提案旨在开发新型流感疫苗，以取代基于蛋的疫苗生产技术，并因此响应NIAID的高优先级流感研究领域，如NOT-AI-06-011所述。