Nanoengineered virus-mimics as templates for design of a universal influenza A va

纳米工程病毒模拟物作为通用甲型流感病毒设计的模板

• 批准号: 8285558
• 负责人: Harvinder Singh Gill
• 金额: $ 21.51万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-27 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8285558
• 关键词: Adjuvant; Affect; Amino Acids; Animal Model; Antigens; B-Lymphocytes; Cells; Charge; Child; Communicable Diseases; Cysteine; Data; Development; Drug Formulations; Economic Burden; Elderly; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Figs - dietary; Future; Genes; Goals; Gold; HIV; HIV-1; High Pressure Liquid Chromatography; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Influenza; Influenza A Virus, H1N1 Subtype; Intramuscular; Isoelectric Point; Life; M2 protein; Magnetism; Measures; Membrane Proteins; Methodology; Monitor; Morbidity - disease rate; Morphology; Mucosal Immunity; Mus; Mutation; N-terminal; Nanotechnology; Nasal Lavage Fluid; Nose; Penetration; Peptides; Philippines; Play; Property; Role; Route; Saliva; Serum; Solutions; Structure; Sulfhydryl Compounds; Surface; System; Techniques; Technology; Testing; Transmission Electron Microscopy; Vaccination; Vaccines; Virion; Virus; Virus Diseases; absorption; anti-influenza; base; cell mediated immune response; density; design; extracellular; flexibility; immunogenic; improved; influenza virus vaccine; influenzavirus; mucosal vaccine; nanoengineering; nanoparticle; neuronal cell body; novel; pandemic disease; particle; protective efficacy; research study; respiratory; response; vaccine delivery; vaccine development; zeta potential

DESCRIPTION (provided by applicant): Influenza virus causes serious respiratory illness and has potential to cause pandemics. Due to the high mutation rate in influenza genes, antigenic drift creates a new strain each year. Consequently there is significant economic burden to monitor virus activity and to create and distribute new influenza vaccines to the public each year. On the surface of the influenza A virion is found a highly conserved membrane protein (M2) which lends itself as a potential target for developing a universal influenza vaccine. However, under natural circumstances, M2 is present in very small numbers (16-22 per virus particles), is not well exposed at the virus surface and is poorly immunogenic. Our approach to overcome these challenges is to emulate virus structure through the use of a synthetic gold (Au) nanoparticle (AuNP) conjugated with different functional peptides creating a nanoengineered virus-mimic (NVM). The NVM can carry an antigen of choice in high density. In addition, other functional peptides can also be easily attached to the NVM. For example, peptides that can enable NVMs to enter cells or to activate the immune cells of the body could be attached. Based on the NVM concept, we propose to develop a universal influenza A vaccine delivery system. As the influenza antigen we have selected the highly conserved extracellular portion of the influenza-A matrix protein M2 (M2e), and as the cell-penetrating peptide to enhance entry of NVMs into cells we have selected tat (47-58) peptide derived from the human immunodeficiency virus (HIV-1). Our hypothesis is that NVMs presenting a high density of M2e on their surface with tat as a helper peptide can stimulate a broadly protective anti-influenza A immune response. The objectives of this study are to optimize NVMs as an influenza vaccine system and to evaluate their protective efficacy in mice animal models using live infectious challenges with heterologous and heterosubtypic influenza strains. Importantly we will evaluate systemic and mucosal B cell immunity for the intranasal routes of immunization. This project is novel because it seeks to exploit nanotechnology to create a modular vaccine delivery system, which like 'lego' pieces, can be used to assemble NVMs with unique functionalities. This concept can be used broadly used to create vaccine delivery systems against a host of infectious diseases. PUBLIC HEALTH RELEVANCE: This project focuses on development of a universal influenza A vaccine that can enable protection against all influenza A strains, thus eliminating the need for yearly vaccination against influenza. Successful completion of the project will reduce much morbidity, especially amongst elderly and children. It also has potential to be deployed on a mass scale as an anti-terror vaccine-agent against influenza.

描述（由申请人提供）：流感病毒会导致严重的呼吸道疾病，并有可能引起大流行病。由于流感基因的高突变率，抗原漂移每年会产生新的菌株。因此，每年都有重大的经济负担来监测病毒活动，并为公众开发和分发新的流感疫苗。在流感的表面上，发现了一个高度保守的膜蛋白（M2），该膜蛋白是开发通用流感疫苗的潜在靶标。但是，在自然情况下，M2的数量很少（每个病毒颗粒16-22），在病毒表面没有很好地暴露，并且免疫原性较差。我们克服这些挑战的方法是通过使用合成黄金（AU）纳米颗粒（AUNP）与不同功能性肽共轭产生纳米工程性病毒模拟（NVM）来效仿病毒结构。 NVM可以携带高密度的抗原。另外，其他功能性肽也可以很容易地连接到NVM上。例如，可以将NVMS进入细胞或激活人体的免疫细胞的肽可以连接。基于NVM概念，我们建议开发一种普遍的流感疫苗输送系统。作为流感抗原，我们选择了流感-A基质蛋白M2（M2E）的高度保守的细胞外部分，以及作为细胞渗透肽来增强NVM的进入细胞中，我们选择了从人类免疫缺陷Virus（Hiv-1）衍生的TAT（47-58）肽。我们的假设是，用TAT作为辅助肽在其表面上呈现高密度M2E的NVM可以刺激广泛的保护性抗Imfluenza免疫反应。这项研究的目标是将NVM优化为流感疫苗系统，并使用具有异源和异源性流感菌株的实时感染挑战来评估小鼠动物模型中的保护性疗效。重要的是，我们将评估鼻内免疫途径的全身和粘膜B细胞免疫。该项目之所以新颖，是因为它试图利用纳米技术来创建一个模块化疫苗输送系统，例如“乐高”零件，可用于组装具有独特功能的NVM。该概念可广泛用于针对许多传染病创建疫苗输送系统。 公共卫生相关性：该项目的重点是开发一种可以保护所有流感菌株的普遍流感疫苗，从而消除了对 每年针对流感的疫苗接种。成功完成该项目将降低大量发病率，尤其是在老年人和儿童中。它也有潜力作为针对流感的抗恐怖疫苗进行大规模部署。