A Novel Mucosal Vaccine Delivery System Using Bacteriophage T4 Nanoparticles

使用噬菌体 T4 纳米颗粒的新型粘膜疫苗输送系统

• 批准号: 8981493
• 负责人: Emily Lynn Messina
• 金额: $ 5.3万
• 依托单位: CATHOLIC UNIVERSITY OF AMERICA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981493
• 关键词: Address; Antibodies; Antigens; Bacteriophage T4; Biological Assay; CD8B1 gene; Capsid; Cell Surface Receptors; Cell surface; Chimeric Proteins; Collaborations; Cytomegalovirus; DNA; DNA Packaging; DNA Vaccines; Digestion; Disease; Dose; Engineering; Enhancers; Epithelial Cells; Epithelium; Flagellin; Fluorescence; Genes; HIV; Head; Hepatitis C virus; Human; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; In Vitro; Infection; Infection prevention; Inflammatory; Intestines; Inverted Terminal Repeat; Laboratories; Learning; Left; Ligands; Measures; Membrane; Mucosal Immune Responses; Mucous Membrane; Mucous body substance; Mus; Muscle; Norwalk virus; Nose; Pattern; Peptide Hydrolases; Plague; Proteins; Public Health; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Route; Safety; Serum; Severe Acute Respiratory Syndrome; Site; Skin; Surface; System; TLR2 gene; TLR5 gene; Techniques; Temperature; Testing; Time; Tissues; Toll-Like Receptor 2; Tongue; Transgenes; Vaccine Adjuvant; Vaccine Design; Vaccines; Vagina; Work; adaptive immunity; anthrax toxin; base; career; career development; cost; cytokine; cytotoxic; design; efficacy testing; experience; falls; forging; in vivo; mouse model; mucosal vaccine; nanocage; nanoparticle; novel; pathogen; porin; public health relevance; receptor; research study; response; success; targeted delivery; transgene expression; vaccine delivery; vaccine development; vector; vector vaccine

 DESCRIPTION (provided by applicant): In this project, we seek to fill an important gap in mucosal vaccine delivery. Most pathogens enter the body at mucosal surfaces such as the nasal and vaginal passageways and the intestines, yet nearly all vaccines to date are injected into the muscle or under the skin. These vaccines stimulate a systemic immune response, but often leave the mucosal epithelium, our primary barrier to infection, vulnerable. We propose to develop a novel and adaptable mucosal vaccine platform using T4-bacteriophage capsids. These capsids can simultaneously package vaccine DNA, present protein antigens, and display targeting ligands on the head surface. Therefore, we can engineer a targeted vaccine vector that presents the immune system with a "protein-prime" and a "DNA-boost" to generate a long-lasting immune response. To do this, we will target the T4-heads to epithelial cells using the cell-surface receptors toll-like receptor 2 and 5 (TLR2 & 5). These receptors are part of the early innate immune response and are targets of vaccine adjuvants. Triggering an innate immune response is key to developing an adaptive, long-lasting response. We will also optimize a transgene cassette encoding vaccine DNA for high-level and long-term expression in epithelial cells. We hypothesize that by targeting the heads to the epithelium and delivering them to mucosal associated tissues, we will elicit a strong immune response systemically and significantly, in the mucosal epithelium. To test this hypothesis, we will deliver targeted-T4 capsids presenting antigen and carrying vaccine-DNA to mice sublingually (under-the-tongue), intranasally, and intramuscularly. We will then compare the innate and adaptive immune responses at both early (day 3) and late time-points (1 year). We expect to observe the most robust adaptive immune response in the groups with the strongest early innate response. We predict that all routes of administration will generate a systemic response, but we will see the most robust mucosal immune response in the sublingual and the intranasal groups. If successful, the work here will generate an effective, novel, mucosal vaccine platform that is inexpensive to produce and readily adaptable to a multitude of diseases.

 描述（由申请人提供）：在本项目中，我们寻求填补粘膜疫苗递送的重要空白。大多数病原体从粘膜表面进入体内，如鼻腔和阴道通道以及肠道，但迄今为止几乎所有的疫苗都注射到肌肉或皮肤下。这些疫苗刺激全身性免疫反应，但往往使粘膜上皮，我们的主要屏障感染，脆弱。我们建议使用T4噬菌体衣壳开发一种新的和适应性强的粘膜疫苗平台。这些衣壳可以同时包装疫苗DNA，呈递蛋白抗原，并在头部表面展示靶向配体。因此，我们可以设计一种靶向疫苗载体，为免疫系统提供“蛋白质启动”和“DNA加强”，以产生持久的免疫应答。为此，我们将使用细胞表面受体toll样受体2和5（TLR2和5）将T4头靶向上皮细胞。这些受体是早期 先天性免疫应答，并且是疫苗佐剂的靶标。触发先天免疫反应是发展适应性持久反应的关键。我们还将优化编码疫苗DNA的转基因盒，用于在上皮细胞中高水平和长期表达。我们假设，通过将头部靶向上皮并将其递送至粘膜相关组织，我们将在粘膜上皮中引起系统性和显著的强烈免疫应答。为了验证这一假设，我们将通过舌下（舌下）、鼻内和肌内途径向小鼠递送呈递抗原并携带疫苗DNA的靶向T4衣壳。然后，我们将比较早期（第3天）和晚期时间点（1年）的先天性和适应性免疫应答。我们期望在具有最强的早期先天性应答的组中观察到最强的适应性免疫应答。我们预测，所有给药途径都将产生全身性应答，但我们将在舌下和鼻内组中看到最强的粘膜免疫应答。如果成功的话，这项工作将产生一种有效的、新型的粘膜疫苗平台，这种疫苗生产成本低，而且很容易适应多种疾病。