Enhancement of protective efficacy of Coccidioides vaccines by adjuvants

佐剂增强球孢子菌疫苗的保护功效

• 批准号: 8970054
• 负责人: CHIUNG-YU HUNG
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970054
• 关键词: Acute; Address; Adjuvant; Agonist; Antibody Formation; Antigen-Presenting Cells; Antigens; Area; Attenuated; C Type Lectin Receptors; Categories; Cell Wall; Cells; Charge; Chimeric Proteins; Chitin; Clinical Trials; Coccidioides; Coccidioidomycosis; Combined Vaccines; Communities; Complex; DNA; Data; Disease; Dose; Double-Stranded RNA; Epitopes; Evaluation Reports; Exposure to; Generations; Glucans; Goals; HLA-DR4 Antigen; Human; Hypersensitivity skin testing; Immune response; Immunity; Immunization; Individual; Infection; Interferons; Interleukin-17; Interleukin-6; Lead; Life; Ligands; Limb structure; Liposomes; Lower respiratory tract structure; Lung diseases; Mannans; Measures; Mediating; Methods; Modeling; Mus; Patients; Pattern recognition receptor; Peptides; Personal Satisfaction; Pneumonia; Poly I-C; Polymers; Populations at Risk; Proline; Proteins; Recombinant Proteins; Recombinant Vaccines; Recombinants; Reporting; Reproduction spores; Resistance; Respiratory Tract Infections; Saccharomyces cerevisiae; Safety; Serum; Splenocyte; Symptoms; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; TLR3 gene; Testing; Toll-like receptors; Transgenic Mice; Trehalose; United States National Institutes of Health; Vaccinated; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral Tumor Antigens; Work; Yeasts; analog; arm; base; cytokine; design; fungus; immunogenic; immunogenicity; inorganic phosphate; microbial; mutant; mycobacterial; novel; novel vaccines; particle; pathogen; peripheral blood; polypeptide; preclinical evaluation; protective efficacy; public health relevance; response; vaccine candidate; vaccine development; vaccine efficacy; volunteer

 DESCRIPTION (provided by applicant): This proposal is focused on the creation and preclinical evaluation of a novel vaccine containing a recombinant, chimeric polypeptide antigen (rCPA) combined with the most immunogenic type of glucan particles (GPs) as an adjuvant and delivery platform in a humanized murine model of coccidioidomycosis. Preliminary data have revealed that vaccine immunity to Coccidioides infection is dependent on both MyD88- and Card9-mediated Th17 and Th1 responses. Furthermore, Th17 immunity is indispensable. GPs are hollow, highly purified yeast cell walls composed predominantly of ß-1,3-glucan that has been shown to stimulate Th17 and Th1 immunity. Preliminary studies demonstrate robust and long-lasting adaptive T-cell responses following immunization of mice with GPs "loaded" with antigens. The central hypothesis is that a multivalent antigen (rCPA) incorporated into the most immunogenic form of GPs, when combined with a ligand(s) that elicits Toll- like receptor (TLR)- or C-type lectin receptor (CLR)-mediated immune responses will augment vaccine efficacy by stimulating robust and durable Th17 and/or Th1 immunity to Coccidioides infection. The two Specific Aims are: Aim 1. To evaluate immunogenicity of rCPA and to optimize antigen design. Multivalent Coccidioides vaccines containing multiple antigens have been shown to be more effective in stimulation of protective immunity than individual antigens. The proposed rCPA that incorporates 4 protective antigens of Coccidioides has been successfully expressed and purified. The immunogenicity of these individual antigens and rCPA will be evaluated using human MHC II-expressing HLA-DR4 transgenic mice and peripheral blood monocytic cells isolated from skin test-positive and -negative volunteers to a clinically-approved antigen of Coccidioides. The design of the rCPA will be optimized to contain only the immunogenic polypeptides among the 4 selected antigens that can stimulate all arms of vaccine immunity including activation of IL-17A- and IFN--producing T cells and antibody production. Aim 2. To identify an effective adjuvant ligand(s) combined with modified GPs to enhance rCPA vaccine immunity to Coccidioides infection. The optimized rCPA will be loaded into 4 different types of glucan/mannan/chitin particles (GxP) and tested individually for protective efficacy in humanized HLA-DR4 transgenic mice. Glucan particles are an experimental vaccine adjuvant under clinical trials. The most protective type of GPs will be co-loaded with a selected ligand(s) for pattern recognition receptors to augment T-cell immunity and protective efficacy. The vaccine(s) that confer resistance to Coccidioides infection will be analyzed to dissect correlates of protection including cytokine expression by T cells and antigen-presenting cells during the efferent and afferent limbs of immune responses after an intranasal challenge with a potentially lethal dose of Coccidioides spores. Upon completion of this project, a novel lead multivalent vaccine candidate will be generated for advancement into clinical trials for assessment of its safety and protective efficacy against coccidioidomycosis.

 描述（由申请人提供）：该提案的重点是创建一种新型疫苗并进行临床前评估，该疫苗含有重组嵌合多肽抗原（rCPA）以及最具免疫原性类型的葡聚糖颗粒（GP）作为佐剂和递送平台。球孢子菌病的人源化鼠模型初步数据表明，疫苗对球孢子菌感染的免疫力依赖于 MyD88 和 Card9 介导的。此外，Th17 免疫是不可或缺的，主要由 β-1,3-葡聚糖组成，初步研究表明其具有强大且持久的免疫力。使用“装载”抗原的 GP 免疫小鼠后的适应性 T 细胞反应 中心假设是，当组合时，多价抗原 (rCPA) 会并入最具免疫原性的 GP 形式中。与引发 Toll 样受体 (TLR) 或 C 型凝集素受体 (CLR) 介导的免疫反应的配体将通过刺激对球孢子菌感染的强大和持久的 Th17 和/或 Th1 免疫力来增强疫苗功效。目的 1. 评估 rCPA 的免疫原性并优化抗原设计，含有多种抗原的多价球孢子菌疫苗已被证明比单个抗原更有效地刺激保护性免疫。所提出的包含 4 种球孢子菌保护性抗原的 rCPA 已成功表达和纯化。将使用表达人类 MHC II 的 HLA-DR4 转基因小鼠和从皮肤测试阳性和分离的外周血单核细胞来评估这些单独抗原和 rCPA 的免疫原性。 -对临床批准的球孢子菌抗原呈阴性的志愿者 rCPA 的设计将被优化，以仅包含可刺激疫苗所有臂的 4 种选定抗原中的免疫原性多肽。免疫，包括激活产生 IL-17A 和 IFN-γ 的 T 细胞和产生抗体。 目标 2. 鉴定与修饰的 GP 结合的有效佐剂配体，以增强 rCPA 疫苗对球孢子菌感染的免疫力。加载到 4 种不同类型的葡聚糖/甘露聚糖/几丁质颗粒 (GxP) 中，并单独测试人源化 HLA-DR4 转基因小鼠的保护功效，这是一种实验性疫苗佐剂。最具保护性的 GP 类型将与模式识别受体的选定配体共同负载，以增强 T 细胞免疫和保护功效，对球孢子菌感染具有抵抗力的疫苗将被分析。在用可能致死剂量的球孢子菌孢子进行鼻内攻击后，剖析保护的相关性，包括在免疫反应的传出和传入肢体中 T 细胞和抗原呈递细胞的细胞因子表达。将产生一种新型的主要多价候选疫苗，以进入临床试验，以评估其对球孢子菌病的安全性和保护功效。