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（由申请方提供）：该提案的重点是在人源化鼠球孢子菌病模型中创建和临床前评价一种新型疫苗，该疫苗含有重组嵌合多肽抗原（rCPA），并与免疫原性最强的葡聚糖颗粒（GP）组合作为佐剂和递送平台。初步数据显示，对球孢子菌感染的疫苗免疫依赖于MyD 88和Card 9介导的Th 17和Th 1应答。此外，Th 17免疫是不可或缺的。GP是中空的、高度纯化的酵母细胞壁，主要由β-1，3-葡聚糖组成，已被证明可刺激Th 17和Th 1免疫。初步研究表明，在用“加载”抗原的GP免疫小鼠后，具有稳健和持久的适应性T细胞应答。中心假设是，当与激发Toll样受体（TLR）或C型凝集素受体（TLR）介导的免疫应答的配体组合时，掺入最具免疫原性形式的GP中的多价抗原（rCPA）将通过刺激对球孢子菌属感染的稳健且持久的Th 17和/或Th 1免疫来增强疫苗功效。这两个具体目标是：目标1。评价rCPA的免疫原性，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。已成功表达并纯化了融合了球孢子菌4种保护性抗原的rCPA。将使用表达人MHC II的HLA-DR 4转基因小鼠和从皮肤试验阳性和阴性志愿者中分离的外周血单核细胞评价这些单个抗原和rCPA对临床批准的球孢子菌抗原的免疫原性。将优化rCPA的设计，以仅包含4种选定抗原中的免疫原性多肽，其可刺激疫苗免疫的所有臂，包括产生IL-17 A和IFN-γ的T细胞的活化和抗体产生。目标2.确定一种有效的佐剂配体与修饰的GP组合，以增强rCPA疫苗对球孢子菌感染的免疫力。将优化的rCPA加载到4种不同类型的葡聚糖/甘露聚糖/几丁质颗粒（GxP）中，并单独测试在人源化HLA-DR 4转基因小鼠中的保护功效。葡聚糖颗粒是临床试验中的实验性疫苗佐剂。最具保护性的GP类型将与模式识别受体的选定配体共负载，以增强T细胞免疫力和保护功效。将分析赋予对球孢子菌属感染的抗性的疫苗，以剖析保护的相关性，包括在用潜在致死剂量的球孢子菌属孢子鼻内激发后免疫应答的传出和传入分支期间T细胞和抗原呈递细胞的细胞因子表达。该项目完成后，将产生一种新的先导多价候选疫苗，用于临床试验，以评估其对球孢子菌病的安全性和保护效力。