Development of a multivalent vaccine against Coccidioides infection

开发针对球孢子菌感染的多价疫苗

• 批准号: 10399515
• 负责人: CHIUNG-YU HUNG
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-08 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399515
• 关键词: Address; Adjuvant; Adoptive Transfer; Affect; Alleles; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Attenuated; Attenuated Vaccines; Autologous; Biological Assay; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD86 gene; Categories; Cathepsins; Cells; Charge; Chimeric Proteins; Chitin; Clinical; Clinical Trials; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Coculture Techniques; Computer software; Custom; Data; Dendritic Cells; Development; Disease; Epitopes; Excision; Exposure to; FDA approved; FOLH1 gene; Formulation; Gene Expression; Genes; Genomics; Glucans; Goals; HLA-DR4 Antigen; Human; Immune; Immune response; Immunity; In Vitro; Infection; Interferon Type II; Interleukin-1 beta; Interleukin-12; Interleukin-17; Interleukin-6; Lower respiratory tract structure; Lung; Lung diseases; Lung infections; MHC Class II Genes; Maps; Mediating; Medical; Mexico; Morphology; Mus; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Persons; Physiologic pulse; Populations at Risk; Process; Proteins; Recombinant Vaccines; Recombinants; Reporting; Role; Safety; Sequence Homologs; Signal Pathway; Site; South America; Southwestern United States; Symptoms; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; TLR1 gene; TNFRSF5 gene; Techniques; Testing; Transgenic Mice; United States; United States National Institutes of Health; Vaccination; Vaccines; Work; acute infection; antigen-specific T cells; base; beta-Glucans; chemotherapy; community acquired pneumonia; cytokine; design; enzyme linked immunospot assay; humanized mouse; immunogenic; macrophage; mouse dectin-2; mouse model; novel; particle; pathogen; pathogenic microbe; polypeptide; protective efficacy; receptor; response; transcriptome; transcriptome sequencing; vaccine development; vaccine formulation; vaccine trial

Project Summary Coccidioidomycosis affects residents in the southwestern United States, northern Mexico and scattered areas of South America. An estimated 150,000 people in the United States become infected with Coccidioides annually. There is an urgent unmet need to develop better chemotherapies and a vaccine against Coccidioides infection. This proposed study is to optimize protective efficacy and delineate immune mechanisms of a newly developed multivalent vaccine against coccidioidomycosis. The vaccine consists of a recombinant chimeric polypeptide antigen (rCPA2) composed of the most immunogenic fragments of 4 previously identified Coccidioides antigens and 5 predicted T-cell epitopes. Preliminary studies demonstrate robust and long-lasting adaptive T-cell responses following vaccination of human MHC II-expressing HLA-DR4 transgenic mice with glucan-chitin particles (GCPs) “loaded” with rCPA2. Furthermore, optimized GCP-rCPA2 vaccine affords the best protective efficacy among 5 tested adjuvant formations and comparable to a live, attenuated ΔT vaccine. The rCPA+GCP vaccine is well processed by macrophages and dendritic cells at the vaccination sites and mediates differential immune gene expressions leading to enhanced antigen presentation and Th1- and Th17- mixed polarization. Th17 immunity has shown to be indispensable for vaccine immunity against coccidioidomycosis. The central hypothesis of this proposal is that an optimized rCPA2 antigen loaded in GCP adjuvant/delivery system with an FDA-approved carrier can elicit a broad spectrum of protective immunity for humanized mice against infection with both species of Coccidioides. The goal is to investigate the protective mechanisms of the optimized GCP-rCPA2 vaccine using humanized murine models of coccidioidomycosis and human immune cells. There are 3 Specific Aims: Aim 1 is to create an optimized rCPA2 that can induce a broad spectrum and durable protective immunity against both species of Coccidioides. Human T-cell epitopes on rCPA2 will be mapped for 3 common human MHC II alleles. There is considerable morphological and genomic diversity among different isolates of C. posadasii and C. immitis. The optimized antigen will include dominant epitopes derived from both species of Coccidioides for multiple HLA alleles. Protective efficacy of the optimized vaccine will be tested to against two selected isolates of each Coccidioides species that present with the least homology of the antigens. Aim 2 is to optimize the GCP adjuvant formulation for eliciting a protective Th1- and Th17-mixed response against Coccidioides infection using both human and mouse APCs and CD4+ T cells. An optimized GCP adjuvant/delivery system will be created to maximize protective efficacy. Aim 3 To study the vaccine induced protective mechanism that guides Th1 and Th17 responses using murine models of coccidioidomycosis. Upon completion of this project an optimized and protective GCP2-rCPA2 vaccine will be identified for advancement to clinical trials for assessment of it safety and protective efficacy against coccidioidomycosis.

项目摘要 球虫病术影响美国西南部，墨西哥和零星地区的居民 南美。估计在美国有15万人感染了球虫 紧急未满足的需要开发更好的化学疗法和针对球虫的疫苗 感染。这项拟议的研究是为了优化新的保护效率，并描述了新近的免疫力学 开发了针对球虫菌病的多价疫苗。该疫苗由重组嵌合 多肽抗原（RCPA2）由4个先前鉴定的最免疫原性片段组成 球球菌抗原和5个预测的T细胞表位。初步研究证明了坚固而持久的 人类MHC II表达HLA-DR4转基因小鼠疫苗后的自适应T细胞反应 用RCPA2“加载”葡萄糖 - 吉他蛋白颗粒（GCPS）。此外，优化的GCP-RCPA2疫苗可提供 在5个测试的可调地层中最有效的有效性，与活的，减弱的ΔT疫苗相当。 RCPA+GCP疫苗通过巨噬细胞和树突状细胞在疫苗部位进行了很好的处理 介导差异免疫表达，导致抗原表现增强以及Th1-和th17-- 混合极化。 TH17免疫his已证明是疫苗免疫史的必不可少的 球菌病。该提案的中心假设是，加载的优化RCPA2抗原 带有FDA批准的载体的GCP调整/输送系统可以引起广泛的保护免疫力 用于人源化小鼠反对两种球虫的感染。目标是调查 使用人源化鼠模型的优化GCP-RCPA2疫苗的保护机制 球菌病和人类免疫力。有3个具体目标：目标1是创建优化 RCPA2可以诱导广泛的频谱和耐用的保护性免疫，以针对这两种物种 球球菌。 RCPA2上的人类T细胞表位将用于3个常见的人类MHC II等位基因。有 posadasii和C. imimitis的不同分离株之间的形态和基因组多样性相当大。这 优化的抗原将包括源自两种Coccidioides的主要HLA的主要表位 等位基因。优化疫苗的保护效率将针对每种选择的两个选定的分离株进行测试 球虫种类的抗原同源性最小。 AIM 2是优化GCP 辅助公式用于引发受保护的Th1和Th17混合反应，以针对球孢子感染 使用人和小鼠APC以及CD4+ T细胞。优化的GCP调整/输送系统将是 为了最大化受保护的效率而创建。 AIM 3研究疫苗引起的受保护机制 Th1和Th17的反应使用球虫菌病的鼠模型。完成该项目后 将确定优化和受保护的GCP2-RCPA2疫苗，以促进临床试验的发展 评估IT的安全性和针对球菌病的保护效率。

项目成果

Lipid Secretion by Parasitic Cells of Coccidioides Contributes to Disseminated Disease.

• DOI: 10.3389/fcimb.2021.592826
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Peláez-Jaramillo CA;Jiménez-Alzate MDP;Araque-Marin P;Hung CY;Castro-Lopez N;Cole GT
• 通讯作者: Cole GT