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 球孢子菌病影响美国西南部、墨西哥北方和分散地区的居民 南美洲的一个地区。据估计，美国有15万人感染了球孢子菌 每年。迫切需要开发更好的化学疗法和抗球孢子菌疫苗 感染这项研究旨在优化新的免疫抑制剂的保护效果并阐明其免疫机制。 开发了抗球孢子菌病的多价疫苗。该疫苗由重组嵌合体 多肽抗原（rCPA 2），由先前鉴定的4种最具免疫原性的片段组成 球孢子菌抗原和5个预测的T细胞表位。初步研究表明， 在用以下疫苗接种表达人MHCII的HLA-DR 4转基因小鼠后的适应性T细胞应答 葡聚糖-几丁质颗粒（GCP）“负载”有rCPA 2。此外，优化的GCP-rCPA 2疫苗提供了 在5种测试的佐剂形式中具有最佳的保护效力，并且与减毒活ΔT疫苗相当。 rCPA+GCP疫苗在接种部位被巨噬细胞和树突状细胞充分处理， 介导差异免疫基因表达，导致增强的抗原呈递和Th 1-和Th 17- 混合极化Th 17免疫已显示对于针对以下疾病的疫苗免疫是不可缺少的： 球孢子菌病该建议的中心假设是，在细胞中加载的优化的rCPA 2抗原可以在细胞中表达。 具有FDA批准的载体的GCP佐剂/递送系统可引发广谱保护性免疫 用于人源化小鼠对抗两种球孢子菌属的感染。目标是调查 使用人源化鼠模型优化的GCP-rCPA 2疫苗的保护机制 球孢子菌病与人类免疫细胞。有3个具体目标：目标1是创建一个优化的 rCPA 2，可以诱导广谱和持久的保护性免疫力，对两种物种， 球孢子菌属。rCPA 2上的人T细胞表位将针对3种常见的人MHC II等位基因进行定位。有 不同的C. posadasii和C.伊米蒂斯。的 优化的抗原将包括来自两个球孢子菌属物种的用于多个HLA的显性表位 等位基因将检测优化疫苗对每种病毒的两种选定分离株的保护效力 球孢子菌属的物种与抗原的同源性最小。目标二是优化GCP 引发抗球孢子菌感染的保护性Th 1-和Th 17-混合应答的佐剂制剂 使用人和小鼠APC和CD 4 + T细胞。将优化GCP佐剂/递送系统， 以最大限度地提高保护效果。目的3研究疫苗诱导的保护机制， 使用球孢子菌病小鼠模型的Th 1和Th 17应答。该项目完成后， 将确定优化的和保护性的GCP 2-rCPA 2疫苗，以推进临床试验， 评估其对球孢子菌病的安全性和保护效力。

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