Development of a multivalent vaccine against Coccidioides infection

开发针对球孢子菌感染的多价疫苗

基本信息

批准号：
9916707
负责人：
CHIUNG-YU HUNG
金额：
$ 37.8万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-08 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916707
关键词：
Address Adjuvant Adoptive Transfer Affect Alleles Antigen Presentation Antigen-Presenting Cells Antigens Area Attenuated Attenuated Live Virus Vaccine 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 Communities 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 Physiologic pulse Pneumonia 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 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 trial

项目摘要

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.

项目概要球孢子菌病影响美国西南部、墨西哥北部和分散地区的居民南美洲估计有 150,000 人感染球孢子菌。每年都迫切需要开发更好的化疗药物和球孢子菌疫苗。这项拟议的研究旨在优化新感染的保护功效并描绘免疫机制。开发了针对球孢子菌病的多价疫苗，该疫苗由重组嵌合体组成。多肽抗原 (rCPA2) 由先前鉴定的 4 个中最具免疫原性的片段组成球孢子菌抗原和 5 个预测的 T 细胞表位经初步研究证明具有稳健性和持久性。表达人 MHC II 的 HLA-DR4 转基因小鼠接种疫苗后适应性 T 细胞反应 “负载”rCPA2 的葡聚糖-几丁质颗粒 (GCP) 此外，优化的 GCP-rCPA2 疫苗提供了在 5 种测试的佐剂制剂中具有最佳保护功效，与活的减毒 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很好地加工，介导差异性免疫基因表达，从而增强抗原呈递以及 Th1- 和 Th17- 混合极化已证明 Th17 免疫对于疫苗免疫是不可或缺的。该提案的中心假设是优化的 rCPA2 抗原加载于球孢子菌病中。 GCP 佐剂/递送系统与 FDA 批准的载体可引发广泛的保护性免疫目的是研究人源化小鼠对抗两种球孢子菌感染的能力。使用人源化小鼠模型优化 GCP-rCPA2 疫苗的保护机制球孢子菌病和人类免疫细胞有 3 个具体目标：目标 1 是创建一个优化的细胞。 rCPA2 可以诱导针对这两种病毒的广谱且持久的保护性免疫力 rCPA2 上的人类 T 细胞表位将被映射为 3 个常见的人类 MHC II 等位基因。 C. posadasii 和 C. immitis 不同分离株之间存在相当大的形态和基因组多样性。优化的抗原将包括来自两种球孢子菌的多种 HLA 的显性表位优化疫苗的保护功效将针对每种选定的两个分离株进行测试。与抗原同源性最低的球孢子菌物种目标 2 是优化 GCP。用于引发针对球孢子菌感染的保护性 Th1 和 Th17 混合反应的佐剂制剂使用人和小鼠 APC 和 CD4+ T 细胞将是一个优化的 GCP 佐剂/递送系统。目标 3 研究指导疫苗诱导的保护机制。使用球孢子菌病小鼠模型进行 Th1 和 Th17 反应。将确定优化的保护性 GCP2-rCPA2 疫苗，以推进临床试验评估其安全性和对球孢子菌病的保护功效。