A Recombinant Protein Vaccine Against Coccidioidomycosis

一种抗球孢子菌病的重组蛋白疫苗

• 批准号: 7775116
• 负责人: GARRY Thomas COLE
• 金额: $ 35.02万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7775116
• 关键词: Animals; Antigen Targeting; Antigens; Attenuated; Attenuated Vaccines; Binding; Bioinformatics; C57BL/6 Mouse; California; Cell Wall; Cellular Immunity; Clinical; Clinical Trials; Coccidioides; Coccidioidomycosis; Dendritic Cells; Detergents; Development; Disease; Engineering; Epitopes; Goals; Health Care Costs; Human; Immune response; Immune system; Immunity; Immunization; Immunocompetent; Inbred BALB C Mice; Individual; Infection; Intervention; Life; Lung; Lung diseases; Major Histocompatibility Complex; Medical; Methods; Modeling; Morbidity - disease rate; Mus; Pattern recognition receptor; Proteins; Proteomics; Recombinant Proteins; Recovery; Research; Soil; T-Lymphocyte; Testing; Texas; Transgenic Mice; Transgenic Organisms; Vaccination; Vaccines; base; desert fever; design; experience; fungus; macrophage; mannose receptor; mutant; novel strategies; pathogen; protective efficacy; public health relevance; response; subcutaneous; vaccine candidate; vaccine efficacy

DESCRIPTION (provided by applicant): Coccidioides is an airborne fungal pathogen that can cause mild to severe respiratory disease (coccidioidomycosis; San Joaquin Valley fever) in immunocompetent individuals. The fungus inhabits desert soil in the Southwestern U.S. between West Texas and Southern California. About 20 million people reside in the endemic region. Although rarely a life-threatening disease, Coccidioides causes significant morbidity in more than 40% of infected individuals, and is responsible for high health care costs related to long term treatment. Although about half of the Coccidioides-infected individuals experience only mild discomfort and do not seek medical intervention, a large body of clinical evidence suggests that reactivation of the respiratory disease may occur months to years after the original insult. Recovery from symptomatic infection typically confers lifelong immunity to reinfection, suggesting that vaccination against coccidioidomycosis is feasible. We have shown that disease- susceptible BALB/c and C57BL/6 mice can be fully protected against coccidioidal infection by vaccination with a genetically engineered, avirulent strain of the pathogen. Preliminary studies have revealed that a detergent extracted protein fraction of the parasitic cell wall of this mutant strain protects mice against pulmonary coccidioidomycosis. In this proposal we outline a novel strategy to develop an epitope-driven chimeric vaccine based upon a subset of cell wall-derived antigens of the live vaccine strain of Coccidioides that interface with the host immune system and elicit a protective response against coccidioidal infection. In Specific Aim 1, we will identify, structurally characterize, express and test in a murine model of coccidioidomycosis the protective efficacy of T-cell-reactive proteins (Tcrp) derived from parasitic cell wall extracts of the genetically-engineered vaccine strain of Coccidioides. In Specific Aim 2, we will compare the protective efficacy of non-glycosylated recombinant proteins selected on the basis of Specific Aim 1 to genetically-engineered N- glycosylated, O-glycosylated, and both N- and O-glycosylated forms of the same selected recombinant proteins, and evaluate the involvement of mannose receptors in the stimulation of protective immunity. In Specific Aim 3, we will incorporate selected promiscuous, human major histocompatibility complex ((MHC) II-binding epitopes identified in vaccine candidates with the highest protective efficacy, as determined by Specific Aims 1 and 2, into a chimeric vaccine and evaluate its ability to protect human MHCII-expressing transgenic mice against pulmonary infection with Coccidioides. We argue that this epitope-driven vaccine can simultaneously direct the immune response to multiple dominant and subdominant epitopes and, thereby, induce robust and durable protection against coccidioidomycosis. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop an epitope-driven, recombinant protein-based vaccine against coccidioidomycosis (San Joaquin Valley fever), which will first be evaluated in a transgenic murine model of the respiratory disease (this project), and ultimately moved forward to human clinical trial.

描述（由申请人提供）：球孢子菌是一种空气传播的真菌病原体，可在免疫功能正常的个体中引起轻度至重度呼吸道疾病（球孢子菌病；圣华金谷热）。这种真菌栖息在美国西南部德克萨斯州西部和加利福尼亚州南部之间的沙漠土壤中。大约有2000万人居住在流行地区。虽然球孢子菌很少是危及生命的疾病，但它会导致 40% 以上的感染者显着发病，并导致与长期治疗相关的高昂医疗费用。尽管大约一半的球孢子菌感染者仅经历轻微不适并且不寻求医疗干预，但大量临床证据表明，呼吸道疾病可能会在最初感染后数月至数年重新激活。从有症状的感染中恢复通常会产生对再感染的终生免疫力，这表明针对球孢子菌病的疫苗接种是可行的。我们已经证明，通过接种基因工程的无毒病原体菌株，可以充分保护疾病易感性的 BALB/c 和 C57BL/6 小鼠免受球孢子菌感染。初步研究表明，从该突变菌株的寄生细胞壁中提取的去污剂蛋白质部分可以保护小鼠免受肺球孢子菌病的侵害。在本提案中，我们概述了一种新策略，开发一种表位驱动的嵌合疫苗，该疫苗基于球孢子菌活疫苗株细胞壁衍生抗原的子集，该抗原与宿主免疫系统相互作用并引发针对球孢子菌感染的保护性反应。在具体目标 1 中，我们将在球孢子菌病小鼠模型中鉴定、结构表征、表达和测试源自球孢子菌基因工程疫苗株寄生细胞壁提取物的 T 细胞反应蛋白 (Tcrp) 的保护功效。在具体目标2中，我们将比较在具体目标1的基础上选择的非糖基化重组蛋白与基因工程N-糖基化、O-糖基化以及同一选定重组蛋白的N-和O-糖基化形式的保护功效，并评估甘露糖受体在刺激保护性免疫中的作用。在具体目标 3 中，我们将根据具体目标 1 和 2 确定的，将选定的混杂的人类主要组织相容性复合物（(MHC) II 结合表位，在候选疫苗中鉴定出具有最高保护功效的嵌合疫苗，并评估其保护人类 MHCII 表达转基因小鼠免受球孢子菌肺部感染的能力。 疫苗可以同时引导免疫反应针对多个显性和亚显性表位，从而诱导针对球孢子菌病的强大而持久的保护。 公共健康相关性：该提案的目标是开发一种表位驱动的、基于重组蛋白的疫苗，用于对抗球孢子菌病（圣华金谷热），该疫苗将首先在呼吸道疾病的转基因小鼠模型中进行评估（本项目），并最终进入人体临床试验。