TB Vaccine Candidates Found in Patients' Bodily Fluids and Murine MHC-1 Molecule

在患者体液和鼠 MHC-1 分子中发现候选结核疫苗

• 批准号: 7525848
• 负责人: Antonio Campos-Neto
• 金额: $ 60.91万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525848
• 关键词: Adjuvant; Adult; Animal Model; Antigens; Antitubercular Agents; Blood Circulation; CD8B1 gene; Calmette-Guerin Bacillus; Cells; Cessation of life; Class; Clinical; Clinical Trials; Code; DNA; Disease; Drug Formulations; Drug resistance in tuberculosis; Evaluation; Facility Construction Funding Category; Future; Genes; Goals; HIV; Histocompatibility Antigens Class I; Host Defense; Human; Immunity; Incidence; Individual; Lesion; Liquid substance; Lung; MHC Class I Genes; Microbe; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasmids; Population; Production; Proteins; Public Health; Pulmonary Tuberculosis; Recombinant Proteins; Reporting; Research; Spleen; Subunit Vaccines; System; T-Lymphocyte; Testing; Time; Translations; Tuberculosis; Tuberculosis Vaccines; Urine; Vaccines; Validation; Virus; Virus Diseases; Work; base; design; gene cloning; gene delivery system; in vivo; innovation; interest; microbial; mortality; novel; pathogen; pre-clinical; prevent; programs; research clinical testing; research study; response; tuberculosis treatment; vaccine development

DESCRIPTION (provided by applicant): The goal of this project is to develop a novel anti-tuberculosis subunit vaccine constituted of new and unique M. tuberculosis antigens formulated either in novel adjuvants approved for human use or in vectored virus delivery systems to be used in prime boost strategies. The vaccine candidates are molecules identified in either bodily fluid of patients with tuberculosis or associated with MHC Class I molecules of adherent spleen cells of M. tuberculosis-infected mice. The M. tuberculosis proteins identified in human secretions are apparently the only antigens reported to date that are derived directly from tuberculosis patients from tuberculosis-endemic regions. This work is based on the central hypothesis that pathogen's antigens that are actively produced during disease are interesting target molecules for vaccine development. Therefore, a vaccine developed from these two groups of in vivo derived antigens represents an important new strategy for producing full protective immunity. The genes coding for most of these antigens have been cloned and the recombinant proteins have been produced and purified. In addition we have begun the production of virus vectored formulations designed to test them as vaccine candidates delivered in a DNA format. The next challenge in the clinical translation of these original findings into promising vaccine candidates is to complete our initial studies that demonstrated that some of the these novel antigens are readily recognized by PBMC from healthy PPD positive individuals and less so by PBMC of patients with tuberculosis and induce protective immunity. Successful completion of this project will result in the validation of an antigen formulation comprising one or more of these novel antigens that is suitable for clinical testing in a future project. The specific Aims are: Aim 1: Construction and evaluation of virus vectored and other gene delivery systems containing the cloned genes coding for MHC class I associated M. tuberculosis peptides/proteins. Aim 2: Selection of adjuvant/antigen formulations and delivery systems that are safe for human use and that promote needed protective T cell responses. Aim 3: Pre-clinical validation of vaccine candidates in protection experiments in animal models of tuberculosis. PUBLIC HEALTH RELEVANCE: Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. The incidence of the disease remains high and is increasing in many parts of the world due in part to its association with human immunodeficiency virus (HIV) infection. It is estimated that one third of the world's population is infected with the microbe that causes tuberculosis and up to 2.5 million deaths occur each year as a consequence of this disease. Effective treatment of tuberculosis is difficult because it requires several medications that must be used over extended periods of time and because more than 50 million people around the world already are infected with incurable drug-resistant M. tuberculosis, the causative agent of this disease. BCG, the only available vaccine, has been in use since the early 1920s and unfortunately has limited or no efficacy to prevent adult pulmonary tuberculosis the most common and contagious form of the disease. The present project proposes to develop and evaluate novel and unique vaccine candidates against M. tuberculosis for assessment in future clinical trials.

描述（由申请人提供）：该项目的目的是开发一种新型的抗结核亚基亚基疫苗，该疫苗由新的和独特的结核分枝杆菌抗原构成，在批准用于人类使用的新型佐剂中，或在用于人类使用的新型佐剂中，或在媒介的病毒递送系统中使用主要提升策略。候选疫苗是在结核病患者的人体液中鉴定出的分子，或与结核分枝杆菌感染小鼠的粘附脾细胞的MHC I类分子有关。在人分泌物中鉴定出的结核分枝杆菌蛋白显然是迄今为止据报道的唯一抗原，直接来自结核病 - 流行区域的结核病患者。这项工作基于以下中心假设：疾病期间积极生产的病原体的抗原是疫苗发育的有趣靶标分子。因此，从这两组体内衍生的抗原开发的疫苗代表了产生完全保护性免疫的重要新策略。编码大多数这些抗原的基因已被克隆，重组蛋白已产生和纯化。此外，我们已经开始生产旨在测试其作为DNA格式的疫苗候选物进行测试的病毒载体配方。这些原始发现转化为有希望的疫苗候选者的临床翻译中的下一个挑战是完成我们的初步研究，这些研究表明，这些新型抗原很容易被健康的PPD阳性个体的PBMC识别，而PBMC的结核病和结核病和结核病和诱导保护性免疫。该项目的成功完成将导致验证抗原配方，其中包含一种或多种新型抗原，适用于未来项目中的临床测试。具体目的是：目标1：对载体和其他基因输送系统的构造和评估，这些病毒和其他基因输送系统包含编码MHC I类相关的结核分枝杆菌肽/蛋白质的克隆基因。 AIM 2：选择可安全使用并促进需要保护性T细胞反应的辅助/抗原制剂和输送系统。 AIM 3：在结核动物模型中的保护实验中，对疫苗候选物进行临床前验证。公共卫生相关性：结核病仍然是全球发病率和死亡率的主要感染原因。该疾病的发病率仍然很高，并且在世界许多地区的一部分是由于其与人类免疫缺陷病毒（HIV）感染的关联。据估计，世界人口中有三分​​之一感染了导致结核病的微生物，由于这种疾病，每年都会发生多达250万人死亡。有效治疗结核病是很困难的，因为它需要几种必须在长时间内使用的药物，而且世界各地超过5000万人已经感染了无法治愈的药物结核分枝杆菌，这是该疾病的病因。 BCG是唯一可用的疫苗，自1920年代初以来就一直在使用，不幸的是，有限或没有疗效以防止成年肺结核是该疾病最常见和最具感染的形式。本项目建议在未来的临床试验中开发和评估针对结核分枝杆菌的新颖和独特的候选候选物进行评估。