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: 8091441
• 负责人: Antonio Campos-Neto
• 金额: $ 54.72万
• 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/8091441
• 关键词: Adjuvant; Adult; Animal Model; Antigens; Antitubercular Agents; Blood Circulation; CD8B1 gene; Cells; Cessation of life; Clinical; Clinical Trials; Code; DNA; Disease; Drug Formulations; Drug resistance in tuberculosis; Evaluation; Future; Genes; Goals; HIV; Health; 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; Pulmonary Tuberculosis; Recombinant Proteins; Reporting; Research; Spleen; Subunit Vaccines; System; T cell response; Testing; Time; Translations; Tuberculosis; Tuberculosis Vaccines; Urine; Vaccines; Validation; Virus; Virus Diseases; Work; base; design; effective therapy; gene cloning; gene delivery system; in vivo; innovation; interest; microbial; mortality; novel; pathogen; pre-clinical; prevent; programs; research clinical testing; research study; vaccine candidate; 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）：本项目的目的是开发一种新型抗结核亚单位疫苗，该疫苗由新的独特的M.结核病抗原配制在批准用于人的新型佐剂中或配制在用于初免加强策略的载体病毒递送系统中。候选疫苗是在结核病患者体液中鉴定的分子或与粘附的M.感染结核病的小鼠。分枝在人分泌物中鉴定的结核蛋白显然是迄今为止报道的唯一直接来源于结核病流行地区的结核病患者的抗原。这项工作是基于一个中心假设，即在疾病期间活跃产生的病原体抗原是疫苗开发的有趣靶分子。因此，从这两组体内衍生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。编码这些抗原中的大多数的基因已经被克隆，并且重组蛋白已经被生产和纯化。此外，我们已经开始生产病毒载体制剂，旨在测试它们作为以DNA形式递送的候选疫苗。将这些原始发现临床转化为有希望的候选疫苗的下一个挑战是完成我们的初步研究，这些研究表明，这些新抗原中的一些容易被来自健康PPD阳性个体的PBMC识别，而不太容易被结核病患者的PBMC识别，并诱导保护性免疫。该项目的成功完成将导致包含一种或多种这些新抗原的抗原制剂的验证，该抗原制剂适用于未来项目的临床试验。具体目标是：目标1：构建和评价含有编码MHC I类相关M.结核肽/蛋白质。目标二：选择对人类使用安全并促进所需保护性T细胞应答的佐剂/抗原制剂和递送系统。目的3：在结核病动物模型中进行保护实验，对候选疫苗进行临床前验证。公共卫生相关性：结核病仍然是全世界发病率和死亡率的主要传染原因。这种疾病的发病率仍然很高，在世界许多地区还在增加，部分原因是它与人体免疫缺陷病毒（艾滋病毒）感染有关。据估计，世界人口的三分之一感染了导致结核病的微生物，每年有多达250万人死于这种疾病。结核病的有效治疗是困难的，因为它需要几种药物，必须在很长一段时间内使用，因为全世界有5000多万人已经感染了无法治愈的耐药M。结核病，这种疾病的病原体。卡介苗是唯一可用的疫苗，自20世纪20年代初以来一直在使用，不幸的是，它对预防成人肺结核（最常见和最具传染性的疾病）的效力有限或没有效力。本项目旨在开发和评估针对M.结核病，用于未来临床试验的评估。