Development of a Conjugate Vaccine for the Prevention of Tularemia

开发预防兔热病的结合疫苗

• 批准号: 7642993
• 负责人: Dennis L. Kasper
• 金额: $ 46.92万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642993
• 关键词: Address; Adverse effects; Area; Arts; Bacteria; Bacterial Infections; Basic Science; Biochemistry; Biomedical Research; Biotechnology; Bioterrorism; Boston; Chemistry; Clinical Research; Clinical Trials; Commit; Communicable Diseases; Communities; Conduct Clinical Trials; Conjugate Vaccines; Connecticut; Creativeness; Data; Depth; Development; Disease; Drug Industry; Emerging Communicable Diseases; Environment; Francisella tularensis; Genetic; Genome; Glycoconjugates; Goals; Home environment; Hospitals; Human; Immune response; Immunity; Immunology; Industry; Infection; Infection prevention; Infectious Diseases Research; Institution; Intervention; Investigation; Learning; Life; Link; Lipid A; Microbe; Microbiology; Mission; Molecular Weight; Movement; Mus; Nature; New England; Nursing Faculty; O Antigens; Organism; Pathogenesis; Personal Satisfaction; Pharmacologic Substance; Phase; Physicians; Polymers; Polysaccharides; Populations at Risk; Preclinical Testing; Preparation; Prevention; Preventive; Proteins; Proteomics; Range; Research; Research Institute; Resources; Role; Scientist; Structure; Surface; Teaching Hospitals; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Thinking; Training; Translating; Translational Research; Tularemia; United States; Universities; Ursidae Family; Vaccinated; Vaccines; Virulence; Virulence Factors; Whole Cell Vaccine; Work; base; biodefense; capsule; catalyst; cell mediated immune response; college; design; immunogenic; innovation; medical schools; novel; novel strategies; pathogen; research and development; therapeutic target; tool; translational approach; vaccine development

Francisella tularensis is a highly infectious bacterium that poses a serious threat as an agent ofbioterrorism. A live whole cell vaccine is currently available for at-risk populations, but it is associated with incomplete immunity and side-effects. Studies of humans and mice vaccinated with this preparation indicate that humoral and cell-mediated immune responses are required for complete protection in the infected host. Currently, little is known concerning the virulence factors associated with F. tularensis that contribute to its ability to cause lethal disease. However, previous studies have identified the capsule and LPS as principle determinants of its pathogenic potential. Our analysis of the recently released genome ofF. tularensis Schu $4 has shown that it possesses a single polysaccharide biosynthetic locus responsible for expression of one surface polysaccharide. Based on these data, we hypothesize that the previously described capsule and O-antigen of this organism actually represents a single O-antigen/capsule that has the same repeating unit structure, but is expressed as a distinct large molecular-weight polymer and smaller molecularweight Lipid A-linked polysaccharide. We predict that this structure has a central role in the pathogenesis of this organism and can be used as the basis for novel glycoconjugate vaccines that will elicit complete protection against experimental tularemia. To address the structural nature of this virulence factor and its role in the pathogenesis and immunity to F. tularensis, we propose to: 1) Characterize the structural and genetic nature of the O-antigen/capsule; 2) Determine the role of the O-antigen/capsule in virulence; 3) Determine the humoral and cell-mediated immune responses to the O-antigen/capsule and proteins ofF. tularensis; and 4) Develop a conjugate vaccine for F. tularensis infections. These studies will employ a proteomics-based approach to identify new immunogenic proteins from F. tularensis that can be used as carriers in the development of novel acellular glycoconjugate vaccines. It is anticipated that these vaccines will activate both humoral and cell-mediated immune responses and elicit complete protection against tularemia. Glycoconjugate vaccines have been among the most effective biologics ever developed for the prevention of bacterial infections. It is expected that this approach can be applied successfully to the development of a vaccine that can ultimately be tested in clinical trials for the prevention of tularemia.

Francisella tularensis是一种高度感染性的细菌，作为生物恐怖主义的特工构成了严重的威胁。 目前有现场直播的全细胞疫苗可用于高危人群，但与不完整有关 免疫力和副作用。对以这种准备接种疫苗的人类和小鼠的研究表明 在感染宿主中完全保护需要进行体液和细胞介导的免疫反应。 目前，关于与f。tularensis相关的毒力因子的知之甚少，这有助于其 引起致命疾病的能力。但是，以前的研究已将胶囊和LPS鉴定为原理 其致病潜力的决定因素。我们对最近发布的基因组的分析。 Tularensis Schu $ 4已表明它拥有一个单一多糖生物合成基因座，负责表达一个 表面多糖。基于这些数据，我们假设先前描述的胶囊和 该生物的O-抗原实际上代表具有相同重复的单个O抗原/胶囊 单位结构，但表示为独特的大分子量聚合物和较小的分子量 脂质A连接多糖。我们预测这种结构在 这种生物的发病机理，可以用作新型糖缀合物疫苗的基础 对实验性疾病进行完全保护。解决此的结构性 毒力因子及其在对f。tularensis的发病机理和免疫力中的作用，我们提出：1）表征 O-抗原/胶囊的结构和遗传性质； 2）确定O-抗原/胶囊在 毒力3）确定对O-抗原/胶囊的体液和细胞介导的免疫反应以及 蛋白质关闭。 tularensis; 4）开发一种用于f。tularensis感染的共轭疫苗。这些研究会 采用一种基于蛋白质组学的方法来鉴定可能是tularensis的新免疫原性蛋白 用作新型腺糖缀合物疫苗开发的载体。预计这些 疫苗将激活体液和细胞介导的免疫反应并引起完全保护 反对tularemia。糖缀合物疫苗一直是有史以来开发的最有效的生物制剂之一 用于预防细菌感染。预计这种方法可以成功地应用于 开发疫苗，最终可以在临床试验中进行预防的疫苗。