PROPHYLACTIC AND THERAPEUTIC IMMUNIZATION AGAINST H PYLORI IN RHESUS MACAQUES

恒河猴中针对幽门螺杆菌的预防性和治疗性免疫

• 批准号: 8172583
• 负责人: JAY V. SOLNICK
• 金额: $ 11.41万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172583
• 关键词: Adjuvant; Aftercare; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antimicrobial Resistance; Biopsy; Cholera Toxin; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Effectiveness; Feces; Frequencies; Funding; Gastric Juice; Gastritis; Goals; Grant; Helicobacter Infections; Helicobacter pylori; Histopathology; Human; Immunity; Immunization; Individual; Infection; Inflammation; Institution; Investigational Therapies; Lead; Macaca; Macaca mulatta; Membrane Proteins; Modeling; Mus; Peptic Ulcer; Pharmaceutical Preparations; Primates; Pylorus; Recurrence; Research; Research Personnel; Resources; Series; Serum; Source; Specific Pathogen Frees; Stomach; Therapeutic; Time; United States National Institutes of Health; Vaccines; base; germ free condition; malignant stomach neoplasm; mouse model; nonhuman primate; novel; preclinical study; prevent; prophylactic; research study; vaccine development

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Helicobacter pylori commonly infects the human stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. Although the infection can be treated with antibiotics, this approach is limited by the requirement for multiple drugs administered over a prolonged period of time, by antimicrobial resistance, and by recurrence of infection after treatment. Numerous H. pylori vaccines have been studied in the mouse model, but sterilizing immunity has typically not been achieved, and the results have rarely been extended to primates. The goal of this proposal is to perform a translational, preclinical study to determine the feasibility of using immunization with the outer membrane proteins, BabA and BabB, together with a novel adjuvant, to prevent and treat experimental H. pylori infection in non-human primates. The project brings together the expertise of the Born lab, which discovered and characterized BabA in a series of elegant studies, and the Solnick lab, which has developed and exploited the specific pathogen free (SPF) rhesus macaque model of H. pylori. Preliminary experiments suggest that immunization with BabA and a novel, non-toxic derivative of cholera toxin (CTA1-DD) is highly effective for prophylactic and therapeutic immunization in mice. Experiment 1 will examine protection from H. pylori challenge in specific pathogen free (SPF) rhesus macaques after immunization with purified BabA and BabB plus CTA1-DD, CTA1-DD alone, or control. Experiment 2 will examine the efficacy of immunization with BabA and BabB plus CTA1-DD for primary therapy of experimental H. pylori infection in macaques, and as an adjunct to antibiotic therapy to prevent reinfection upon secondary challenge. The primary endpoint will be quantitative cultures of gastric biopsies performed two and eight weeks after challenge. We will also examine BabA- and BabB-specific antibodies in serum, gastric juice, and feces, as well as histopathology to evaluate inflammation and the topography of infection. If the encouraging results from mouse studies can be replicated in non-human primates, they would serve as the basis for PhaseI/II clinical trials in humans. Helicobacter pylori is a common infection that causes peptic ulcer disease and gastric cancer. Although infection can be treated with antibiotics, this approach is limited by antibiotic resistance and recurrence of infection after treatment. The goal of this proposal is to determine the effectiveness of an Helicobacter pylori vaccine in non-human primates. These experiments could lead to development of a vaccine to prevent and treat Helicobacter pylori infection, which would likely reduce the frequency of peptic ulcer disease and gastric cancer.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 幽门螺杆菌通常会感染人类胃，其中所有个体引起炎症（胃炎），有些人在某些人中引起炎症（胃炎）。尽管感染可以用抗生素治疗，但这种方法受到长时间内服用多种药物，抗菌耐药性以及治疗后感染的复发的限制。在小鼠模型中已经研究了许多幽门螺杆菌疫苗，但是通常没有实现灭菌的免疫力，并且结果很少扩展到灵长类动物。该提案的目的是进行一项翻译的临床前研究，以确定与外膜蛋白，BABA和BABB一起使用免疫的可行性，以及新型辅助剂，以预防和治疗非人类灵长类动物中的幽门螺杆菌感染。该项目汇集了Born Lab的专业知识，该实验室在一系列优雅的研究中发现和表征了Baba，Solnick Lab已开发并利用了H. Pylori的特定病原体（SPF）鼠尾草模型。初步实验表明，BABA的免疫和一种新型的霍乱毒素（CTA1-DD）的无毒衍生物对小鼠的预防性和治疗性免疫非常有效。实验1将在用纯化的BABA和BABB加上CTA1-DD，CTA1-DD，单独或对照的情况下，检查特定病原体（SPF）猕猴的幽门螺杆菌挑战的保护。实验2将检查BABA和BABB Plus CTA1-DD免疫的功效，用于猕猴中幽门螺杆菌感染的一级治疗，并作为抗生素治疗的辅助性，以防止在第二次挑战中再感染。主要终点将是在挑战后两周和八周进行的胃活检的定量培养。我们还将检查血清，胃汁和粪便中的BABA和BABB特异性抗体，以及组织病理学，以评估炎症和感染的地形。如果可以在非人类灵长类动物中复制小鼠研究的令人鼓舞的结果，则它们将作为人类中阶段/II临床试验的基础。幽门螺杆菌是一种常见的感染，可引起消化性溃疡疾病和胃癌。尽管感染可以用抗生素治疗，但这种方法受到治疗后感染的抗生素耐药性和复发性的限制。该提案的目的是确定幽门螺杆菌疫苗在非人类灵长类动物中的有效性。这些实验可能导致疫苗的发展以预防和治疗幽门螺杆菌感染，这可能会降低消化性溃疡疾病和胃癌的频率。