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: 8357306
• 负责人: JAY V. SOLNICK
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357306
• 关键词: Adjuvant; Aftercare; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antimicrobial Resistance; Biopsy; California; Cholera Toxin; Clinical Trials; Effectiveness; Feces; Frequencies; Funding; Gastric Juice; Gastritis; Goals; Grant; Helicobacter Infections; Helicobacter pylori; Histopathology; Human; Immunity; Immunization; Individual; Infection; Inflammation; Investigational Therapies; Lead; Macaca; Macaca mulatta; Membrane Proteins; Modeling; Mus; National Center for Research Resources; Peptic Ulcer; Pharmaceutical Preparations; Primates; Principal Investigator; Recurrence; Research; Research Infrastructure; Resources; Series; Serum; Source; Specific Pathogen Frees; Stomach; Therapeutic; Time; United States National Institutes of Health; Vaccines; base; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 幽门螺杆菌通常感染人类胃，导致所有个体出现炎症（胃炎），并导致某些个体出现消化性溃疡或胃癌。虽然感染可以用抗生素治疗，但这种方法受到需要长期服用多种药物、抗菌素耐药性以及治疗后感染复发的限制。已经在小鼠模型中研究了许多幽门螺杆菌疫苗，但通常尚未实现绝育免疫，并且结果很少扩展到灵长类动物。该提案的目标是进行一项转化性临床前研究，以确定使用外膜蛋白 BabA 和 BabB 以及新型佐剂进行免疫来预防和治疗非人类灵长类动物实验性幽门螺杆菌感染的可行性。该项目汇集了 Born 实验室和 Solnick 实验室的专业知识，Born 实验室在一系列出色的研究中发现并表征了 BabA，而 Solnick 实验室开发并利用了幽门螺杆菌的特定无病原体 (SPF) 恒河猴模型。初步实验表明，用 BabA 和一种新型无毒霍乱毒素衍生物 (CTA1-DD) 进行免疫对于小鼠的预防性和治疗性免疫非常有效。实验 1 将检查用纯化的 BabA 和 BabB 加 CTA1-DD、单独的 CTA1-DD 或对照免疫后，无特定病原体 (SPF) 恒河猴对幽门螺杆菌攻击的保护作用。实验 2 将检查用 BabA 和 BabB 加 CTA1-DD 进行免疫接种作为猕猴实验性幽门螺杆菌感染的主要治疗的功效，以及作为抗生素治疗的辅助疗法以防止二次攻击时的再感染。主要终点是攻击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、胃液和粪便中的 BabA 和 BabB 特异性抗体，以及组织病理学，以评估炎症和感染的形态。如果小鼠研究的令人鼓舞的结果可以在非人类灵长类动物中复制，它们将成为人类 I/II 期临床试验的基础。幽门螺杆菌是一种常见感染，可导致消化性溃疡病和胃癌。虽然感染可以用抗生素治疗，但这种方法受到抗生素耐药性和治疗后感染复发的限制。该提案的目标是确定幽门螺杆菌疫苗在非人类灵长类动物中的有效性。这些实验可能会导致开发出预防和治疗幽门螺杆菌感染的疫苗，这可能会降低消化性溃疡病和胃癌的发病率。