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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 幽门螺杆菌通常感染人类胃，在所有个体中引起炎症（胃炎），在一些个体中引起消化性溃疡疾病或胃癌。虽然感染可以用抗生素治疗，但这种方法受到以下因素的限制：需要在长时间内给予多种药物，抗菌素耐药性以及治疗后感染复发。大量H.幽门螺杆菌疫苗已经在小鼠模型中进行了研究，但通常没有实现杀菌免疫，并且结果很少扩展到灵长类动物。本提案的目标是进行转化的临床前研究，以确定使用外膜蛋白BabA和BabB以及新型佐剂免疫的可行性，以预防和治疗实验性H。非人类灵长类动物中的幽门螺杆菌感染。该项目汇集了Born实验室和Solnick实验室的专业知识，Born实验室在一系列优雅的研究中发现并表征了BabA，Solnick实验室开发并利用了无特定病原体（SPF）的恒河猴模型H。幽门。初步实验表明，用BabA和一种新型的、无毒的霍乱毒素衍生物（CTA 1-DD）进行免疫对于小鼠的预防性和治疗性免疫是非常有效的。实验1将研究对H的保护。在用纯化的BabA和BabB加CTA 1-DD、单独的CTA 1-DD或对照免疫后，在无特定病原体（SPF）恒河猴中进行幽门螺杆菌攻击。实验2将检查用BabA和BabB加CTA 1-DD免疫用于实验H的初级治疗的功效。幽门螺杆菌感染的猕猴，并作为抗生素治疗的辅助，以防止二次攻击后的再感染。主要终点将是攻毒后2周和8周进行的胃活检定量培养。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地形。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，它们将作为人类I/II期临床试验的基础。幽门螺杆菌是引起消化性溃疡和胃癌的常见感染。尽管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。本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。这些实验可能会导致开发一种疫苗来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发生率。