PROPHYLACTIC AND THERAPEUTIC IMMUNIZATION AGAINST H PYLORI IN RHESUS MACAQUES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 幽门螺杆菌通常感染人的胃，在那里它会引起所有人的炎症(胃炎)，在一些人中会引起消化性溃疡疾病或胃癌。虽然感染可以用抗生素治疗，但这种方法受到长期服用多种药物的要求、抗菌素耐药性以及治疗后感染复发的限制。许多幽门螺杆菌疫苗已经在小鼠模型中进行了研究，但绝育免疫通常没有实现，而且结果很少扩展到灵长类动物。这项建议的目的是进行一项翻译的临床前研究，以确定使用外膜蛋白BABA和BABB以及一种新型佐剂免疫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实验室在一系列优雅的研究中发现了Baba并确定了其特征，Solnick实验室开发和利用了无特定病原体(SPF)的恒河猴幽门螺杆菌模型。初步实验表明，BABA和一种新的无毒霍乱毒素衍生物(CTA1-DD)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将检测在纯化的Baba和BABB加CTA1-DD、单独的CTA1-DD或对照免疫后，无特定病原体(SPF)猕猴对幽门螺杆菌攻击的保护作用。实验2将检验BABA和BABB加CTA1-DD免疫对实验猕猴幽门螺杆菌感染的一次治疗的效果，以及作为抗生素治疗的辅助措施以防止二次攻击时的再次感染。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。我们还将检测血清、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部位。如果老鼠研究的令人鼓舞的结果能够在非人类灵长类动物身上复制，它们将成为在人类身上进行I/II期临床试验的基础。幽门螺杆菌是一种常见的感染，可导致消化性溃疡和胃癌。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。这项提议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，这可能会减少消化性溃疡疾病和胃癌的发生率。

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.