FIMH ADHESIN VACCINES TO PREVENT URINARY TRACT INFECTION

FIMH 粘附素疫苗预防尿路感染

• 批准号: 2770552
• 负责人: Solomon Langermann
• 金额: $ 37.21万
• 依托单位: MEDIMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770552
• 关键词: Escherichia coli; Primates; adhesin; bacterial vaccines; cross immunity; disease /disorder model; humoral immunity; interstitial cystitis; laboratory mouse; urinary tract infection; vaccine development

Bacterial attachment to host epithelium is an important early event in the pathogenesis of Escherichia coli urinary tract infections. This attachment is mediated by adhesin proteins that are associated with heteropolymeric fiber-like structures on the bacterial surface, called pili. The identification of tip adhesins at the distal end of pili provides an important novel target for vaccine development as early attempts to use whole pili were not successful in protecting against a broad range of pathogenic bacterial isolates. Uropathogenic E.coli are capable of producing a variety of adhesins as well as pilus types, which confer host cell receptor specifically to the pathogens. These structures dictate the tissue tropism, sites of colonization within the urogenital tract, and the resultant diseases that ensue from infection. The FimH adhesin which is associated with the type l -pilus binds to alpha-D-mannoside glycoconjugates which are abundant on bladder epithelium. Epidemiological and experimental evidence supports a role for type l -piliated E.coli in the development of cystitis. We have recently found that antibody raised specifically against two forms of the purified FimH adhesin prevents type l -piliated E.coli from binding to a- D-mannoside receptors, as measured by inhibition of agglutination of guinea pig erythrocytes and blocking of attachment by type l -piliated E.coli to human bladder cells in vitro. Furthermore, both the FimH-derived vaccines resulted in reduced colonization of the bladder by uropathogenic isolates of type l-piliated E.coli in vivo in murine cystitis model. These data suggest that anti-bacterial vaccines targeting adhesins may block attachment in vivo, and may be a means of preventing recurrent and acute urinary tract infections. Our objectives in this study are: 1.) to evaluate a third FimH-based vaccine candidate, type l tip fibrillae, which should induce maximal protective immunity, targeted to the binding domain of this lectin based on the conformation of FimH in this complex, 2.) to assay the best candidate FimH vaccine among the three with a number of adjuvants including alum, MF-59 and rBCG to determine which adjuvant stimulates the best functional immune response as measured both in vitro and in vivo, and 3.) to test antisera raised against the best candidate FimH vaccine for in vitro functional activity against a wide range of primary uropathogenic E.coli clinical isolates. PROPOSED COMMERCIAL APPLICATION: These studies may lead to the development of a vaccine against bacterial urinary tract infections, one of the most common disorders prompting medical attention. The mucosal adjuvants being tested may stimulate mucosal as well as humoral immune responses against uropatheogenic bacteria.

细菌对宿主上皮的附着是细菌感染中重要的早期事件。 大肠杆菌尿路感染的发病机制。此附件 是由粘附素蛋白介导的， 细菌表面的纤维状结构，称为皮利。的 在皮利远端的尖端粘附素的鉴定提供了一种 作为早期尝试使用疫苗开发重要新靶点 完整的皮利不能成功地防止广泛的 致病性细菌分离物。 尿路致病性大肠杆菌能够产生多种粘附素， 以及菌毛类型，其赋予宿主细胞受体特异性， 病原体这些结构决定了组织的向性， 泌尿生殖道内的定植，以及由此产生的疾病， 由感染引起的。FimH粘附素与 l -菌毛结合α-D-甘露糖苷糖缀合物，所述甘露糖苷糖缀合物在 膀胱上皮流行病学和实验证据支持 l型纤毛大肠杆菌在膀胱炎发展中的作用。我们有 最近发现，抗体专门针对两种形式的 纯化的FimH粘附素防止l型纤毛大肠杆菌与a- D-甘露糖苷受体，通过抑制凝集测定， 豚鼠红细胞与L型纤毛的粘附阻断作用 大肠杆菌对体外人膀胱细胞的作用。此外，FimH衍生的 疫苗导致尿路病原体在膀胱的定植减少， 在鼠膀胱炎模型中的体内L型纤毛大肠杆菌分离物。这些 数据表明，以粘附素为靶点的抗菌疫苗可以阻断 附着在体内，并可能是一种手段，防止复发和急性 尿路感染本研究的目的是：1）。到 评估第三种基于FimH的候选疫苗，l型尖端纤丝， 应诱导最大的保护性免疫，靶向结合结构域 基于该复合物中FimH的构象，2.）到 在三种疫苗中检测最佳候选FimH疫苗， 佐剂包括明矾、MF-59和rBCG，以确定哪种佐剂 刺激最佳的功能性免疫应答， 和体内，以及3.）来测试针对最佳候选人的抗血清 FimH疫苗针对广泛的免疫缺陷病毒的体外功能活性 原发性尿路致病性大肠杆菌临床分离株。 拟议的商业应用：这些研究可能导致开发 细菌性尿路感染的疫苗， 引起医疗注意的常见疾病。粘膜佐剂是 测试可能刺激粘膜以及体液免疫反应， 尿路致病菌