Peptide Conformation Constrainment Technology and Novel Mucosal Adjuvants to

接种疫苗是预防传染病最成功和最具成本效益的方法之一。这个 然而，胃肠道感染的有效疫苗的开发一直令人失望。 对这些疫苗的需求是至关重要的，因为肠道感染性疾病是 世界范围内婴幼儿死亡的第二大传染病原因。一些有感染性的 引起腹泻疾病的病原体包括轮状病毒、致病性大肠杆菌、志贺氏菌、 沙门氏菌、隐孢子虫、溶组织内阿米巴和霍乱弧菌。其原因是 缺乏合适的肠道病原体疫苗是指缺乏可口服的有效佐剂。 用疫苗来增强其刺激免疫反应的效力。最具实验性的口腔 佐剂无效或保持一定程度的毒性。为解决这个问题，我们建议 将肠道病原体合成的多肽偶联到安全稳定的佐剂氧化铝上 用于口服免疫的纳米颗粒。多肽将以一种方式与纳米颗粒偶联 保留它们的天然构象，以优化免疫反应，识别天然的 病原体。由于肠道疾病和免疫的小动物模型很少存在，我们将使用人类 幽门螺杆菌(Hp)感染小鼠胃粘膜，我们将测试这项技术 通过1)识别幽门螺杆菌CagL上对细菌与宿主细胞结合至关重要的表位 用人类细胞系进行抗体阻断试验，2)测试这些CagL表位的能力，偶联到 氧化铝纳米颗粒，在攻击前给予小鼠以诱导保护性免疫，3) 测试那些与氧化铝纳米颗粒偶联的CagL表位诱导抗体的能力 阻断由幽门螺杆菌感染引起的致病和致癌事件，以及4)评估抗体 感染人群的反应以确定这些封闭抗体是否由天然抗体诱导 感染，以确定接种疫苗诱导这些抗体是否有益于 人类病人。通过减少幽门螺杆菌模型中的感染、炎症或癌变 用稳定的、靶向的多肽表位偶联到纳米颗粒上的免疫将提供令人信服的 后续应用于人类其他肠道细菌感染的证据 世界范围内的重大发病率和死亡率。

Vaccination is one of the most successful and cost-effective ways of preventing infectious disease. The development of effective vaccines for infections of the gastrointestinal tract however has been disappointing. The need for these vaccines is crucial since diarrheal diseases due to infectious agents of the gut are the second leading infectious cause of death in infants and young children world wide. Some of the Infectious agents that cause diarrheal diseases include rotavirus, pathogenic Escherichia coli, Shigella spp., Salmonella spp., Cryptosporidium pan/urn, Entamoeba histolytica, and Vibrio cholera. The reason for the lack of suitable vaccines for enteric pathogens is the lack of an effective adjuvant that can be delivered orally with the vaccine to increase its potency at stimulating an immune response. Most experimental oral adjuvants are ineffective or maintain some degree of toxicity. To address this problem, we propose to couple synthetic peptides from enteric pathogens to a safe and stable adjuvant, aluminum oxide nanoparticles for oral immunization. The peptides will be coupled to the nanoparticles in a way that preserves their native conformation in order to optimize the immune response to recognize the native pathogen. Since very few small animal models of enteric disease and immunity exist, we will use the human pathogen Helicobacter pylori (H. pylori) to infect the mouse gastric mucosa and we will test this technology by 1) Identifying epitopes on H. pylori CagL that are crucial for binding of the bacteria to host cells using an antibody blocking assay with human cell lines, 2) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce protective immunity when delivered to mice prior to challenge, 3) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce antibodies that block pathogenic and carcinogenic events due to H. pylori infection, and 4) Evaluating the antibody response of infected human subjects to determine if these blocking antibodies are induced by natural infection in order to determine if the induction of these antibodies by vaccination would be beneficial to human patients. A reduction of infection, inflammation, or carcinogenesis in the H. pylori model by immunization with stable, targeted peptide epitopes coupled to nanoparticles would provide compelling evidence for subsequent applications against other enteric bacterial infections in humans that induce significant world wide morbidity and mortality.