Immunoprophylactic Strategies to Control Emerging Enteric Infections

描述(申请人提供)：肠道病原体在生活在发展中国家和工业化国家的个人中引起疾病，其中一些病原体是普遍存在的，而另一些病原体主要限于某些环境。某些肠道病原体在流行病学上正在出现或重新出现。来自工业化国家的旅行者访问发展中国家，形成了一个特殊的风险群体，连接了这两个广泛的生态系统。最后，从民用生物防御的角度来看，一些肠道病原体特别令人感兴趣，因为它们被邪恶的个人用来传播生物恐怖(非伤寒沙门氏菌)，或具有适合于这种目的的特性(志贺氏菌痢疾1)。在这项肠道翻译研究卓越中心的建议中所描述的五个项目，以“控制新出现的肠道感染的免疫预防策略”为主题，将进行翻译研究，以开发预防由几种重要的细菌和原虫病原体引起的肠道疾病的产品，包括：肠道发热沙门氏菌血清型伤寒沙门氏菌、副伤寒沙门氏菌A和副伤寒沙门氏菌B(项目1)；艰难梭菌(项目2)；志贺氏菌、产肠毒素大肠杆菌(ETEC)、肠聚集性大肠杆菌(EAEC)和产生志贺毒素的肠出血性大肠杆菌(项目3)；引起侵袭性疾病和/或胃肠炎的非伤寒沙门氏菌血清型(重点是C组血清型)(项目4)；原生动物物种人隐孢子虫和微小隐孢子虫(项目5)。虽然每种病原体都代表着重要的公共卫生优先事项，但只有一种伤寒沙门氏菌已经获得了预防疾病的许可疫苗，而且这些疫苗并不理想。三个项目打算使新的候选疫苗进展到可以准备研究性新药申请(IND)以启动第一阶段临床试验的地步。这些措施包括：i)表达保护性抗原的志贺氏菌活载体疫苗，以防止临床 这些疫苗包括：由几种致病类型的致泻性大肠杆菌引起的疾病疫苗(项目3)；ii)Core-O多糖-鞭毛蛋白结合肠外疫苗，以及经改造的重组减毒疫苗，以防止由C1和C2组沙门氏菌非伤寒血清型引起的侵袭性疾病(项目4)；iii)基于人芽胞杆菌和微小弧菌子孢子蛋白质的疫苗；iv)用于预防难辨梭菌病复发的双价佐剂cTxAB类毒素疫苗(项目2)。我们还将研究一种独特的被动抗体方法来预防艰难梭菌疾病(项目2)。最后，项目1旨在解释在大规模现场试验中观察到的交叉保护，其中口服活伤寒疫苗株Ty21a可对副伤寒沙门氏菌B产生交叉保护，而对甲型副伤寒沙门氏菌没有保护作用。大多数项目将利用创新的动物模型，包括衰老小鼠模型(以探索衰老如何影响对疫苗的免疫反应)和共生仔猪模型。所有项目都包括调查人员在该联盟的多个机构之间的合作。肠道CETRPL/PD在转化研究和疫苗产品开发方面经验丰富。

DESCRIPTION (provided by applicant): Enteric pathogens cause disease among individuals living in both developing and industrialized countries, with some pathogens being universal, while others are largely restricted to certain settings. Certain enteric pathogens are epidemiologically emerging or re-emerging. Travelers from industrialized countries who visit developing countries form a special risk group that bridges the two broad ecologies. Finally, a few enteric pathogens are of special interest from the civilian biodefense perspective, as they have been used by nefarious individuals to promulgate bioterror (non-typhoidal Salmonella), or have properties that suit them to such a purpose (Shigella dysenteriae 1). The five Projects described in this Enteric Center for Excellence in Translation Research ("Enteric CETR") proposal, bonded by the theme "Immunoprophylactic Strategy to Control Emerging Enteric Infections", will undertake translational research towards developing products to prevent enteric disease caused by several important bacterial and protozoal pathogens, including: the enteric fever Salmonella serovars S. Typhi, S. Paratyphi A and S. Paratyphi B (Project 1); Clostridium difficile (Project 2); Shigella, enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC) and Shiga toxin-producing enterohemorrhagic E. coli (EHEC) diarrheal pathogens (Project 3); non-typhoidal Salmonella serovars that cause invasive disease and/or gastroenteritis (emphasizing group C serovars) (Project 4); the protozoan species Cryptosporidium hominis and C. parvum (Project 5). Whereas each pathogen represents an important public health priority, only one, S. Typhi, already has licensed vaccines to prevent disease and those are not ideal. Three projects intend to progress new vaccine candidates to the point where Investigational New Drug Applications (IND) could be prepared to initiate Phase 1 clinical trials. These include: i) a Shigella live vector vaccine expressing protective antigens to prevent clinical illness caused by several pathotypes of diarrhea-causing Escherichia coli (Project 3); ii) Core-O polysaccharide-flagellin conjugate parenteral vaccines, as well as engineered recombinant attenuated strains, to prevent invasive disease caused by non-typhoidal serovars of Salmonella Group C1 & C2 (Project 4); iii) a vaccine based on proteins from C. hominis and C. parvum sporozoites; iv) a bivalent adjuvanted cTxAB toxoid vaccine to prevent recurrent C. difficile disease (Project 2). We will also investigate a unique passive antibody approach to prevent C. difficile disease (Project 2). Finally, Project 1 aims to explain the cross protection observed in large-scale field trials wherein oral immunization with live S. Typhi vaccine strain Ty21a conferred cross protection against S. Paratyphi B, whereas no protection was afforded against S. Paratyphi A. Most projects will utilize innovative animal models including senescent mouse models (to explore how aging influences immune response to vaccines) and the gnotobiotic piglet model. All projects include collaborations of investigators across multiple institutions of he consortium. The Enteric CETR PL/PD is highly experienced in translational research and vaccine product development.