Immunoprophylactic Strategies to Control Emerging Enteric Infections

描述（由申请人提供）：肠道病原体在生活在发展中国家和工业化国家的个体中引起疾病，其中一些病原体是普遍的，而其他病原体在很大程度上限于某些环境。某些肠道病原体正在流行病学上出现或重新出现。来自工业化国家访问发展中国家的旅行者构成了一个特殊的风险群体，将这两大生态联系在一起。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），或者具有适合于这种目的的特性（志贺氏菌1）。在这五个项目中所描述的卓越翻译研究（“肠道CETR”）的建议，结合主题“免疫预防战略，以控制新兴肠道感染”，将进行转化研究，以开发产品，以防止肠道疾病引起的几个重要的细菌和原虫病原体，包括：肠热病沙门氏菌血清型S。伤寒沙门氏菌S.甲型副伤寒和甲型副伤寒副伤寒B（项目1）;艰难梭菌（项目2）;志贺氏菌，肠致病性E.大肠杆菌（ETEC）、肠聚集性E.大肠杆菌（EAEC）和产滋贺毒素的肠出血性大肠杆菌（E.大肠杆菌（EHEC）大肠杆菌病原体（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（强调C组血清型）（项目4）;原生动物物种人隐孢子虫（Cryptosporidiumhominis）和隐孢子虫（C. parvum（项目5）。尽管每种病原体都代表着一个重要的公共卫生优先事项，但只有一种，S。伤寒，已经有许可的疫苗来预防疾病，但这些疫苗并不理想。三个项目旨在将新的候选疫苗进展到可以准备新药申请（IND）以启动1期临床试验的程度。这些包括：i）表达保护性抗原的志贺氏菌活载体疫苗，以预防临床 ii）核心-O多糖-鞭毛蛋白缀合物肠胃外疫苗，以及工程化重组减毒菌株，以预防由沙门氏菌C1和C2组的非伤寒血清型引起的侵袭性疾病（项目4）; iii）基于来自C. hominis和C. iv）二价佐剂cTxAB类毒素疫苗，以预防复发的C.艰难梭菌病（项目2）。我们还将研究一种独特的被动抗体方法来预防C。艰难梭菌病（项目2）。最后，项目1旨在解释在大规模田间试验中观察到的交叉保护，其中口服活沙门氏菌免疫。伤寒疫苗株Ty 21 a对沙门氏菌具有交叉保护作用。副伤寒B，而对S.甲型副伤寒大多数项目将利用创新的动物模型，包括衰老小鼠模型（探索衰老如何影响对疫苗的免疫反应）和gnotobiotic仔猪模型。所有项目都包括财团多个机构的研究人员合作。肠溶CETR PL/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.