Immunoprophylactic Strategies to Control Emerging Enteric Infections

描述（由申请人提供）：肠道病原体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存在的，而另一些则主要局限于某些环境。某些肠道病原体正在流行病学上出现或重新出现。来自工业化国家的游客访问发展中国家，形成了一个特殊的风险群体，架起了两大生态的桥梁。最后，从民用生物防御的角度来看，一些肠道病原体是特别有趣的，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），或者具有适合它们的特性（痢疾志贺氏菌1）。该Enteric卓越转化研究中心（“Enteric ctr”）提案中描述的五个项目，以“控制新发肠道感染的免疫预防策略”为主题，将进行转化研究，以开发产品，预防由几种重要的细菌和原虫病原体引起的肠道疾病，包括：肠热沙门氏菌血清型S.伤寒沙门氏菌，S.副伤寒沙门氏菌A和S.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）和产志贺毒素肠出血性大肠杆菌（EHEC）腹泻病原体（项目3）；引起侵袭性疾病和/或肠胃炎的非伤寒沙门氏菌血清型（强调C组血清型）（项目4）；原生动物种人隐孢子虫和小隐孢子虫（项目5）。虽然每种病原体都是重要的公共卫生重点，但只有一种，即伤寒沙门氏菌，已经获得了预防疾病的许可疫苗，而且这些疫苗并不理想。三个项目打算推进新的候选疫苗，以便准备新药研究申请（IND），启动1期临床试验。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

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.