Immunoprophylactic Strategies to Control Emerging Enteric Infections

控制新发肠道感染的免疫预防策略

• 批准号: 9447098
• 负责人: Myron Max Levine
• 金额: $ 497.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447098
• 关键词: Address; Adjuvant; Affect; Age; Aging; Animal Model; Antibiotic Resistance; Antibodies; Antigens; Attenuated; Basic Science; Bioterrorism; Categories; Child; Clinical; Clostridium; Clostridium difficile; Collaborations; Country; Cryptosporidium; Cryptosporidium parvum; Developed Countries; Developing Countries; Development; Diarrhea; Disease; Dysentery; Ecology; Elderly; Engineering; Enteral; Epidemiology; Escherichia coli; Escherichia coli EHEC; Flagellin; Gastroenteritis; Germ; Gnotobiotic; Hemorrhagic colitis; Human; Immune response; Immunization; Immunoglobulins; Individual; Infection; Infection prevention; Institution; Intervention; Investigational New Drug Application; Modeling; Oral; Paratyphoid Fever; Persons; Phase I Clinical Trials; Polysaccharides; Population; Property; Proteins; Protozoa; Recombinants; Recurrence; Research; Research Personnel; Risk; Salmonella; Salmonella paratyphi; Salmonella typhi; Shiga Toxin; Shigella; Shigella dysenteriae; Sporozoites; Testing; Toxoids; Translating; Translational Research; Ty21a typhoid vaccine; Typhoid Fever; Vaccine Antigen; Vaccines; Visit; base; biodefense; enteric pathogen; enteroaggregative Escherichia coli; enterotoxigenic Escherichia coli; experience; innovation; interest; microorganism; mouse model; multidisciplinary; novel vaccines; passive antibodies; pathogen; prevent; product development; public health priorities; public health relevance; senescence; tool; vaccine candidate; vector vaccine

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.

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存在的，而另一些病原体则主要局限于某些环境。某些肠道病原体在流行病学上正在出现或重新出现。来自工业化国家访问发展中国家的旅行者形成了一个特殊的风险群体，连接着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，因为它们已被邪恶的个人用来传播生物恐怖（非伤寒沙门氏菌），或者具有适合此类目的的特性（志贺氏菌1）。本肠病转化研究卓越中心（“肠病CETR”）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，将开展转化研究，以开发产品来预防由几种重要疾病引起的肠道疾病细菌和原虫病原体，包括：肠热沙门氏菌血清型伤寒沙门氏菌、甲型副伤寒沙门氏菌和乙型副伤寒沙门氏菌（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）；原生动物物种隐孢子虫 (Cryptosporidium hominis) 和小隐孢子虫 (C. parvum)（项目 5）。尽管每种病原体都代表着重要的公共卫生优先事项，但只有一种病原体——伤寒沙门氏菌——已经获得了预防疾病的许可疫苗，但这些疫苗并不理想。三个项目打算将新候选疫苗进展到可以准备新药研究申请（IND）以启动第一阶段临床试验的程度。其中包括： i) 表达保护性抗原以预防临床症状的志贺氏菌活载体疫苗 由几种引起腹泻的大肠杆菌致病型引起的疾病（项目 3）； ii) Core-O多糖-鞭毛蛋白结合肠胃外疫苗以及工程重组减毒株，用于预防沙门氏菌C1和C2组非伤寒血清型引起的侵袭性疾病（项目4）； iii) 基于来自人隐孢子虫和小隐孢子虫子孢子的蛋白质的疫苗； iv) 一种二价佐剂 cTxAB 类毒素疫苗，用于预防复发性艰难梭菌疾病（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，其中使用活伤寒沙门氏菌疫苗株 Ty21a 口服免疫可提供针对乙型副伤寒沙门氏菌的交叉保护，而对甲型副伤寒沙门氏菌则没有提供任何保护。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）和无菌仔猪模型。所有项目都包括该联盟多个机构的研究人员的合作。 Enteric CETR PL/PD 在转化研究和疫苗产品开发方面拥有丰富的经验。

项目成果

Pilin Vaccination Stimulates Weak Antibody Responses and Provides No Protection in a C57Bl/6 Murine Model of Acute Clostridium difficile Infection.

Pilin 疫苗接种会刺激弱抗体反应，并且在急性艰难梭菌感染的 C57Bl/6 小鼠模型中不提供保护。

• 发表时间: 2016
• 作者: Maldarelli, Grace A;Matz, Hanover;Gao, Si;Chen, Kevin;Hamza, Therwa;Yfantis, Harris G;Feng, Hanping;Donnenberg, Michael S
• 通讯作者: Donnenberg, Michael S

Immunogenicity and protective efficacy against Salmonella C2-C3 infection in mice immunized with a glycoconjugate of S. Newport Core-O polysaccharide linked to the homologous serovar FliC protein.

使用与同源血清型 FliC 蛋白连接的 S. Newport Core-O 多糖糖复合物免疫小鼠，对沙门氏菌 C2-C3 感染具有免疫原性和保护功效。

• 发表时间: 2019
• 影响因子: 4.8
• 作者: Schuster, Ofir;Sears, Khandra T;Ramachandran, Girish;Fuche, Fabien J;Curtis, Brittany;Tennant, Sharon M;Simon, Raphael
• 通讯作者: Simon, Raphael

Modeling Enteropathy or Diarrhea with the Top Bacterial and Protozoal Pathogens: Differential Determinants of Outcomes.

用主要细菌和原虫病原体模拟肠病或腹泻：结果的不同决定因素。

• 发表时间: 2021
• 影响因子: 5.3
• 作者: Guerrant, Richard L;Bolick, David T;Swann, Jonathan R
• 通讯作者: Swann, Jonathan R

Host-targeted niclosamide inhibits C. difficile virulence and prevents disease in mice without disrupting the gut microbiota.

靶向宿主的氯硝柳胺可抑制艰难梭菌毒力并预防小鼠疾病，且不会破坏肠道微生物群。

• 发表时间: 2018
• 影响因子: 16.6
• 作者: Tam, John;Hamza, Therwa;Ma, Bing;Chen, Kevin;Beilhartz, Greg L;Ravel, Jacques;Feng, Hanping;Melnyk, Roman A
• 通讯作者: Melnyk, Roman A

Increased Urinary Trimethylamine N-Oxide Following Cryptosporidium Infection and Protein Malnutrition Independent of Microbiome Effects.

隐孢子虫感染和蛋白质营养不良后尿三甲胺一氧化氮增加，与微生物组的影响无关。

• 发表时间: 2017-07-01
• 作者: Bolick, David T;Mayneris;Medlock, Greg L;Kolling, Glynis L;Papin, Jason A;Swann, Jon R;Guerrant, Richard L
• 通讯作者: Guerrant, Richard L