Active Vaccination and Passive Antibody Strategies to Prevent Disease Caused by Multidrug-Resistant Bacterial Pathogens

主动疫苗接种和被动抗体策略预防多重耐药细菌病原体引起的疾病

基本信息

批准号：
10584474
负责人：
Myron Max Levine
金额：
$ 250万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584474
关键词：
Acceleration Active immunity Affect Animal Model Animals Antibiotic Resistance Antibiotics Antibodies Antigens Antimicrobial Resistance Archives Attenuated B-Lymphocytes Bacteria Bacterial Antibiotic Resistance Bacterial Antibodies Bacterial Infections Blood Circulation Campylobacter jejuni Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Child Clinical Clinical Medicine Clinical Trials Clostridium difficile Conjugate Vaccines Country Data Developing Countries Development Diarrhea Disease Drug resistance Drug-resistant Campylobacter Dryness Dysentery Elderly Engineering Enteral Epidemiology Flagellin Future Gastroenteritis Genes Germ Haemophilus influenzae type b Hemorrhagic colitis Hospitals Human Immune Immune response Immune system Immunocompromised Host Immunologics Impairment Individual Infant Infection Infection prevention Invaded Investigational New Drug Application Klebsiella pneumoniae Licensing Link Measurement Mediating Mobile Genetic Elements Morbidity - disease rate Multi-Drug Resistance Nosocomial Infections Oral Oral Administration Ozone Passive Immunity Phase I Clinical Trials Plasmids Polysaccharide-K Population Prevention Prevention strategy Preventive Probiotics Property Pseudomembranous Colitis Pseudomonas aeruginosa Public Health R-factor Recombinants Research Research Personnel Research Project Grants Research Proposals Resistance Risk Factors Running Saccharomyces Salmonella Salmonella Vaccines Salmonella paratyphi Salmonella typhi Salmonella typhimurium Serotyping Serum Shigella Shigella dysenteriae Specimen Speed Streptococcus pneumoniae T-Lymphocyte Thinness Toxin Translational Research Typhoid Fever United States Food and Drug Administration Vaccinated Vaccination Vaccines Yeasts aged antimicrobial biodefense cross reactivity diarrheal disease enteric infection enteric pathogen enterotoxigenic Escherichia coli experience fungus gut colonization health care settings immunogenicity improved innovation interest microorganism mortality non-typhoidal Salmonella novel vaccines oral vaccine passive antibodies pathogen pathogenic bacteria pre-clinical pressure prevent resistant Shigella safety assessment tool vector vaccine

项目摘要

CETR OVERALL ABSTRACT Widespread antimicrobial resistance (AMR), both in the USA and globally, has made it increasingly difficult to treat enteric and invasive nosocomial bacterial infections that were previously responsive to antimicrobials. Among the most important enteric bacterial pathogens that cause severe clinical disease and death if they cannot be treated with effective antibiotics are ones that cause diarrhea, dysentery or enteric fever. Some bacterial enteric pathogens are epidemiologically emerging or re-emerging, e.g.: multi-drug resistant H58 lineage of Salmonella Typhi; S. Paratyphi A; multi-drug resistant Shigella; drug-resistant Campylobacter jejuni and Clostridium difficile. A few bacterial enteropathogens are of special interest from the civilian biodefense perspective, as they have been used by nefarious individuals to promulgate bioterror (non-typhoidal Salmonella [NTS]), or have properties that suit them to such a purpose (Shigella dysenteriae 1). Two of the most important opportunistic drug-resistant bacterial pathogens that cause invasive infections in compromised hosts are Klebsiella pneumoniae and Pseudomonas aeruginosa. Vaccines and other preventives against these pathogens can ameliorate the AMR problem by preventing clinical disease, thereby precluding the need to administer antibiotics and relieving selection pressure. The five projects described in this Center of Excellence for Translational Research (CETR) proposal, bonded by the theme “Active Vaccination and Passive Antibody Strategies to Prevent Disease Caused by Multidrug-Resistant Bacterial Pathogens”, will undertake translational research towards developing the following countermeasures to prevent disease caused by important multi-drug resistant bacterial pathogens: an improved Shigella live vector vaccine consisting of 6 attenuated strains of key serotypes, each expressing protective antigens to prevent clinical illness caused by ETEC, as well as Shigella (Project 1); engineered attenuated NTS strains representing serogroups B, C1, C2 & D to serve as a multivalent broadly protective live oral vaccine (Project 2); a conjugate vaccine consisting of O polysaccharides of K. pneumoniae serotypes O1, O2, O3 & O5, representing the vast majority of invasive isolates, linked to flagellin type A or B of P. aeruginosa, to prevent invasive disease (Project 3); the probiotic yeast Saccharomyces boulardii engineered to secrete antibodies against K. pneumoniae fimbriae that mediate intestinal colonization, thereby diminishing a major risk factor (colonization) for invasive disease (Project 3); recombinant S. boulardii that secrete antibodies directed against C. difficile toxins and somatic antigens or against flagellin of C. jejuni, administered orally to inhibit gut colonization and prevent diarrheal disease (Project 4); a compendium of immune response measurements to Salmonella serovars to identify correlates of protection and guide development of broadly protective live oral Salmonella vaccines (Project 5). Translational research will advance these countermeasures to where Investigational New Drug Applications (IND) can be prepared to initiate Phase 1 clinical trials.

总体摘要在美国和全球范围内，广泛的抗菌耐药性（AMR）使得越来越难以治疗先前对抗菌药物有反应的肠和浸润性医院细菌。在最重要的肠细菌病原体中，会导致严重的临床疾病和死亡无法用有效的抗生素治疗会引起腹泻，痢疾或肠发烧的抗生素。一些细菌启动子病原体在流行病学上出现或重新出现，例如：耐多药H58 沙门氏菌的谱系； S. paratyphi a;多药耐药志贺氏菌；耐药的弯曲杆菌空肠和艰难梭菌。一些细菌的肠病原体引起了平民生物福音的特别感兴趣透视图，因为邪恶的个体已经使用了它们来颁布生物环沙门氏菌[nts]），或具有适合这种目的的特性（志贺氏菌1）。两个最重要的机会性药物抗药性细菌病原体，导致受损的侵入性感染宿主是肺炎克雷伯菌和铜绿假单胞菌。疫苗和其他预防药物反对这些病原体可以通过预防临床疾病来改善AMR问题，从而排除需要管理抗生素和缓解选择压力。在这个卓越中心中描述的五个项目用于翻译研究（CERT）提案，由主题“主动疫苗接种和被动抗体预防由多种耐药细菌病原体引起的疾病的策略将进行翻译为了开发以下对策，以预防重要多药引起的疾病抗性细菌病原体：改进的志贺氏菌活载体疫苗，由6个抑制菌株组成血清型，每种表达受保护的抗原以预防ETEC引起的临床疾病，以及志贺氏菌（项目1）;工程的减弱NTS菌株代表血清群B，C1，C2和D充当多价广泛保护的现场口服疫苗（项目2）；由O多糖组成的共轭疫苗 K.肺炎血清型O1，O2，O3和O5，代表绝大多数侵入性分离株，链接到铜绿假单胞菌的A型鞭毛蛋白A型，以防止侵入性疾病（项目3）；益生菌酵母 Saccharomyces boulardii设计为秘密抗体，抗肺炎菌毛的抗体肠道定殖，从而减少了侵入性疾病的主要危险因素（定植）（项目3）；重组S. boulardii，针对艰难梭菌毒素和躯体抗原或反对鞭毛梭菌的鞭毛蛋白，口服以抑制肠道定植并预防腹泻病（项目4）;对沙门氏菌血清射击的免疫反应测量的汇编，以识别保护和指导开发广泛保护的现场口服沙门氏菌疫苗（项目5）。翻译研究将把这些对策提高到研究性新药物应用（IND）的位置准备启动1期临床试验。