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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.

中心总体摘要