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

• 批准号: 9893801
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893801
• 关键词: 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; Bioterrorism; Blood Circulation; Campylobacter jejuni; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Clinical; Clinical Medicine; Clinical Trials; Clostridium difficile; Colitis; Conjugate Vaccines; Country; Data; Developing Countries; Development; Diarrhea; Disease; Drug resistance; Drug-resistant Campylobacter; 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; Link; Measurement; Mediating; Mobile Genetic Elements; Morbidity - disease rate; Multi-Drug Resistance; Nosocomial Infections; Oral; Passive Immunity; Phase I Clinical Trials; Plasmids; Polysaccharide-K; Population; Prevention; Prevention strategy; Preventive; Probiotics; Property; Pseudomonas aeruginosa; Public Health; R-factor; Recombinants; Research; Research Personnel; Research Project Grants; Research Proposals; Resistance; Risk Factors; Running; Saccharomyces; Safety; Salmonella; Salmonella Vaccines; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Savings; 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; tool; vector vaccine

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.

CETR总体摘要 在美国和全球范围内广泛存在的抗菌素耐药性 (AMR) 使得抗菌药物耐药性变得越来越困难 治疗以前对抗菌药物有反应的肠道和侵入性医院细菌感染。 最重要的肠道细菌病原体之一，如果它们存在，会导致严重的临床疾病和死亡 无法用有效抗生素治疗的疾病是引起腹泻、痢疾或肠热病的疾病。一些 细菌性肠道病原体在流行病学上正在出现或重新出现，例如：多重耐药性 H58 伤寒沙门氏菌谱系；甲型副伤寒沙门氏菌；多重耐药志贺氏菌；耐药空肠弯曲菌 和艰难梭菌。民用生物防御特别关注一些细菌性肠道病原体 的观点，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 [NTS]），或具有适合此类目的的特性（痢疾志贺氏菌 1）。其中两个 最重要的机会性耐药细菌病原体，可在受损人群中引起侵袭性感染 宿主是肺炎克雷伯菌和铜绿假单胞菌。疫苗和其他预防措施 病原体可以通过预防临床疾病来改善 AMR 问题，从而无需 施用抗生素并缓解选择压力。该卓越中心描述的五个项目 转化研究（CETR）提案，以“主动疫苗接种和被动抗体”为主题 预防多重耐药细菌病原体引起的疾病的策略”，将进行转化 研究制定以下对策以预防重要的多种药物引起的疾病 耐药细菌病原体：一种改良的志贺氏菌活载体疫苗，由 6 种关键减毒菌株组成 每种血清型都表达保护性抗原，以预防 ETEC 以及志贺氏菌引起的临床疾病 （项目1）；设计了代表血清群 B、C1、C2 和 D 的减毒 NTS 菌株，作为 多价广泛保护性口服活疫苗（项目2）；由 O 多糖组成的结合疫苗 肺炎克雷伯菌血清型 O1、O2、O3 和 O5 代表绝大多数侵入性分离株，与 铜绿假单胞菌 A 型或 B 型鞭毛蛋白，用于预防侵袭性疾病（项目 3）；益生菌酵母 布拉氏酵母菌经过改造，可分泌针对肺炎克雷伯菌菌毛的抗体，从而介导 肠道定植，从而减少侵袭性疾病的主要危险因素（定植）（项目 3）； 重组布拉氏酵母菌，其分泌针对艰难梭菌毒素和体细胞抗原的抗体，或 对抗空肠弯曲菌鞭毛蛋白，口服可抑制肠道定植并预防腹泻病 （项目4）；对沙门氏菌血清型的免疫反应测量概要，以确定相关性 保护并指导开发具有广泛保护性的口服沙门氏菌活疫苗（项目 5）。翻译性 研究将把这些对策推进到研究性新药申请 (IND) 的阶段 准备启动1期临床试验。