Active Vaccination and Passive Antibody Strategies to Prevent Klebsiella and Pseudomonas Disease

预防克雷伯氏菌和假单胞菌病的主动疫苗接种和被动抗体策略

• 批准号: 10584481
• 负责人: Raphael Simon
• 金额: $ 45.62万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584481
• 关键词: Acceleration; Active Immunization; Adherence; Alpaca; Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Antimicrobial Resistance; Bacteria; Bacterial Infections; Binding; Catheters; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Colistin; Complication; Coupling; Cutaneous; Cyclophosphamide; Data; Department of Defense; Development; Disease; Engineering; Enterobacteriaceae; Epidemiology; Epithelium; Fimbriae Proteins; Fimbrial Adhesins; Flagellin; Funding; Glycoconjugates; Goals; Hospitalization; Human; Immune response; Immunity; Immunization; Immunocompromised Host; Immunosuppression; In Situ; Incidence; Infection; Infection prevention; Intestines; Intravenous; Klebsiella; Klebsiella pneumoniae; Lead; Licensing; Link; Lipopolysaccharides; Mediating; Modeling; Mucous Membrane; Multi-Drug Resistance; Mus; Nosocomial Infections; Operative Surgical Procedures; Oral Administration; Oral Ingestion; Ozone; Patients; Pattern; Phase; Pneumonia; Polysaccharides; Preventive measure; Probiotics; Protein Subunits; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Recombinants; Regimen; Risk; Risk Factors; Route; Saccharomyces; Sepsis; Septicemia; Serotyping; Serum; Site; Surface; Systemic disease; Testing; Urinary tract infection; Vaccination; Vaccines; Virulence Factors; World Health Organization; Wound Infection; Yeasts; aged; burn wound; emerging antimicrobial resistance; fimbria; gastrointestinal; gut colonization; healthcare-associated infections; immunogenic; immunosenescence; immunosuppressed; improved; intestinal epithelium; novel; passive antibodies; pathogen; pathogenic bacteria; pre-clinical; prevent; prophylactic; resistance gene; resistant Klebsiella pneumoniae; respiratory; vaccine access; vaccine candidate; vaccine development; Acceleration; Active Immunization; Adherence; Alpaca; Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Antimicrobial Resistance; Bacteria; Bacterial Infections; Binding; Catheters; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Colistin; Complication; Coupling; Cutaneous; Cyclophosphamide; Data; Department of Defense; Development; Disease; Engineering; Enterobacteriaceae; Epidemiology; Epithelium; Fimbriae Proteins; Fimbrial Adhesins; Flagellin; Funding; Glycoconjugates; Goals; Hospitalization; Human; Immune response; Immunity; Immunization; Immunocompromised Host; Immunosuppression; In Situ; Incidence; Infection; Infection prevention; Intestines; Intravenous; Klebsiella; Klebsiella pneumoniae; Lead; Licensing; Link; Lipopolysaccharides; Mediating; Modeling; Mucous Membrane; Multi-Drug Resistance; Mus; Nosocomial Infections; Operative Surgical Procedures; Oral Administration; Oral Ingestion; Ozone; Patients; Pattern; Phase; Pneumonia; Polysaccharides; Preventive measure; Probiotics; Protein Subunits; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Recombinants; Regimen; Risk; Risk Factors; Route; Saccharomyces; Sepsis; Septicemia; Serotyping; Serum; Site; Surface; Systemic disease; Testing; Urinary tract infection; Vaccination; Vaccines; Virulence Factors; World Health Organization; Wound Infection; Yeasts; aged; burn wound; emerging antimicrobial resistance; fimbria; gastrointestinal; gut colonization; healthcare-associated infections; immunogenic; immunosenescence; immunosuppressed; improved; intestinal epithelium; novel; passive antibodies; pathogen; pathogenic bacteria; pre-clinical; prevent; prophylactic; resistance gene; resistant Klebsiella pneumoniae; respiratory; vaccine access; vaccine candidate; vaccine development

Project summary – RP3 Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA) are major causes of healthcare-associated Infections (HAI) including surgical site and wound infections, pneumonias, catheter based infections, urinary tract infections, and septicemia, both in the USA and worldwide. Importantly, previously successful antibiotic regimens for KP and PA are rapidly becoming ineffective due to the growing incidence of antimicrobial resistance (AMR), including to antibiotics of last resort such as polymixin/colistin, threatening a return to the pre-antibiotic era. As the clinico-epidemiological patterns for nosocomial infections with these pathogens are similar, a broad spectrum approach is warranted and would offer a potentially straightforward way to meaningfully reduce their combined incidence. Vaccine and prophylactic antibody approaches are unaffected by the evasion mechanisms mediating resistance to antibiotics, and thus represent a promising approach toward reducing the burden of AMR KP and PA infections. There are no available vaccines or antibody-based preventive measures for KP and PA however. Our overall goal is to develop vaccine and antibody-based countermeasures to prevent KP and PA HAIs. We propose here to continue assessment of a promising glycoconjugate vaccine for KP and PA developed under Department of Defense funding that is based on coupling of the four most common KP lipopolysaccharide-associated O polysaccharide (OPS) serotypes (60- 80% of clinical isolates worldwide) with the two types of PA flagellar major subunit proteins. We additionally propose to develop a novel antibody-based approach to prevent KP colonization of the intestine, a major risk factor for subsequent infection, by secretion of anti-KP fimbrial multi-specific single-chain antibody constructs from an orally ingested Saccharomyces boulardii probiotic. In Aim 1, we will determine whether immunization with the glycoconjugate generates immunity against relevant KP and PA clinical isolates in different challenge models approximating pneumonia, sepsis and wound infection. In Aim 2, we will assess protection in models of immunosenescence and immuno-compromise. Aims 3 and 4 will be focused on the development of a S. boulardii strain engineered to secrete a multi-specific single-chain (VHH) antibody construct targeting the KP fimbriae types important for intestinal attachment and colonization. These aims will assess whether conjugate immunization and/or administration with S. boulardii secreting anti-fimbrial VHHs can prevent intestinal colonization with KP. At the conclusion of this project, we expect to have generated important preclinical data to support advancement of these products to Phase 1 clinical studies.

项目摘要 - RP3 克雷伯菌肺炎（KP）和铜绿假单胞菌（PA）是医疗保健相关的主要原因 感染（HAI）包括手术部位和伤口感染，肺炎，基于导管的感染，尿 在美国和世界各地，道感染和败血症。重要的是，以前成功的抗生素 由于抗菌剂的不断增长，KP和PA的方案迅速变得无效 抗药性（AMR），包括对诸如多晶型/colistin之类的最后手段的抗生素，威胁到回归 抗生素前时代。由于使用这些病原体的医院感染的临床流行病学模式是 类似，有必要采用广泛的方法，并将提供一种潜在的直接方法 有意义地减少他们的合并事件。疫苗和预防性抗体方法不受影响 通过介导抗生素抗性的进化机制，因此代表了一种有前途的方法 旨在减少AMR KP和PA感染的Burnen。没有可用的疫苗或抗体 但是，KP和PA采取了预防措施。我们的总体目标是开发疫苗和抗体 预防KP和PA Hais的对策。我们在这里建议继续评估承诺 在国防部资助下开发的KP和PA的糖缀合疫苗，该疫苗是基于 四个最常见的KP脂多糖相关的O多糖（OPS）血清型的耦合（60- 全世界80％的临床分离株）具有两种类型的PA旗杆主要亚基蛋白。我们另外 提出开发一种基于抗体的新方法来防止肠道殖民化的新方法，这是主要风险 随后感染的因素，通过分泌抗KP纤维多特异性单链抗体构建体的分泌 来自口服摄入的葡萄糖boulardii益生菌。在AIM 1中，我们将确定是否免疫 在糖缀合物的情况下，在不同挑战中对相关的KP和PA临床分离株产生免疫力 近似肺炎，败血症和伤口感染的模型。在AIM 2中，我们将评估模型的保护 免疫衰老和免疫敏捷。目标3和4将集中于S的发展。 Boulardii菌株设计为分泌一个针对KP的多特异性单链（VHH）抗体构建体 纤维化类型对于肠道附着和定殖重要。这些目标将评估是否结合 用S. boulardii进行免疫和/或给药，分泌抗膜的VHHS可以防止肠道 用KP殖民化。在该项目的结论结束时，我们希望已经生成重要的临床前数据 支持这些产品的进步到第一阶段临床研究。