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: 10364712
• 负责人: Raphael Simon
• 金额: $ 32万
• 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/10364712
• 关键词: 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; Epithelial; Fimbriae Proteins; Fimbrial Adhesins; Flagellin; Funding; Glycoconjugates; Goals; Hospitalization; Human; Immune response; Immunity; Immunization; Immunosuppression; In Situ; Incidence; Infection; Infection prevention; Intestines; Intravenous; Klebsiella; Klebsiella pneumoniae; Lead; Link; Lipopolysaccharides; Mediating; Modeling; Mucous Membrane; Multi-Drug Resistance; Mus; Nosocomial Infections; Operative Surgical Procedures; Oral; 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; Resort; 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; base; 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; vaccine-induced antibodies

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-RP 3 肺炎克雷伯菌（KP）和铜绿假单胞菌（PA）是医疗保健相关性肺炎的主要原因。 感染（HAI），包括手术部位和伤口感染、肺炎、导管感染、泌尿系统感染 感染和败血症，在美国和世界范围内。重要的是，以前成功的抗生素 KP和PA的方案由于抗菌药物的发生率增加而迅速变得无效， 耐药性（AMR），包括对最后手段的抗生素，如多粘菌素/粘菌素，威胁着 前抗生素时代由于这些病原体医院感染的临床流行病学模式是 类似地，一个广泛的方法是有道理的，并将提供一个潜在的直接的方式， 降低其综合发病率。疫苗和预防性抗体方法不受影响 通过逃避机制介导对抗生素的耐药性，因此代表了一种有前途的方法 减少AMR KP和PA感染的负担。没有可用的疫苗或基于抗体的 然而，KP和PA的预防措施。我们的总体目标是开发基于疫苗和抗体的 预防KP和PA HAI的对策。我们在此建议继续评估一个有希望的 在国防部资助下开发的KP和PA糖缀合物疫苗， 偶联四种最常见的KP脂多糖相关的O多糖（OPS）血清型（60- 100）， 全世界80%的临床分离株）具有两种类型的PA鞭毛主要亚基蛋白。我们另外 我建议开发一种新的基于抗体的方法来预防KP在肠道的定植，这是一个主要的风险。 随后感染的因子，通过分泌抗KP菌毛多特异性单链抗体构建体 来自口服布拉酵母菌益生菌。在目标1中，我们将确定免疫是否 与糖缀合物在不同的攻击中产生针对相关KP和PA临床分离株的免疫力 肺炎、败血症和伤口感染的近似模型。在目标2中，我们将评估 免疫衰老和免疫妥协。目标3和4将集中在发展一个S。 经工程改造以分泌靶向KP的多特异性单链（VHH）抗体构建体的布拉氏菌菌株 菌毛类型对肠道附着和定植很重要。这些目标将评估是否结合 免疫和/或施用S.布拉氏酵母分泌抗菌毛VHH， 与KP合作。在这个项目结束时，我们希望已经产生了重要的临床前数据 以支持这些产品进入I期临床研究。