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

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.

项目总结 – RP3 肺炎克雷伯菌 (KP) 和铜绿假单胞菌 (PA) 是医疗保健相关疾病的主要原因 感染 (HAI)，包括手术部位和伤口感染、肺炎、导管感染、尿路感染 重要的是，在美国和世界范围内，以前成功的抗生素。 由于抗菌药物发生率不断上升，KP 和 PA 治疗方案很快变得无效 耐药性（AMR），包括对多粘菌素/粘菌素等最后手段的抗生素的耐药性，威胁着重返 由于这些病原体的医院感染的临床流行病学模式是前抗生素时代。 类似地，广泛的方法是必要的，并且将提供一种潜在的直接方法 有意义地降低其综合发病率 疫苗和预防性抗体方法不受影响。 通过介导抗生素耐药性的逃避机制，因此代表了一种有前途的方法 减轻 AMR KP 和 PA 感染的负担 目前尚无可用的疫苗或抗体。 然而，我们的总体目标是开发基于疫苗和抗体的 KP 和 PA 预防措施。 我们在此建议继续评估有希望的预防 KP 和 PA HAI 的对策。 在国防部资助下开发的 KP 和 PA 糖复合疫苗基于 四种最常见的 KP 脂多糖相关 O 多糖 (OPS) 血清型的耦合 (60- 全球 80% 的临床分离株）具有两种类型的 PA 鞭毛主要亚基蛋白。 建议开发一种新的基于抗体的方法来防止 KP 在肠道定植，这是一个主要风险 通过分泌抗 KP 菌毛多特异性单链抗体构建体，成为后续感染的因素 在目标 1 中，我们将确定是否进行免疫接种。 与糖复合物在不同的挑战中产生针对相关 KP 和 PA 临床分离株的免疫力 在目标 2 中，我们将评估肺炎、脓毒症和伤口感染模型的保护作用。 免疫衰老和免疫受损的目标 3 和 4 将重点关注 S. boulardii 菌株经过改造，可分泌针对 KP 的多特异性单链 (VHH) 抗体构建体 这些目的将评估对于肠道附着和定植是否重要的​​菌毛类型。 免疫和/或施用分泌抗菌毛 VHH 的布拉氏酵母菌可以预防肠道疾病 在该项目结束时，我们预计会产生重要的临床前数据。 支持这些产品进入一期临床研究。