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