A Novel Mucosal Vaccine for Pseudomonas aeruginosa Infection

一种针对铜绿假单胞菌感染的新型粘膜疫苗

• 批准号: 10550157
• 负责人: Paul Michael Arnaboldi
• 金额: $ 19.59万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10550157
• 关键词: Acute; Acute respiratory infection; Acute suppurative arthritis due to bacteria; Adjuvant; Age Years; Anaerobic Bacteria; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Antimicrobial Resistance; Bacteremia; Bacteria; Cancer Patient; Capsid Proteins; Cells; Cellular Immunity; Chronic; Classification; Collaborations; Combined Antibiotics; Communicable Diseases; Contact Lenses; Critical Illness; Defect; Development; Disease; Dose; Enzymes; Exotoxins; Eye Infections; Folliculitis; Goals; HIV; Health care facility; Healthcare; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunize; Immunologist; Implant; Individual; Infection; Intranasal Administration; Keratitis; Link; Long-Term Care for Elderly; Lung infections; Malignant Neoplasms; Mediating; Meningitis; Microbial Biofilms; Military Personnel; Modeling; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Multi-Drug Resistance; Mus; Nature; Operative Surgical Procedures; Organ Transplantation; Osteomyelitis; Otitis Externa; Patients; Phagocytosis; Pharmaceutical Preparations; Pilot Projects; Plants; Pneumonia; Pneumonic Plague; Prevention; Protein Subunits; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Public Health; Recombinant Proteins; Recurrence; Research; Research Personnel; Resistance to infection; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Risk; Scheme; Sepsis; Serotyping; Skin Tissue; Soft Tissue Infections; Soldier; Subunit Vaccines; Surface; Surgical Wound Infection; System; Systemic infection; T cell response; T-Lymphocyte; Testing; Tobacco Mosaic Virus; Tobacco use; Toxoids; Transplant Recipients; Treatment Protocols; Urinary tract infection; Vaccination; Vaccine Antigen; Vaccines; Virulence Factors; World Health Organization; Wound Infection; Yersinia pestis; base; burn wound; catheter associated UTI; colistin resistance; combat wound; cystic fibrosis infection; cystic fibrosis patients; ear infection; effective therapy; efflux pump; experience; first responder; healthcare-associated infections; high risk; high risk population; human pathogen; immunogenicity; model organism; mortality; mouse model; mucosal vaccination; mucosal vaccine; multidrug-resistant Pseudomonas aeruginosa; novel; older patient; opportunistic pathogen; pathogen; preclinical development; prevent; protective efficacy; prototype; resistance mechanism; resistant strain; response; severe burns; vaccine development; vaccine efficacy; vaccine immunogenicity; ventilator-associated pneumonia

Project Summary Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes a diverse array of disease manifestations. It is a major cause of healthcare associated infections worldwide, chronic lung infection in patients with cystic fibrosis (CF), and burn wound infections. There is a high rate of antimicrobial resistance in PA, leading to significant morbidity and mortality from infection. The World Health Organization has classified multidrug resistant (MDR) PA as a priority 1 pathogen for research. As infections with MDR strains of PA have become commonplace, treatment options have become limited. We propose to develop a vaccine to prevent PA infection in high-risk individuals. Prior attempts to develop a PA vaccine have focused on protection from respiratory infection, most notably ventilator-associated pneumonia and lung infection in CF patients. These attempts have been unsuccessful despite the induction of detectable vaccine-specific antibody responses in immunized patients. We and others hypothesize that the parenteral immunization scheme and adjuvants used in these studies do not produce the full spectrum of balanced humoral and cellular immunity necessary for effective protection from PA in the respiratory tract. This can be overcome through direct immunization at the mucosal surface with an adjuvant that can induce Th17 immunity, as Th17 immunity has been shown to be a critical component for protection to PA. Furthermore, vaccines administered at mucosal surfaces have also been shown to generate protective systemic immune responses. We are developing a vaccine that can be administered mucosally, providing complete protection not only against respiratory infection with PA, but also against non-mucosal disease manifestations; thus, providing complete immunity to the pathogen. The vaccine will consist of a minimum of four virulence factors to provide broad protection against the large number of PA serotypes present in nature. In this application, we will evaluate PcrV, OprF, OprI, and Exotoxin A toxoid as vaccine targets. These antigens will be conjugated to Tobacco Mosaic Virus, which we have previously demonstrated to be an effective delivery platform for the mucosal delivery of subunit vaccine antigens. In a pilot study, we demonstrated that IN delivery of TMV-PcrV protected 66% of mice from lethal challenge with 10xLD50 of PA in an acute lung infection model, whereas all uninfected mice succumbed to infection. In the present study we will optimize vaccine immunogenicity for each of the four TMV conjugates, evaluating functional antibody and T cell responses following IN vaccination, and testing protective efficacy in an acute lung infection model of PA. We will then test the ability of a combined multivalent vaccine against five different strains of PA using both the lung infection model, and a foreign implant biofilm model. Using this we will establish proof of principle for our approach and develop a prototype vaccine to move into preclinical development in a subsequent R01 application.

项目摘要 铜绿假单胞菌（PA）是一种机会致病菌，可引起多种疾病 表现。它是全球医疗保健相关感染的主要原因， 囊性纤维化（CF）和烧伤伤口感染的患者。有一个高比率的抗菌素耐药性， PA，导致感染的显著发病率和死亡率。世界卫生组织已经将 多药耐药（MDR）PA作为研究的优先1病原体。由于PA的MDR菌株感染， 在这种情况下，治疗选择变得有限。我们建议开发一种预防PA的疫苗 感染高危人群。先前开发PA疫苗的尝试集中在保护免受 呼吸道感染，最明显的是CF患者中的呼吸机相关性肺炎和肺部感染。这些 尽管诱导了可检测的疫苗特异性抗体应答， 免疫患者我们和其他人假设，胃肠外免疫方案和使用的佐剂 在这些研究中，没有产生平衡的体液和细胞免疫所需的全谱， 有效保护呼吸道免受PA的侵害。这可以通过直接免疫来克服， 粘膜表面与佐剂，可以诱导Th 17免疫，因为Th 17免疫已被证明是一种免疫， 保护PA的关键部件。此外，在粘膜表面施用的疫苗也已被广泛应用。 能产生保护性的全身免疫反应我们正在研制一种疫苗 粘膜给药，不仅提供对PA呼吸道感染的完全保护， 针对非粘膜疾病表现;因此，提供对病原体的完全免疫。疫苗 将由至少四个毒力因子组成，以提供广泛的保护，防止大量的PA 自然界中存在的血清型。在本申请中，我们将评估PcrV、OprF、OprI和外毒素A类毒素， 疫苗目标这些抗原将结合到烟草花叶病毒，我们以前已经 证明是用于粘膜递送亚单位疫苗抗原的有效递送平台。以试点 研究中，我们证明了TMV-PcrV的IN递送保护了66%的小鼠免受10 xLD 50的致死性攻击 PA在急性肺部感染模型中的作用，而所有未感染的小鼠都死于感染。在本研究中 我们将优化四种TMV结合物的疫苗免疫原性，评估功能性抗体， IN疫苗接种后的T细胞应答，并在PA的急性肺部感染模型中测试保护功效。 然后，我们将测试组合的多价疫苗针对五种不同PA菌株的能力， 肺感染模型和外来植入物生物膜模型。利用这一点，我们将为我们的 接近并开发原型疫苗，以便在随后的R 01应用中进入临床前开发。