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: 10446501
• 负责人: Paul Michael Arnaboldi
• 金额: $ 24.91万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10446501
• 关键词: Acute; Acute respiratory infection; Acute suppurative arthritis due to bacteria; Adjuvant; Age-Years; Anaerobic Bacteria; Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Antimicrobial Resistance; Bacteremia; Bacteria; Cancer Patient; Capsid Proteins; Cells; Cellular Immunity; Chronic; Collaborations; Combined Antibiotics; Communicable Diseases; Contact Lenses; Critical Illness; Defect; Development; Disease; Dose; Elderly; 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; 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; Resort; 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 patients; ear infection; effective therapy; efflux pump; experience; first responder; healthcare-associated infections; high risk; human pathogen; immunogenicity; 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)是一种能引起多种疾病的条件致病菌。 表现形式。它是全球医疗保健相关感染的主要原因，慢性肺部感染 囊性纤维化(CF)和烧伤创面感染患者。中国的抗菌素耐药率很高。 PA，导致严重的发病率和感染死亡率。世界卫生组织已将 多药耐药(MDR)PA作为优先研究的1号病原体。由于感染了多药耐药株的PA 变得司空见惯，治疗选择变得有限。我们建议开发一种疫苗来预防PA 高危人群中的感染。以前开发PA疫苗的尝试都集中在预防 呼吸道感染，最明显的呼吸机相关性肺炎和肺部感染的CF患者。这些 尽管诱导了可检测到的疫苗特异性抗体反应，但尝试一直未获成功 接种疫苗的病人。我们和其他人假设肠外免疫方案和佐剂使用了 在这些研究中没有产生平衡的体液和细胞免疫所需的全部光谱 有效保护呼吸道免受PA侵袭。这可以通过直接免疫来克服 粘膜表面有一种可以诱导Th17免疫的佐剂，因为Th17免疫已被证明是一种 保护PA的关键组件。此外，在粘膜表面接种的疫苗也已 被证明能产生保护性的系统免疫反应。我们正在开发一种疫苗，可以 粘膜给药，不仅对PA呼吸道感染提供完全保护，而且还 抵抗非粘膜疾病的表现；因此，对病原体具有完全的免疫力。疫苗 将由至少四个毒力因子组成，以提供对大量PA的广泛保护 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类毒素为 疫苗靶标。这些抗原将与烟草花叶病毒偶联，我们之前已经 证明是一种有效的粘膜递送亚单位疫苗抗原的平台。在试行中 研究表明，在TMV-PcrV的传递中，以10xLD50保护66%的小鼠免受致死攻击 在急性肺部感染模型中，所有未感染的小鼠均死于感染。在目前的研究中 我们将优化四种TMV结合物的疫苗免疫原性，评估功能性抗体和 接种IN疫苗后的T细胞反应，并测试PA急性肺部感染模型的保护效果。 然后我们将测试针对五种不同PA菌株的组合多价疫苗的能力，使用两种 肺部感染模型和异种植入体生物被膜模型。利用这一点，我们将为我们的 接近并开发一种原型疫苗，以便在随后的R01应用中进入临床前开发。