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

基本信息

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
项目类别：
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

项目摘要

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）是一种机会性病原体，会引起各种各样的疾病表现。它是全球医疗保健相关感染的主要原因，慢性肺部感染患有囊性纤维化（CF）的患者和烧伤伤口感染。抗菌素耐药性高 PA，导致感染的明显发病率和死亡率。世界卫生组织已分类多药耐药（MDR）PA作为研究的优先级病原体。由于PA的MDR菌株感染变得司空见惯，治疗方案变得有限。我们建议开发一种疫苗以防止PA 高风险个体感染。事先尝试开发PA疫苗已重点是保护 CF患者的呼吸道感染，最著名的是呼吸机相关的肺炎和肺部感染。这些尽管诱导了可检测的疫苗特异性抗体反应，但尝试却没有成功免疫患者。我们和其他人假设使用的肠胃外免疫方案和佐剂使用在这些研究中，没有产生平衡的体液和细胞免疫的全部光谱在呼吸道中有效保护PA。这可以通过直接免疫来克服粘膜表面具有可诱导Th17免疫力的佐剂，因为TH17免疫已被证明是一种保护PA的关键组件。此外，在粘膜表面施用的疫苗也已经显示出保护性全身免疫反应。我们正在开发一种可以是的疫苗通过粘液施用，不仅为PA提供呼吸道感染提供了完全保护，还提供反对非粘膜疾病表现；因此，提供对病原体的完全免疫力。疫苗至少由四个毒力因素组成，可为大量PA提供广泛的保护自然界中存在的血清型。在此应用中，我们将评估PCRV，OPRF，OPRI和Exotoxin A毒素为疫苗目标。这些抗原将与烟草病毒相结合，我们以前已经证明是亚基疫苗抗原的粘膜递送的有效输送平台。在飞行员中研究，我们证明，在TMV-PCRV的递送时，用10XLD50保护了66％的小鼠免于致命挑战急性肺部感染模型中的PA，而所有未感染的小鼠屈服于感染。在目前的研究中我们将针对四个TMV偶联物中的每一个都优化疫苗免疫原性，从而评估功能抗体和疫苗接种后的T细胞反应，并在PA的急性肺部感染模型中测试保护性功效。然后，我们将使用两者都使用五种不同的PA菌株测试合并的多价疫苗的能力肺部感染模型和外国植入物生物膜模型。使用它，我们将为我们的原则建立原则证明接近并开发原型疫苗，以在随后的R01应用中进入临床前开发。