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.

项目概要铜绿假单胞菌 (PA) 是一种机会性病原体，可引起多种疾病表现形式。它是全球医疗保健相关感染的主要原因，其中慢性肺部感染患有囊性纤维化（CF）和烧伤创面感染的患者。抗菌药物耐药率很高 PA，导致感染引起的显着发病率和死亡率。世界卫生组织已分类多重耐药 (MDR) PA 作为研究的首要病原体。由于 PA 的 MDR 菌株感染已变得司空见惯，治疗选择也变得有限。我们建议开发一种疫苗来预防 PA 高危人群中的感染。先前开发 PA 疫苗的尝试主要集中于预防呼吸道感染，尤其是呼吸机相关性肺炎和 CF 患者的肺部感染。这些尽管在体内诱导了可检测到的疫苗特异性抗体反应，但尝试并未成功已免疫的患者。我们和其他人假设肠外免疫方案和所使用的佐剂这些研究并没有产生平衡体液和细胞免疫的全谱。有效保护呼吸道免受 PA 侵害。这可以通过直接免疫来克服粘膜表面含有可诱导 Th17 免疫的佐剂，因为 Th17 免疫已被证明是一种保护 PA 的关键部件。此外，在粘膜表面施用的疫苗也已被显示可产生保护性全身免疫反应。我们正在开发一种疫苗，可以粘膜给药，不仅可以提供全面的保护，防止 PA 呼吸道感染，还可以对抗非粘膜疾病表现；因此，提供对病原体的完全免疫力。疫苗将包含至少四个毒力因子，以针对大量 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 和外毒素 A 类毒素：疫苗目标。这些抗原将与我们之前研究过的烟草花叶病毒结合被证明是亚单位疫苗抗原粘膜递送的有效递送平台。在飞行员中研究中，我们证明 TMV-PcrV 的 IN 递送可保护 66% 的小鼠免受 10xLD50 的致命攻击在急性肺部感染模型中，PA 的含量增加，而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 缀合物中每一种的疫苗免疫原性，评估功能性抗体和 IN 疫苗接种后的 T 细胞反应，并在 PA 急性肺部感染模型中测试保护功效。然后，我们将使用两种方法测试联合多价疫苗针对五种不同 PA 菌株的能力。肺部感染模型和外来植入物生物膜模型。利用这个我们将为我们的原则建立证明方法并开发原型疫苗，以在随后的 R01 应用中进入临床前开发。