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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：
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
项目类别：
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

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.

项目总结