A Novel Vaccine for Burkholderia pseudomallei and Burkholderia mallei

鼻疽伯克霍尔德菌和鼻疽伯克霍尔德菌的新型疫苗

基本信息

批准号：
9261678
负责人：
ROBERT J HOGAN
金额：
$ 61.96万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261678
关键词：
Acute Address Adenoviruses Aerosols Antibiotic Resistance Antibiotic Therapy Antibody titer measurement Antigen Targeting Antigens Bacteremia Bacteria Biological Warfare Burkholderia Burkholderia Infections Burkholderia mallei Burkholderia pseudomallei Canis familiaris Cell Line Cells Chronic Complex Coughing Country Data Development Diagnosis Disease Dose Engineering Equus caballus FDA approved G-substrate GTP-Binding Proteins Glanders Goals Gram-Negative Bacteria Human Immune Immune response Immunity Immunization Immunize Infection Infectious Agent Influenza Influenza A Virus, H5N1 Subtype Influenza Hemagglutinin Intranasal Administration Invaded Knowledge Lesion Life Liver Lung Mammalian Cell Medical Melioidosis Mucosal Immune Responses Mus NP protein Organism Paramyxoviridae Paramyxovirus Pathogenesis Pathogenicity Phase Pneumonia Population Production Proteins Rabies Rabies virus Recombinants Respiratory Tract Infections Route Safety Soil Spleen Sterility Tissues Vaccinated Vaccination Vaccine Antigen Vaccine Production Vaccines Vaccinia Vero Cells Virulence Virus Zoonoses adaptive immune response bacterial resistance base cost effective extracellular genetic manipulation immunogenicity improved lymph nodes mortality neutralizing antibody novel novel vaccines parainfluenza virus pathogen pathogenic bacteria programs recombinant virus respiratory success trait tropical coastal water vaccine development vector vector vaccine virus characteristic

项目摘要

SUMMARY Burkholderia pseudomallei, the causative agent of melioidosis, is a saprophytic bacterium readily isolated from soil and stagnant water of tropical countries. Burkholderia mallei is a host-adapted clone of B. pseudomallei that does not persist outside of its equine reservoir and causes the zoonosis glanders. Infection by these organisms typically occurs via the respiratory or percutaneous route, and the most common manifestations are life-threatening pneumonia and bacteremia. Melioidosis and glanders are difficult to diagnose and require prolonged antibiotic therapy that has a low success rate. There is no vaccine to protect against these highly pathogenic bacteria, and there is concern regarding their use as biological warfare agents given that B. mallei has already been utilized in this manner on multiple occasions. For these reasons, the Federal Select Agent Program has classified B. pseudomallei and B. mallei as Tier 1 agents and the development of medical countermeasures is a priority. Parainfluenza virus 5 (PIV5), a paramyxovirus, is thought to be a contributing factor of kennel cough. Several characteristics of the virus make it an excellent vector for developing countermeasures including safety, replication in mammalian cell lines approved for vaccine production, and efficacy (single dose immunization provides protective immunity against multiple infectious agents). Moreover, intranasal immunization of PIV5-based vaccines elicits robust mucosal immune responses, thus providing an ideal platform for vaccinating against respiratory pathogens. In this application, we present preliminary data demonstrating that single dose immunization with PIV5 expressing the Burkholderia autotransporter protein BatA provides excellent protective immunity against lethal respiratory infection with B. pseudomallei and B. mallei. Based on these results, we propose to use PIV5 to develop a vaccine for these Tier 1 select agents focusing on 2 specific aims. In Aim 1, we will examine the mechanisms of protection by PIV5-BatA and improve efficacy. In Aim 2, we will develop a PIV5-based vaccine containing multiple Burkholderia high-value antigens.

概括类鼻疽伯克霍尔德氏菌是类鼻疽的病原体，是一种容易腐生的细菌与热带国家的土壤和积水隔离。鼻疽伯克霍尔德氏菌 (Burkholderia mallei) 是伯克霍尔德氏菌 (Burkholderia mallei) 的宿主适应克隆。假鼻疽不会在其马宿主之外持续存在并导致人畜共患病鼻疽。感染这些生物体通常通过呼吸道或经皮途径发生，最常见的是表现为危及生命的肺炎和菌血症。类鼻疽和鼻疽很难诊断并需要长期抗生素治疗，但成功率较低。没有疫苗可以保护针对这些高致病性细菌，人们担心它们用作生物战剂鉴于鼻疽杆菌已多次以这种方式被利用。由于这些原因，联邦精选病原体计划已将类鼻疽伯克虫和鼻疽伯克氏杆菌列为一级病原体，制定医疗对策是当务之急。副流感病毒 5 (PIV5) 是一种副粘病毒，被认为是导致犬窝咳的一个因素。该病毒的几个特征使其成为制定对策的绝佳载体，包括安全性、在批准用于疫苗生产的哺乳动物细胞系中的复制以及功效（单剂量免疫提供针对多种传染源的保护性免疫力）。此外，鼻内基于 PIV5 的疫苗的免疫可引发强烈的粘膜免疫反应，从而提供理想的呼吸道病原体疫苗接种平台。在此应用中，我们提供了初步数据，证明 PIV5 单剂量免疫表达伯克霍尔德杆菌自转运蛋白 BatA 可提供出色的针对致命性的保护性免疫力鼻疽伯克霍尔德氏菌和鼻疽伯克氏菌的呼吸道感染。基于这些结果，我们建议使用 PIV5 为这些一级精选药物开发疫苗，重点关注两个具体目标。在目标 1 中，我们将检查 PIV5-BatA 的保护机制并提高疗效。在目标 2 中，我们将开发基于 PIV5 的疫苗含有多种伯克霍尔德杆菌高价值抗原。