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

• 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
• 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

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 Burkholderia pseudomallei是Melioidosis的病因，是一种腐生细菌 从热带国家的土壤和停滞水中分离出来。 Burkholderia Mallei是B. 不持续在其马储层之外并引起人畜共患腺体的假单胞菌。感染 这些生物通常是通过呼吸道或经皮途径发生的，最常见的 表现是威胁生命的肺炎和菌血症。 Melioidosis和腺体很难 诊断并需要长时间的抗生素疗法，其成功率较低。没有疫苗可以保护 反对这些高度致病的细菌，并且担心它们用作生物战剂 鉴于B. Mallei已经多次以这种方式使用。由于这些原因， 联邦精选代理计划已将B. Pseudomallei和B. Mallei归类为1级代理商 医疗对策的发展是当务之急。 帕氏素病毒5（PIV5），一种帕托氏病毒，被认为是养蜂咳嗽的促成因素。 该病毒的几种特征使其成为开发对策的绝佳媒介 安全性，批准用于疫苗生产的哺乳动物细胞系中的复制和功效（单剂量 免疫提供了针对多种传染剂的保护性免疫力）。而且，鼻内 基于PIV5的疫苗的免疫接种会引起稳健的粘膜免疫反应，因此提供了理想 用于针对呼吸道病原体接种疫苗的平台。 在此应用中，我们提供了初步数据，表明使用PIV5进行单剂量免疫 表达Burkholderia自转运蛋白蛋白BATA可为致命提供出色的保护性免疫力 假单胞菌和马利芽孢杆菌的呼吸道感染。基于这些结果，我们建议将PIV5用于 为这些层1选择剂开发疫苗，专注于2个特定目标。在AIM 1中，我们将检查 PIV5-BATA保护机制并提高功效。在AIM 2中，我们将开发基于PIV5的疫苗 包含多个Burkholderia高价值抗原。