A Novel Vaccine for Burkholderia pseudomallei and Burkholderia mallei

总结 类鼻疽伯克霍尔德氏菌是类鼻疽的病原体， 与热带国家的土壤和死水隔绝。鼻疽伯克霍尔德菌是B的宿主适应性克隆。 假鼻疽在马的宿主之外不会持续存在，并引起人畜共患病鼻疽。感染 这些微生物通常通过呼吸或经皮途径发生，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 诊断并需要长期的抗生素治疗，成功率低。没有疫苗可以保护 针对这些高致病性细菌，人们担心它们被用作生物战剂， 考虑到B.锤骨已经以这种方式在多个场合使用。由于这些原因， 联邦特选探员计划将其列为B类。类鼻疽和B.鼻疽作为一级特工， 制定医疗对策是一个优先事项。 副流感病毒5型（PIV 5）是一种副粘病毒，被认为是犬舍咳嗽的促成因素。 该病毒的几个特征使其成为制定对策的绝佳载体， 安全性、在批准用于疫苗生产的哺乳动物细胞系中的复制和有效性（单剂量 免疫提供针对多种感染因子的保护性免疫）。此外，鼻内 基于PIV 5的疫苗的免疫激发了强有力的粘膜免疫应答，从而提供了理想的 为呼吸道病原体接种疫苗提供平台。 在本申请中，我们提供了初步数据，表明用PIV 5单次免疫 表达伯克霍尔德氏菌自转运蛋白BatA提供了针对致死性的极好的保护性免疫， 呼吸道感染B。类鼻疽和B.鼻疽基于这些结果，我们建议使用PIV 5来 针对这些1级精选病原体开发疫苗，重点关注2个特定目标。在目标1中，我们将检查 通过PIV 5-BatA的保护机制并提高疗效。在目标2中，我们将开发一种基于PIV 5的疫苗 含有多种伯克霍尔德氏菌高价值抗原。

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.