Multi-intracellular Pathogen Epitope-based Vaccine

在这项提议的背景下，我们将使用先前存在的图拉氏菌(FT)的已定义表位，以及 使用核心三联疫苗设计工具包，定义假鼻疽伯克霍尔德菌(BPM)的新表位和 马来伯克霍尔德氏菌(BM)，分别是旋毛虫病和腺体的病原体，用于基于表位的多病原体 预防性疫苗。FT被列为A类生物战剂，因世界 第二次世界大战和冷战时期的生物武器研究。BPM是类鼻疽病的病原体，它是一种 在热带地区，估计20%的败血症和大约40%的死亡是由细菌败血症引起的 世界。BM是一种相关细菌，也会导致人和动物的致命感染(被归类为腺体)。与英国《金融时报》一样， BM作为一种气雾剂具有很强的传染性。所有三种病原体(FT和BPM/BM)都是细胞内细菌，因此 容易受到细胞免疫反应的攻击。基于表位的疫苗设计平台已经 已经产生了图拉氏F·A(亚种)的原型。图拉氏菌：Schu S4)疫苗，免疫60% 用减毒活疫苗株(LVS)保护异种致死性呼吸道攻击 亚种。冬虫夏草衍生品。据我们所知，目前还没有针对图拉热症的亚单位疫苗达到类似水平。 在这个发展良好的致命呼吸挑战模型中的保护作用。这一里程碑是在 为期24个月的资助期。在本U19的背景下提供的相同的疫苗设计工具 计划项目，将促进针对这三种病原体的新型联合疫苗的开发。我们会 在现场挑战中测试组合疫苗组件，并优化剂量、递送工具和佐剂 模特。除了评估我们的表位驱动疫苗外，我们还将探索是否将我们的 FT/BPM/BM多病原体疫苗与Steven Opal博士和他的同事开发的抗LPS疫苗将 带来针对实时挑战的更好保护。挑战研究将在#年在NERCE进行。 与布朗大学(Steve Gregory，Steve Opal)调查人员合作。这一里程碑式的计划 将导致原则证明(针对现场挑战的保护证据)和开发可许可的 在五年时间内接种多病原体生物防御疫苗。

In the context of this proposal, we will use pre-existing defined epitopes for Fransicella tularensis (FT), and using the core TRIAD vaccine design toolkit, define new epitopes for Burkholderia pseudomallei (BPM) and Burkholderia mallei (BM), the agents of meloidosis and glanders, respectively, for use in an epitope-based multipathogen prophylactic vaccine. FT has been listed as a Category A biological warfare agent as a result of World War II and Cold War-era biowarfare research. BPM, the etiological agent of melioidosis, is responsible for an estimated 20% of septicemias and approximately 40% of deaths due to bacterial sepsis in tropical regions of the world. BM, a related bacterium, also causes fatal infections (classified as glanders) in man and animals. Like FT, BM is highly infectious as an aerosol. All three pathogens (FT and BPM/BM) are intracellular bacteria and thus amenable to attack by cell-mediated immune response. The EpiMatrix epitope-based vaccine design platform has already yielded a prototype F. tularensis Type A (subsp. tularensis: SCHU S4) vaccine that confers 60% protection against heterologous lethal respiratory challenge with the live vaccine strain (LVS), an attenuated subsp. holarctica derivative. To our knowledge no subunit vaccine for tularemia has achieved a comparable level of protection in this well-developed lethal respiratory challenge model. This milestone was reached over the course of a 24 month funding period. The same vaccine design tools, made available in the context of this U19 program project, will facilitate the development a novel combined vaccine against the three pathogens. We will test the combined vaccine components, and optimize dose, delivery vehicle, and adjuvants, in a live challenge model. In addition to evaluating our epitope-driven vaccine, we will explore whether combining our FT/BPM/BM multi-pathogen vaccine with the anti-LPS vaccine developed by Dr. Steven Opal and colleagues will lead to improved protection against live challenge. The challenge studies will be carried out at NERCE in collaboration with Brown University (Steve Gregory, Steve Opal) investigators. This milestone-driven program will lead to proof-of-principle (evidence for protection against live challenge) and development of a licensable multi-pathogen biodefense vaccine within a five year time frame.