Translational Immunology Research and Accelerated [vaccine] Development (TRIAD)

描述(由申请人提供)：为了应对新出现的传染病和工程生物武器/生物恐怖制剂的双重威胁，迫切需要更有效的疫苗开发系统。以罗德岛大学生物技术计划为基础的TIAD或翻译免疫学研究和加速[疫苗]开发计划，已率先在硅胶、体外和体内疫苗设计计划中开发和应用集成的“基因到疫苗”，以满足这一需求。三合会选择了A类病原体图拉氏杆菌、B类病原体伯克霍尔德氏菌和马利伯克霍尔德氏菌，以及新出现的传染病(丙型肝炎病毒、幽门螺杆菌、壁虱传播疾病)作为这项建议的重点。利用三合会免疫信息学工具包，三合会调查人员将针对这些病原体开发第二代基于表位的免疫衍生疫苗，同时解决前几代基于表位的疫苗的缺陷。我们将使用经过验证的免疫信息学工具来最大化有效负荷量，这些工具允许选择高度保守和免疫原性的最佳T细胞表位。我们将通过选择在人PBMC中显示抗原性的表位以及在已建立的小鼠疾病/感染模型中进行保护来确保有效载荷的质量。我们将选择混杂的II类表位组合，而I类超类型表位将提供99%的人类群体覆盖率。我们将避免交叉反应表位，并在改进疫苗设计的背景下探索调节性T细胞的作用。在适当的情况下，我们将把我们的表位驱动疫苗与广谱抗内毒素疫苗结合起来。我们将通过探索一系列递送选择[树突状细胞、DEC205、DNA、电穿孔、粘膜递送]来优化有效载荷、递送、配方和调整。三合会项目旨在开发具有广谱活性的疫苗，包括交叉保护和多组分疫苗，以及有可能有效对抗多种新出现和重新出现的传染病的递送技术。我们努力将合理的设计与疫苗交付方面的最新进展结合起来，这将体现在一个协调的工具包和一批知情的用户中，他们将准备并能够应用这些工具来发现新出现的传染病和生物防御的新疗法。 相关性：转译免疫学研究和加速[疫苗]开发(TRIAD)联盟将联手加速开发更安全、更有效的疫苗，用于生物防御和新出现的传染病。三合会还将支持疫苗设计方法的开发，这些方法可以显著减少将医学对策推向市场所需的时间和成本。 项目1：基于多细胞内病原体表位的疫苗(德格鲁特，A) 项目1描述(申请人提供)：在这项建议的背景下，我们将使用已有的图拉氏方济氏菌(FT)的已定义表位，并使用核心三合一疫苗设计工具包，分别为假鼻疽伯克霍尔德氏菌(BPM)和马来伯克霍尔德氏菌(BM)定义新的表位，用于基于表位的多病原预防性疫苗。由于第二次世界大战和冷战时期的生物武器研究，FT已被列为A类生物战剂。BPM是类鼻疽病的病原体，在世界热带地区，约有20%的败血症和约40%的死亡是由细菌败血症引起的。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。这三种病原体(FT和BPM/BM)都是细胞内细菌，因此容易受到细胞介导的免疫反应的攻击。基于EpiMatrix表位的疫苗设计平台已经产生了图拉氏F·A(亚种)的原型。图拉氏菌：Schu S4)疫苗，对异种致死呼吸道攻击提供60%的保护，活疫苗株(LVS)是一种减毒亚种。冬虫夏草衍生品。据我们所知，在这一发展良好的致命呼吸道挑战模型中，还没有针对图拉热症的亚单位疫苗达到可比的保护水平。这一里程碑是在24个月的资助期内实现的。在这个U19计划项目的背景下提供的相同的疫苗设计工具将促进针对这三种病原体的新型联合疫苗的开发。我们将在活体挑战模型中测试组合疫苗组件，并优化剂量、递送载体和佐剂。除了评估我们的表位驱动疫苗外，我们还将探索将我们的FT/BPM/BM多病原体疫苗与Steven Opal博士及同事开发的抗内毒素疫苗相结合，是否会改善对活体挑战的保护。挑战研究将在NERCE与布朗大学(Steve Gregory，Steve Opal)调查人员合作进行。这一里程碑式的计划将在五年内导致原则证明(针对活体挑战的保护证据)和可许可的多病原体生物防御疫苗的开发。 相关信息：由于担心它们可能成为武器，图拉氏菌、假鼻疽伯克霍尔德氏菌和马雷伯克霍尔德氏菌被列入A类(FT)和B类生物恐怖分子(BPM、BM)名单。针对这些生物威胁的有效和安全疫苗的开发和许可仍然是NIAID和国防部的一个有效但尚未实现的目标。

DESCRIPTION (provided by applicant): To meet the dual threats of emerging infectious diseases and engineered biowarfare/bioterror agents, there is a pressing need for more efficient systems for vaccine development. TRIAD, or the Translational Immunology Research and Accelerated [Vaccine] Development program, based in the Biotechnology Program at the University of Rhode Island, has pioneered the development and application of an integrated "gene to vaccine" in silico, in vitro and in vivo vaccine design program to address this need. TRIAD has selected Category A pathogens F. tularensis, Category B agents Burkholderia pseudomallei and Burkholderia mallei, and emerging infectious diseases (HCV, H. pylori, tick borne diseases) as the focal point of this proposal. Using the TRIAD immunoinformatics Toolkit, TRIAD investigators will pursue the development of second generation epitope based immunme-derived vaccines for these pathogens, while addressing the failings of prior generations of epitope based vaccines. We will maximize payload quantity using validated immunoinformatics tools that permit selection of optimal T cell epitopes that are highly conserved and immunogenic. We will ensure payload quality by choosing epitopes that demonstrate antigenicity in human PBMC as well as protection in established murine models of disease/infection. We will select a combination of promiscuous Class II epitopes, and Class I supertype epitopes will provide >99% coverage of human populations. We will avoid cross-reactive epitopes and explore the role of regulatory T cells in the context of improving vaccine design. Where appropriate, we will combine our epitope-driven vaccines with broad-spectrum anti-LPS vaccines. We will optimize payload, delivery, formulation, and adjuvanting by exploring a range of delivery options [Dendritic cells, DEC205, DNA, electroporation, mucosal delivery). The TRIAD project aims to develop vaccines demonstrating broad spectrum activity include crossprotective and multiple component vaccines, and delivery technologies that have the potential to be effective against multiple emerging and re-emerging infectious diseases. Our efforts to merge rational design with recent advances in vaccine delivery will manifest in a coordinated toolkit and a cadre of informed users, who will be ready and able to apply the tools to discover new treatments for emerging infectious disease and biodefense. RELEVANCE: The Translational Immunology Research and Accelerated [Vaccine] Development (TRIAD) consortium will join forces to accelerate the development of safer, more efficient vaccines for biodefense and emerging infectious diseases. The TRIAD will also support the development of vaccine design methods that significantly reduce the time and cost required to bring medical countermeasures to market. PROJECT 1: Multi-intracellular Pathogen Epitope-based Vaccine (De Groot, A) PROJECT 1 DESCRIPTION (provided by applicant): In the context of this proposal, we will use pre-existing defined epitopes for Francisella 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 meloidosis, 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. RELEVANCE: Fransicella tularensis, Burkholderia pseudomallei and Burkholderia mallei are included on the list of Category A (FT) and B bioterrorist agents (BPM, BM) due to concern about their potential for weaponizaton. Development and licensure of effective and safe vaccines for these biowarfare threats remains a valid but unmet NIAID and DoD objective.