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战/生物恐怖剂的双重威胁，迫切需要更有效的疫苗开发系统。TRIAD，或翻译免疫学研究和加速[疫苗]开发计划，总部设在罗得岛大学的生物技术计划，已经率先开发和应用一个集成的“基因疫苗”在电脑，在体外和体内疫苗设计计划，以满足这一需求。TRIAD选择了A类病原体F。土拉热菌、类鼻疽伯克霍尔德菌和鼻疽伯克霍尔德菌B类病原体以及新发传染病（HCV、H. pylori，蜱传播疾病）作为本提案的重点。利用TRIAD免疫信息学工具包，TRIAD研究人员将继续开发针对这些病原体的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失败问题。我们将使用经验证的免疫信息学工具最大化有效负载量，该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中表现出抗原性的表位以及在已建立的疾病/感染鼠模型中的保护来确保有效负载质量。我们将选择混杂的II类表位的组合，并且I类超型表位将提供>99%的人群覆盖率。我们将避免交叉反应性表位，并探讨调节性T细胞在改进疫苗设计中的作用。在适当的情况下，我们将联合收割机将我们的表位驱动的疫苗与广谱抗LPS疫苗相结合。我们将通过探索一系列递送选项[树突状细胞、DEC 205、DNA、电穿孔、粘膜递送]来优化有效载荷、递送、制剂和佐剂。TRIAD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。我们努力将合理设计与疫苗输送的最新进展相结合，这将体现在一个协调的工具包和一批知情的用户中，他们将准备好并能够应用这些工具来发现新的治疗方法，用于新兴的传染病和生物防御。 相关性：转化免疫学研究和加速[疫苗]开发（TRIAD）联盟将联手加速开发更安全，更有效的生物防御和新兴传染病疫苗。TRIAD还将支持开发疫苗设计方法，大大减少将医疗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（De Groot，A） 项目1描述（由申请方提供）：在本提案的背景下，我们将使用土拉弗朗西斯菌（FT）的预先存在的确定表位，并使用核心TRIAD疫苗设计工具包，分别为类鼻疽伯克霍尔德菌（BPM）和鼻疽伯克霍尔德菌（BM）（类鼻疽和鼻疽的病原体）定义新表位，用于基于表位的多病原体预防性疫苗。由于第二次世界大战和冷战时期的生物战研究，FT已被列为A类生物战剂。BPM是类鼻疽病的病原体，在世界热带地区估计造成20%的败血症和约40%的细菌败血症死亡。BM，一种相关的细菌，也会导致人类和动物的致命感染（归类为鼻疽）。像FT一样，BM作为气溶胶具有高度传染性。所有三种病原体（FT和BPM/BM）都是细胞内细菌，因此易于受到细胞介导的免疫应答的攻击。EpiMatrix基于表位的疫苗设计平台已经产生了F。土拉菌A型（subsp.土拉热：SCHU S4）疫苗，该疫苗赋予60%的针对用活疫苗株（LVS）的异源致死性呼吸道攻击的保护力，该活疫苗株是一种减毒的亚群。全北极星衍生物据我们所知，在这种成熟的致死性呼吸道攻击模型中，没有兔热病亚单位疫苗达到可比的保护水平。这一里程碑是在24个月的供资期内实现的。在U19计划项目的背景下提供的相同疫苗设计工具将促进开发针对三种病原体的新型联合疫苗。我们将在活菌攻毒模型中测试组合疫苗组分，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博士及其同事开发的抗LPS疫苗结合是否会改善对活菌攻击的保护。挑战研究将在NERCE与布朗大学（Steve Gregory，Steve Opal）研究者合作进行。这一里程碑式的项目将在五年时间框架内导致原理验证（针对活菌攻击的保护证据）和可获得许可的多病原体生物防御疫苗的开发。 相关性：土拉热弗朗西氏菌、类鼻疽伯克霍尔德氏菌和鼻疽伯克霍尔德氏菌因其潜在的武器化而被列入A类（FT）和B类生物恐怖分子制剂（BPM，BM）。针对这些生物战威胁的有效和安全疫苗的开发和许可仍然是一个有效但尚未实现的NIAID和国防部目标。

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.