Multi-intracellular Pathogen Epitope-based Vaccine

基于多细胞内病原体表位的疫苗

• 批准号: 8378738
• 负责人: Anne Searls DeGroot
• 金额: $ 31万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378738
• 关键词: Adjuvant; Aerosols; Animals; Antibodies; Attenuated; Attenuated Vaccines; Bacteria; Binding; Bioinformatics; Biological Assay; Biological Warfare; Burkholderia; Burkholderia mallei; Burkholderia pseudomallei; CD8-Positive T-Lymphocytes; Cancer Center Support Grant; Categories; Cessation of life; Collaborations; Combined Vaccines; DNA; DR1 gene; Databases; Development; Dose; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Francisella tularensis; Funding; Gene Expression; Glanders; Human; Immunology; In Vitro; Infection; Lead; Licensure; Life; MHC Class II Genes; Measures; Melioidosis; Modeling; National Institute of Allergy and Infectious Disease; Outcome; Peptides; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Phenotype; Population; Production; Proteins; Relative (related person); Research; Research Personnel; Route; Sepsis; Septicemia; Subunit Vaccines; Survivors; TNFRSF10A gene; Testing; Time; Transgenic Mice; Tularemia; Universities; Vaccine Design; Vaccines; War; World War II; base; biodefense; cell mediated immune response; cytokine; design; genome database; genome sequencing; immunogenic; immunogenicity; improved; in vivo; mRNA Differential Displays; man; novel; pathogen; programs; prophylactic; prototype; respiratory; success; tool; vaccine development; vaccine evaluation; vector

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.

在该提议的上下文中，我们将使用预先存在的土拉弗朗西斯菌（FT）的限定表位，并且 使用核心TRIAD疫苗设计工具包，定义类鼻疽伯克霍尔德菌（BPM）的新表位， 鼻疽伯克霍尔德菌（BM），分别是类鼻疽和鼻疽的病原体，用于基于表位的多病原体 预防性疫苗FT已被列为A类生物战剂，由于世界 二战和冷战时期的生物战研究。BPM是类鼻疽的病原体， 估计20%的败血症和大约40%的死亡是由于热带地区的细菌败血症 世界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）。和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反应的攻击。EpiMatrix基于表位的疫苗设计平台 已经得到了一个原型F土拉菌A型（subsp.土拉热：SCHU S4）疫苗，赋予60% 用减毒活疫苗株（LVS）对异源致死性呼吸道攻击的保护作用 亚种全北极星衍生物据我们所知，没有一种兔热病亚单位疫苗达到可比较的水平 在这个成熟的致命呼吸挑战模型中具有保护作用。这一里程碑是在 24个月的融资期。同样的疫苗设计工具，在U19的背景下提供， 该计划项目将促进开发针对这三种病原体的新型联合疫苗。我们将 在活菌攻毒中测试组合疫苗组分，并优化剂量、递送载体和佐剂 模型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博士及其同事开发的抗LPS疫苗将 从而改善对活体挑战保护。挑战研究将在NERCE进行， 与布朗大学（史蒂夫格雷戈里，史蒂夫蛋白石）研究人员合作。这个里程碑式的计划 将导致原理证明（保护免受现场挑战的证据）和可许可的 多病原体生物防御疫苗。