Multi-intracellular Pathogen Epitope-based Vaccine

基于多细胞内病原体表位的疫苗

基本信息

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
项目类别：
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

项目摘要

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.

在本提案的背景下，我们将使用土拉弗兰西菌 (FT) 预先存在的定义表位，并且使用核心 TRIAD 疫苗设计工具包，定义鼻疽伯克霍尔德菌 (BPM) 的新表位，并鼻疽伯克霍尔德氏菌 (BM)，分别是根结线虫病和鼻疽病的病原体，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，因为世界第二次世界大战和冷战时期的生物战研究。 BPM 是类鼻疽的病因，负责据估计，热带地区 20% 的败血症和约 40% 的死亡是由细菌性败血症引起的世界。 BM 是一种相关细菌，也会引起人类和动物的致命感染（称为马鼻疽）。和英国《金融时报》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具有已经生产出 A 型 tularensis（tularensis 亚种：SCHU S4）疫苗原型，可提供 60% 的疫苗接种效率使用活疫苗株（LVS）预防异源致死性呼吸道攻击，这是一种减毒疫苗亚种holarctica 衍生物。据我们所知，目前还没有针对兔热病的亚单位疫苗达到了可比的水平在这种成熟的致命呼吸挑战模型中的保护作用。这一里程碑是在 24个月的资助期。相同的疫苗设计工具，在本次 U19 背景下可用该计划项目将促进针对三种病原体的新型联合疫苗的开发。我们将在现场挑战中测试组合疫苗成分，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 Steven Opal 博士及其同事开发的 FT/BPM/BM 多病原体疫苗与抗 LPS 疫苗将从而改善对现场挑战的保护。挑战研究将在 NERCE 进行与布朗大学（Steve Gregory、Steve Opal）研究人员合作。这个里程碑驱动的计划将导致原理验证（针对实时挑战的保护证据）和可许可的开发五年内开发多病原体生物防御疫苗。