Translation of immunologic technologies from basic research into pre-clinical non

免疫学技术从基础研究到临床前非临床研究的转化

• 批准号: 7696151
• 负责人: Shinichiro Kurosawa
• 金额: $ 40.44万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696151
• 关键词: Address; Animal Model; Anthrax disease; Antibodies; Antibody Therapy; Antigens; Archives; Attenuated; Bacillus anthracis; Bacillus anthracis spore; Bacteremia; Bacteria; Basic Science; Biothrax; Blood Coagulation Disorders; Breathing; Cessation of life; Clinical Trials; Cloning; Complex; Data; Development; Disease; Disease model; Epitopes; Event; FDA approved; Foundations; Functional disorder; Funding; Germination; Grant; Human; Immune; Immune response; Immunization; Immunization Schedule; Immunologics; Immunologist; Immunology; Immunotherapeutic agent; Individual; Infection; Infection prevention; Inflammation; Infusion procedures; Lung; Manuscripts; Mediating; Military Personnel; Modality; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Organ; Papio; Passive Immunity; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Prevention; Prevention Protocols; Primate Diseases; Primates; Probability; Reaction; Recombinants; Recording of previous events; Relative (related person); Reproduction spores; Research Personnel; Resources; Risk; Role; Sampling Studies; Selection Criteria; Sepsis; Severity of illness; Soldier; Specificity; Speed; Staging; Stratification; System; Technology; Testing; Therapeutic; Time; Toxin; Translations; Vaccinated; Vaccination; Vaccines; Validation; Virulent; Work; anthrax lethal factor; base; cohort; data sharing; high risk; human monoclonal antibodies; mortality; new technology; nonhuman primate; novel strategies; pathogen; polyclonal antibody; polyclonal human antibody; pre-clinical; response; vaccine candidate

Does the vaccine protect? Soldiers are vaccinated against anthrax due to the high probability of malicious infection with the spores of B. anthracis. But will the vaccine actually protect them from disease morbidity and mortality? There is no means to test the FDA-approved AVA vaccine or any other vaccine candidate directly in humans. Antibody tilers, epitope specificity, and toxin neutralizing activity in vaccinated individuals show a disturbing degree of variability. In concert with our U19 immunologists, this proposal will address these issues using nonhuman primate models of anthrax that mimic human responses. In the previous funding period, we developed, characterized and validated a baboon anthrax bacteremia model that mimics late stage disease in humans after spore germination, demonstrating the critical role of sepsis toward lethality. The current proposal builds on this foundation and is based on the hypothesis that if antibodies of known specificity and neutralizing activity can prevent infection or reduce disease severity due to B.anthracis in validated baboon models, then vaccinated individuals with similar antibodies will likewise be protected. Since not everyone responds in the same way to the vaccine, this information may contribute to risk stratification of vaccinated individuals. We aim to 1) identify polyclonal and monoclonal antibodies of known epitope specificity and functionality; 2) develop and characterize pulmonary spore models in baboons; and use these to 3) test whether the characterized antibodies are protective in the nonhuman primate disease models. The approach is strong because both baboon and human humoral responses to AVA will be characterized, many antigen-specific antibodies will be screened, and the most promising will be comprehensively tested in the baboon disease models. Minimally, we will be able to identify several candidate antibodies that may be useful immediately as passive immunity adjunctive therapeutics. We have a unique opportunity to answer critical questions by combining a genetically diverse nonhuman primate model which has a proven history of mimicking human responses to anthrax challenge with novel technologies provided by the immunologists on this U19 grant.

疫苗有保护作用吗？士兵接种炭疽疫苗，由于恶意感染的可能性很高， B的孢子炭疽病但疫苗真的能保护他们免受疾病的发病率和死亡率吗？没有 是指直接在人体中测试FDA批准的AVA疫苗或任何其他候选疫苗。抗体瓦片， 表位特异性和毒素中和活性显示出令人不安的变异程度。在 与我们的U19免疫学家合作，这项提议将使用非人类灵长类炭疽模型来解决这些问题 模仿人类的反应。在上一个资助期，我们开发了一种狒狒， 炭疽菌血症模型，模拟孢子萌发后人类的晚期疾病，证明了关键的 败血症对致死性的作用。目前的建议是建立在这个基础上的，并基于这样的假设，即如果 已知特异性和中和活性的抗体可以预防感染或降低疾病的严重程度， B.炭疽杆菌，则具有类似抗体的接种个体同样会受到保护。 由于不是每个人都以相同的方式对疫苗作出反应，因此这些信息可能有助于对 接种疫苗的人。我们的目标是1）鉴定已知表位特异性的多克隆和单克隆抗体， 功能性; 2）开发和表征狒狒的肺孢子模型;并使用这些模型来3）测试 特征抗体在非人灵长类动物疾病模型中具有保护性。这种方法很强大，因为 狒狒和人对AVA的体液反应都将被表征，许多抗原特异性抗体将被 筛选，最有希望的将在狒狒疾病模型中进行全面测试。至少我们会 能够鉴定几种候选抗体，这些抗体可以立即用作被动免疫抑制剂， 治疗学我们有一个独特的机会通过将遗传多样性的非人类结合起来来回答关键问题 灵长类动物模型，该模型具有用新技术模拟人类对炭疽挑战的反应的历史 由免疫学家提供。