Augmenting innate and vaccine immune response with der-G

使用 der-G 增强先天免疫和疫苗免疫反应

• 批准号: 6643824
• 负责人: Daniel Hill Zimmerman
• 金额: $ 10.41万
• 依托单位: CEL-SCI CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643824
• 关键词: MHC class II antigen; Poxviridae disease; active immunization; analog; bioterrorism /chemical warfare; cellular immunity; drug screening /evaluation; enzyme linked immunosorbent assay; flow cytometry; host organism interaction; immunologic substance development /preparation; immunomodulators; immunoregulation; immunotherapy; laboratory mouse; microorganism immunology; mucosal immunity; polymerase chain reaction; smallpox vaccine; smallpox virus; toxicology; vaccine development; vaccinia virus; virus load; virus replication

DESCRIPTION (provided by applicant): Concerns regarding the United States' vulnerability to a terrorist attack with smallpox have stimulated development of new vaccines, prophylactics and therapeutics. However, a new and successful smallpox vaccine intervention program, or one to treat exposed individual requires not only an effective vaccine, but also agents to treat the complications arising from a widespread vaccination program. Recently, we found that derG, an N terminal deamidated analogue of the human MHC II beta-chain (aa135-149) showed significant protective activity in infectious disease models of malaria and HSV and adjuvant activity for vaccines. The primary goals of this application are to determine the protective activity of derG for vaccinia infections, identify its mechanism of action to support its' development as an immunotherapeutic and/or prophylactic for vaccinia and smallpox infections as a single agent and as an adjuvant for vaccinia vaccines. The ultimate goal of these Phase I studies is to develop sufficient data to justify studies in a primate model of efficacy and animal safety and toxicology studies to support human clinical trials. In addition to the concern that smallpox may be used as a weapon of mass destruction, recombinant vaccinia viruses (VV) are also used as vaccines or as vectors for immunotherapy resulting in the recommendation that individuals working with VV vectors be vaccinated. However, the present vaccines, when available, are associated with serious complications in approximately 1:10,000 primary vaccinees, and mortality in about 1:10 6 primary vaccinations. Our strategy is to use derG as prophylaxsis and as an adjuvant for a replication incompetent vaccine prime to limit the toxicity by live vaccinia virus and to target mucosal activity. Thus, these studies will deliver derG and the vaccine by intranasal administration and will monitor both systemic and mucosal (pulmonary) immunity. We propose to use derG, together with an infectious, but replication incompetent VV (irradiated) vaccine to examine the hypothesis that immune augmentation with derG will prolong survival and also provide adjuvant activity for a replication incompetent vaccine, thereby providing an additional reduction in viral burden and prolongation of survival for vaccinia-infected mice as a model of smallpox infection. This hypothesis will be tested with the following Specific Aims: 1: Determine the immunoregulatory and adjuvant properties of derG during VV vaccination of mice. 2: Determine the immune augmenting and adjuvant activity of derG in mice sub-lethally infected with vaccinia as a model of smallpox. 3: Determine the therapeutic potential of immune intervention in the treatment of lethal vaccinia virus infections and identify surrogates of therapeutic activity. In these studies we will follow survival and ovarian viral titers after intranasal challenge with VV. The studies will also analyze the mechanism of action to identify immune surrogates for use in clinical studies.

描述（由申请人提供）：对美国容易遭受天花恐怖袭击的担忧刺激了新疫苗、预防剂和治疗剂的开发。 然而，一项新的成功的天花疫苗干预计划，或治疗暴露个体的计划，不仅需要有效的疫苗，还需要治疗广泛疫苗接种计划引起的并发症的药物。 最近，我们发现 derG，一种人类 MHC II β 链 (aa135-149) 的 N 端脱酰胺类似物，在疟疾和 HSV 传染病模型中表现出显着的保护活性以及疫苗的佐剂活性。 本申请的主要目标是确定 derG 对痘苗感染的保护活性，确定其作用机制，以支持其作为痘苗和天花感染的免疫治疗和/或预防剂的开发，作为单一药剂和痘苗疫苗的佐剂。 这些第一阶段研究的最终目标是开发足够的数据来证明灵长类动物模型的功效研究以及动物安全性和毒理学研究的合理性，以支持人体临床试验。 除了担心天花可能被用作大规模杀伤性武器外，重组牛痘病毒 (VV) 也被用作疫苗或免疫治疗的载体，因此建议使用 VV 载体的个人接种疫苗。 然而，现有的疫苗，当可获得时，与约1:10,000初次接种者的严重并发症相关，以及约1:10 6初次接种者的死亡率相关。 我们的策略是使用 derG 作为预防措施，并作为复制缺陷疫苗的佐剂，以限制活痘苗病毒的毒性并针对粘膜活性。 因此，这些研究将通过鼻内给药来递送 derG 和疫苗，并将监测全身和粘膜（肺部）免疫。 我们建议将 derG 与一种具有传染性但复制能力不强的 VV（辐照）疫苗一起使用，以检验以下假设：使用 derG 增强免疫将延长生存期，并为复制能力不强的疫苗提供佐剂活性，从而进一步减少病毒负荷并延长作为天花感染模型的痘苗感染小鼠的生存期。 该假设将通过以下具体目标进行检验： 1：确定 derG 在小鼠 VV 疫苗接种过程中的免疫调节和佐剂特性。图2：确定derG在作为天花模型的亚致死感染牛痘的小鼠中的免疫增强和佐剂活性。 3：确定免疫干预在治疗致命痘苗病毒感染中的治疗潜力并确定治疗活性的替代物。 在这些研究中，我们将跟踪 VV 鼻内攻击后的存活率和卵巢病毒滴度。 这些研究还将分析作用机制，以确定用于临床研究的免疫替代物。