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）：对美国对天花恐怖袭击的脆弱性的担忧刺激了新的疫苗，预防药物和治疗学的发展。 但是，一项新的成功的天花疫苗干预计划，或一项治疗暴露个人的疫苗，不仅需要有效的疫苗，而且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是人类MHC IIβ链（AA135-149）的N末端脱膜类似物（AA135-149）在疟疾和HSV的传染病模型中显示出显着的保护活性，以及​​疫苗的辅助活性。 本应用的主要目标是确定Derg对疫苗感染的保护活性，确定其作用机理，以支持其作为疫苗和天花感染作为单一药物的免疫治疗性和/或预防性的发育机制，并作为一种疫苗疫苗的辅助药物。 这些第一阶段研究的最终目标是制定足够的数据，以证明在功效和动物安全和毒理学研究的灵长类动物模型中为支持人类临床试验的研究合理。 除了担心天花可以用作大规模破坏的武器外，重组离发病毒病毒（VV）还被用作疫苗或免疫疗法的向量，从而建议对使用VV载体的人接种疫苗。 但是，目前的疫苗在大约1：10,000次疫苗中与严重并发症有关，大约1:10 6主要疫苗接种。 我们的策略是将DERG用作预防性，并作为复制无能力疫苗素的辅助药，以限制活疫苗病毒的毒性并靶向粘膜活性。 因此，这些研究将通过鼻内给药提供DERG和疫苗，并将监测全身和粘膜（肺）免疫。 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. 该假设将以以下特定目的进行检验：1：确定小鼠VV疫苗接种期间DERG的免疫调节和辅助性质。 2：确定Derg在牛ac牛的亚当时感染的小鼠中Derg的免疫增强和辅助活性，作为天花模型。 3：确定免疫干预在治疗致命疫苗病毒感染并鉴定治疗活性替代的治疗潜力。 在这些研究中，我们将遵循VV内鼻内挑战后的生存和卵巢病毒滴度。 研究还将分析鉴定免疫替代物用于临床研究的作用机理。