Augmenting innate and vaccine immune response with der-G

描述（由申请人提供）：对美国容易受到天花恐怖袭击的担忧刺激了新疫苗、预防措施和治疗方法的开发。然而，一个新的成功的天花疫苗干预计划，或者一个治疗暴露个体的计划，不仅需要有效的疫苗，还需要治疗广泛接种计划引起的并发症的药物。最近，我们发现人类MHC II β链的N端脱酰胺类似物（aa135-149） derG在疟疾和HSV传染病模型中具有显著的保护活性，并对疫苗具有佐剂活性。本申请的主要目的是确定derG对牛痘感染的保护活性，确定其作用机制，以支持其作为牛痘和天花感染的免疫治疗和/或预防的单一剂和作为牛痘疫苗的佐剂的发展。这些I期研究的最终目标是开发足够的数据来证明在灵长类动物模型中进行有效性研究以及动物安全性和毒理学研究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，重组痘苗病毒（VV）也被用作疫苗或作为免疫治疗的载体，因此建议使用痘苗病毒载体的个人接种疫苗。然而，目前的疫苗，当可用时，与约1:10 000初级疫苗接种者的严重并发症和约1:10 6初级疫苗接种者的死亡率相关。我们的策略是使用derG作为预防和作为复制能力不足的疫苗的佐剂，以限制活痘苗病毒的毒性和靶向粘膜活性。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。我们建议将derG与一种传染性但复制能力不足的VV（辐照）疫苗一起使用，以检验用derG增强免疫可以延长生存期的假设，并为复制能力不足的疫苗提供佐剂活性，从而为牛痘感染小鼠作为天花感染模型提供额外的病毒负担减少和延长生存期。这一假设将通过以下具体目的进行验证：1 .确定小鼠接种VV疫苗时derG的免疫调节和佐剂特性。2：测定牛痘亚致死性感染小鼠的derG的免疫增强和佐剂活性。3：确定免疫干预治疗致命牛痘病毒感染的治疗潜力，并确定治疗活性的替代品。在这些研究中，我们将跟踪鼻内注射VV后的生存率和卵巢病毒滴度。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。

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.