Augmenting innate and vaccine immune response with der-G

描述（由申请人提供）：关于美国对天花恐怖袭击的脆弱性的担忧刺激了新疫苗、免疫学和治疗学的开发。 然而，一个新的和成功的天花疫苗干预计划，或一个治疗暴露的个人不仅需要一个有效的疫苗，但也代理人治疗并发症所产生的广泛的疫苗接种计划。 最近，我们发现derG，一个N末端脱酰胺类似物的人MHC II β链（aa 135 -149）在疟疾和HSV感染性疾病模型中显示出显着的保护活性和疫苗的佐剂活性。 本申请的主要目的是确定derG对牛痘感染的保护活性，鉴定其作用机制以支持其作为单一药剂作为牛痘和天花感染的免疫增强剂和/或预防剂以及作为牛痘疫苗的佐剂的开发。 这些I期研究的最终目标是开发足够的数据来证明灵长类动物有效性模型研究和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之外，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，当可用时，在约1：10，000的初次接种者中与严重并发症相关，并且在约1：106的初次接种中与死亡相关。 我们的策略是使用derG作为佐剂，用于复制缺陷疫苗初免，以限制活牛痘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递送derG和疫苗，并将监测全身和粘膜（肺）免疫。 我们建议使用derG，连同一种感染性的，但复制能力低下的VV（辐照）疫苗，以检查这一假设，免疫增强derG将延长生存期，并提供佐剂活性的复制能力低下的疫苗，从而提供了一个额外的减少病毒负荷和延长生存期的牛痘感染的小鼠作为天花感染的模型。 该假设将通过以下特定目的进行检验：1：确定小鼠VV疫苗接种期间derG的免疫调节和佐剂特性。2：在用牛痘亚致死性感染的小鼠中测定derG的免疫增强和佐剂活性，作为天花模型。 第三章：确定免疫干预在治疗致命性牛痘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鼻内激发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。

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.