Novel immune stimulating adjuvants for an HIV DNA Vaccine

描述(由申请人提供)：本文件包含Proectus BioSciences要求不得向政府以外的人发布的专有信息，除非是出于审查和评估的目的。摘要DNA疫苗具有安全性高、稳定性好、产品开发速度快等优点，是预防和治疗HIV疫苗的有效途径。不幸的是，成功的灵长类DNA疫苗需要多次接种不受欢迎的大剂量质粒。基因编码的佐剂可以提供实现实用的基于DNA的艾滋病毒疫苗所需的免疫刺激和节省剂量的效果。我们的佐剂方法利用RIG-1信号级联反应，识别病毒病原体的感染并触发先天免疫反应。我们已经构建了RIG-1样解旋酶及其适配器蛋白(IPS-1)的显性阳性版本，当以质粒DNA的形式导入细胞时，它可以模拟病毒感染。我们的目标是确定这些表达RIG-1的构建体是否将在小鼠中更大程度地佐剂HIV DNA疫苗，而不是“基准”佐剂IL-12。我们将通过以下具体目标来实现我们的目标：(1)确定一种佐剂或佐剂组合，以诱导针对HIV GP160的最大B和T细胞介导的免疫反应；(2)证明主要佐剂在疫苗-HIV挑战模型中提供增强的保护。在小鼠中具有免疫原性和保护性的联合配方将在更多的小鼠和灵长类动物研究中作为先进的艾滋病毒DNA疫苗的组成部分在后续的第二阶段SBIR应用中进行评估。2. 公共卫生相关性：该项目的目标是为HIV DNA疫苗开发新的佐剂。这种疫苗/佐剂组合是抗击艾滋病毒流行所必需的。

DESCRIPTION (provided by applicant): This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract The enhanced safety, stability, and accelerated product development generally provided by DNA vaccination make it an appealing approach to develop prophylactic and therapeutic HIV vaccines. Unfortunately, successful DNA vaccination of primates requires multiple inoculations with undesirably large doses of plasmid. Genetically encoded adjuvants could provide the immune stimulating and dose-sparing effects necessary to realize a practical DNA-based vaccine for HIV. Our adjuvant approach exploits the RIG-1 signaling cascades that recognize infection with viral pathogens and trigger innate immune responses. We have constructed dominant-positive versions of RIG-1-like helicases and their adaptor protein (IPS-1) that mimic viral infection when transfected into cells as plasmid DNA. Our objective is to determine whether these plasmid expressed RIG-1 based constructs will adjuvant an HIV DNA vaccine in mice to a greater extent than the "bench mark" adjuvant IL-12. We will pursue our objective through the following specific aims: (1) Identify an adjuvant or adjuvant combination that induces maximal B and T cell mediated immune responses against HIV GP160; (2) Demonstrate that the lead adjuvant provides enhanced protection in a Vaccinia-HIV challenge model. The co-formulation that is immunogenic and protective in mice will be evaluated in additional mice and primate studies as components of an advanced HIV DNA vaccine in follow-on Phase II SBIR applications. 2 PUBLIC HEALTH RELEVANCE: The objective of this project is to develop novel adjuvants for an HIV DNA vaccine. Such a vaccine/adjuvant combination is needed to combat the HIV epidemic.