Novel immune stimulating adjuvants for an HIV DNA Vaccine

描述（由申请人提供）：本文件包含Profectus BioSciences要求不得向政府以外的人员发布的专有信息，除非用于审查和评估目的。摘要DNA疫苗的安全性、稳定性和产品开发速度的提高使其成为开发预防性和治疗性HIV疫苗的一种有吸引力的方法。不幸的是，灵长类动物的成功DNA疫苗接种需要用不期望的大剂量质粒进行多次接种。基因编码的佐剂可以提供必要的免疫刺激和剂量节省效应，以实现一个实用的基于DNA的艾滋病毒疫苗。我们的佐剂方法利用RIG-1信号级联，识别病毒病原体感染并触发先天免疫应答。我们已经构建了显性阳性版本的RIG-1样解旋酶和它们的衔接蛋白（IPS-1），当作为质粒DNA转染到细胞中时模拟病毒感染。我们的目的是确定这些质粒表达的RIG-1为基础的构建体是否会在小鼠中比“基准”佐剂IL-12更大程度地佐剂HIV DNA疫苗。我们将通过以下具体目标实现我们的目标：（1）鉴定诱导最大B和T细胞介导的抗HIV GP 160免疫应答的佐剂或佐剂组合;（2）证明主要佐剂在疫苗-HIV攻击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共制剂将在额外的小鼠和灵长类动物研究中作为后续II期SBIR应用中的高级HIV DNA疫苗的组分进行评价。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。需要这种疫苗/佐剂组合来对抗艾滋病毒流行病。

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.