An Adjuvanted Therapeutic DNA Vaccine for AIDS

说明（申请人提供）：PowderJect Vaccines，Inc.项目申请书。(PJV)匹兹堡大学的研究人员在恒河猴中使用猿猴免疫缺陷病毒（SIV）模型对人类免疫缺陷病毒（HIV）感染的治疗性DNA疫苗方案进行了评估。待评价的治疗性DNA疫苗是编码SIVmac 239的17 e Fr克隆的gag、RT和nef产物的基于CMV启动子的单一DNA疫苗载体。该疫苗将使用经临床验证的颗粒介导（基因枪）递送装置递送，该装置已显示在人和猴中引发Th 1体液和细胞应答。SIV DNA疫苗载体的设计旨在紧密模拟临床HIV-1 DNA疫苗载体，该载体通过GlaxoSmithKline（GSK）和PJV的联合临床开发工作正在进行人体评价的临床跟踪。因此，本申请中描述的活动是GSK/PJV预防性和治疗性艾滋病疫苗临床共同开发工作的组成部分，并将起到促进临床成功的三个重要作用。首先，这些活动将提供GSK临床DNA疫苗载体策略在高度相关的SIV/恒河猴模型中的免疫原性和治疗性疫苗潜力的非人灵长类动物模型验证。我们最近在恒河猴模型中使用早期载体的DNA疫苗试验证明了我们通过颗粒介导的DNA疫苗技术诱导显著的预防和治疗效果的能力，此外，这些活性将允许评价编码大肠杆菌不耐热肠毒素的令人兴奋的新DNA疫苗佐剂载体。杆菌该佐剂载体已在广泛的非人灵长类动物安全性试验中被证明是安全的，并显著增强小鼠和猴对各种模型抗原的Th 1细胞免疫应答。最后，本申请中描述的活性将提供关于在恒河猴SIV模型中治疗性DNA疫苗接种（有和没有佐剂）后诱导全身和粘膜免疫以及病毒载量遏制的重要机制数据。具体而言，拟议的治疗性DNA疫苗试验将允许确定全身细胞应答的强度和质量的重要性、粘膜免疫的作用和肠道病毒储库的重要性，以及DC / T细胞相互作用在治疗性DNA疫苗功效中的重要性。

DESCRIPTION (provided by applicant): The program project application of PowderJect Vaccines, Inc. (PJV) and the University of Pittsburgh entails the evaluation of a therapeutic DNA vaccine regimen for human immunodeficiency virus (HIV) infection using the simian immunodeficiency virus (SIV) model in rhesus macaques. The therapeutic DNA vaccine to be evaluated is a single, CMV promoter-based DNA vaccine vector encoding the gag, RT, and nef products of the 17e Fr clone of SIVmac239. This vaccine will be delivered using the clinically-proven particle-mediated (gene gun) delivery device that has been shown to elicit Th1 humoral and cellular responses in man and monkeys. The design of the SIV DNA vaccine vector is intended to closely mimic a clinical HIV-1 DNA vaccine vector that is on a clinical track for human evaluation via the joint clinical development efforts of GlaxoSmithKline (GSK) and PJV. Therefore, the activities described in this application are an integral part of the GSK/PJV clinical co-development efforts for prophylactic and therapeutic AIDS vaccines and will serve three important functions to promote clinical success. First, these activities will provide non-human primate model validation of the immunogenicity and therapeutic vaccine potential of GSK's clinical DNA vaccine vector strategy in the highly relevant SIV/rhesus monkey model. Our recent DNA vaccine trials in the rhesus model using earlier vectors have proven our ability to induce significant prophylactic and therapeutic effects via particle-mediated DNA vaccine technology, in addition, these activities will allow for the evaluation of an exciting new DNA vaccine adjuvant vector encoding the heat-labile enterotoxin of E. coli. This adjuvant vector has been proven safe in an extensive nonhuman primate safety trial and dramatically augments Th1 cellular immune responses to a variety of model antigens in mice and monkeys. Finally, activities described in this application will provide important mechanistic data regarding the induction of systemic and mucosal immunity and virus load containment following therapeutic DNA vaccination (with and without adjuvant) in the rhesus SIV model. Specifically, the proposed therapeutic DNA vaccine trials will allow for determination of the importance of the strength and quality of systemic cellular responses, the role of mucosal immunity and importance of gut viral reservoirs, and the importance of DC / T cell interactions in therapeutic DNA vaccine efficacy.