Optimization of a Therapeutic HIVSIV Multi-Antigen DNA Vaccine

艾滋病毒大流行是历史上最大的公共卫生挑战之一。据估计，有3 300万人感染艾滋病毒，其中270万人是新感染者。在一些发达国家，由于使用高效抗逆转录病毒疗法，与艾滋病毒1型感染有关的死亡风险急剧下降。不幸的是，新的艾滋病毒感染率仍然没有减少，即使预防方案和高效抗逆转录病毒疗法的可用性不断增加。因此，迫切需要一种能够预防或控制艾滋病毒传播的疫苗。最近的一项研究表明，与新型佐剂共同配制的皮肤递送治疗性DNA疫苗刺激了SIV感染的猕猴中的粘膜T细胞应答，并在停止ART后在一部分动物中导致了持久的病毒抑制。这些结果与以前采用肌肉内递送DNA的治疗性疫苗形成鲜明对比，这些疫苗未能诱导效果，诱导病毒血症减少1-2个对数或病毒反弹的瞬时控制。我们建议通过以下方式使治疗性DNA疫苗接种更加有效：1）使用更有效的药物组合（cART）以使疫苗的效果最大化，2）使用更有效的佐剂策略，其增加DNA疫苗对抗体和T细胞应答的诱导并刺激这些应答归巢至肠道相关淋巴组织，和3）使用新的电穿孔DNA递送装置，其更有效地将DNA递送到皮肤（比肌肉更具有免疫活性的部位，用于诱导全身和粘膜反应）中。我们的总体假设是，疫苗诱导的功能性治愈将由强烈的粘膜反应介导，并且通过使用优化的粘膜佐剂和递送到皮肤中来增加和集中这些对肠道的反应以最大限度地抑制感染，将最大限度地减少或防止停止cART后残留病毒从肠道储库中出现。为此，我们已经组装了一组四个基于DNA的佐剂，我们假设将诱导强大的抗HIV粘膜和全身免疫反应时，组合。在这种快速SBIR下，我们将研究与我们的HIV/SIV多抗原（MAG）DNA疫苗的佐剂组合，所述疫苗由表达env（gp 160）的质粒、gag/pol融合物和nef/达特/vif融合物组成。我们预计，这些佐剂的最佳组合将使我们的MAG DNA疫苗的性能提高到值得人体试验的水平。

DESCRIPTION: The HIV pandemic is one of the greatest public health challenges in history. It is estimated that 33 million people are living with HIV and 2.7 million of those are newly infected In a number of developed countries, the risk of death associated with HIV-1 infection has sharply declined due to the use of highly active antiretroviral therapy (HAART). Unfortunately, the rate of new HIV infections remains undiminished, even with the ever increasing availability of prevention programs and HAART. For these reasons, a vaccine that could prevent or control the spread of HIV is urgently needed. A recent study showed that a skin-delivered therapeutic DNA vaccine co-formulated with a novel adjuvant stimulated mucosal T cell responses in SIV-infected macaques and led to durable viral suppression in a subset of animals after stopping ART. These results are in striking contrast to previous therapeutic vaccines employing intramuscular delivery of DNA that failed to induce an effect or at best, induced a 1-2 log reduction in viremia or transient control of viral rebound. We propose to make therapeutic DNA vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a more potent adjuvant strategy that increases DNA vaccine induction of antibody and T cell responses and stimulates homing of these responses to gut associated lymphoid tissues, and 3) using a novel electroporation DNA delivery device that more efficiently delivers DNA into the skin (a more immunocompetent site than muscle for induction of systemic and mucosal responses). Our overarching hypothesis is that a vaccine-induced functional cure will be mediated by strong mucosal responses, and that increasing and focusing these responses to the gut in maximally suppressed infections via use of an optimized mucosal adjuvant and delivery into skin will maximally reduce or prevent residual viruses from emerging from the gut reservoir after stopping cART. To this end, we have assembled a panel of four DNA-based adjuvants that we hypothesize will induce robust anti-HIV mucosal and systemic immune responses when combined. Under this fast track SBIR, we will investigate adjuvant combinations with our HIV/SIV multi-antigen (MAG) DNA vaccine consisting of plasmids expressing env (gp160), a gag/pol fusion, and a nef/tat/vif fusion. We anticipate that an optimal combination of these adjuvants will elevate the performance of our MAG DNA vaccine to a level worthy of human trials.