Optimization of an innate immune stimulating adjuvant for an HIV DNA vaccine

产品说明：越来越多的共识是，针对HIV感染的保护需要抗病毒抗体应答以及具有强效裂解活性的多功能CD 4+和CD 8 + T细胞。为了刺激所需的反应的广度、效力和速率，Profectus Biosciences打算利用其基于DNA疫苗与遗传佐剂结合的电穿孔的平台技术。作为朝着这个方向迈出的一步，最近的一项1期临床试验HVTN-080显示，与单独电穿孔相比，电穿孔与我们的IL-12佐剂组合可以使疫苗接种者的CD 4+和CD 8 + T细胞应答率增加一倍1。即使取得了这一成功，我们也认识到，真正有效的艾滋病毒疫苗将需要一种方案，该方案可以以>95%的比率持续提供高强度、长寿命的应答，同时尽可能少地进行加强免疫。我们认为佐剂是开发这种疫苗的关键。在先前的I期SBIR中，我们鉴定了一类新的遗传佐剂，其利用RIG-1信号级联并触发有效的抗病毒先天免疫应答。这些先天性应答与TLR诱发的先天性应答和DAMP/alarmin整合以诱发有效的抗病毒适应性免疫应答。我们证明了这些新佐剂具有与“金标准”遗传佐剂IL-12相当的活性。不幸的是，这些佐剂的性能没有达到我们进展到II期的里程碑，这是优于IL-12的。我们随后发现，由这些新佐剂产生的I型干扰素严重减弱由CMV启动子驱动的DNA疫苗质粒的疫苗抗原表达。在该后续I期SBIR中，我们将鉴定一种前导干扰素不敏感启动子以驱动我们的疫苗抗原和佐剂表达，并在小鼠研究中用我们的前导RIG-1通路活化佐剂测试该启动子，将其活性与IL-12进行比较。我们完全预期，由干扰素不敏感启动子驱动的我们的主要RIG-1途径激活佐剂将产生我们最初对该佐剂预期的结果，因此将达到或超过我们进行II期的里程碑。在第二阶段，我们将联合收割机将这种主要的RIG-1通路激活佐剂与我们的其他佐剂在猕猴中结合，以引起被认为最适合预防/对抗HIV感染的类型的有效的抗病毒先天性和适应性免疫应答。

DESCRIPTION: There is a growing consensus that protection against HIV infection will require BOTH antiviral antibody responses as well as polyfunctional CD4+ and CD8+ T cells with potent lytic activity. To stimulate the breadth, potency, and rate of response required, Profectus Biosciences intends to utilize its platform technologies based on electroporation of DNA vaccines combined with genetic adjuvants. As a step in that direction, a recent phase 1 clinical trial, HVTN-080, showed that electroporation in combination with our IL-12 adjuvant can double the CD4+ and CD8+ T cell response rate in vaccinees over electroporation alone1. Even with this success, we recognize that a truly effective HIV vaccine will require a regimen that can consistently provide high magnitude, long-lived responses at rates >95% with as few booster immunizations as possible. We believe that adjuvants are a key to developing such a vaccine. Under a previous phase I SBIR, we identified a new class of genetic adjuvants that exploit the RIG-1 signaling cascades and trigger potent anti-viral innate immune responses. These innate responses integrate with TLR evoked innate responses and DAMPs/alarmins to evoke potent anti-viral adaptive immune responses. We demonstrated that these new adjuvants have comparable activity to the "gold standard" genetic adjuvant IL-12. Unfortunately, the performance of these adjuvants fell short of reaching our milestone for progression to phase II, which was superiority over IL-12. We have subsequently discovered that type I interferons produced by these new adjuvants severely attenuate vaccine antigen expression from our DNA vaccine plasmid that is driven by a CMV promoter. Under this follow-on phase I SBIR, we will identify a lead interferon insensitive promoter to drive our vaccine antigen and adjuvant expression and test this promoter in mouse studies with our lead RIG-1 pathway activating adjuvant comparing its activity to IL-12. We fully anticipate that our lead RIG-1 pathway activating adjuvant driven from an interferon insensitive promoter will yield the results that we originally anticipated for this adjuvant and will therefore meet or exceed our milestone for proceeding to phase II. Under phase II, we will combine this lead RIG-1 pathway activating adjuvant with our other adjuvants in macaques to evoke potent antiviral innate and adaptive immune responses of the type believed best suited to prevent/combat HIV infections.