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

描述：人们越来越一致地认为，对艾滋病毒感染的保护将需要抗病毒抗体反应以及具有强大溶解活性的多功能CD4+和CD8+T细胞。为了刺激所需的广度、效力和反应速度，教授生物科学公司打算利用其基于DNA疫苗电穿孔和遗传佐剂的平台技术。作为朝着这个方向迈出的一步，最近的一项第一阶段临床试验，HVTN-080，表明电穿孔与我们的IL-12佐剂相结合，可以使接种疫苗的CD4+和CD8+T细胞响应率比单独使用电穿孔1翻一番。即使取得了这样的成功，我们也认识到，真正有效的艾滋病毒疫苗将需要一种方案，在尽可能少的加强免疫的情况下，能够以95%的比率持续提供高强度、长期的应答率。我们认为佐剂是开发这种疫苗的关键。在之前的第一阶段SBIR中，我们发现了一类新的基因佐剂，它们利用RIG-1信号级联反应，触发强大的抗病毒先天性免疫反应。这些先天反应与TLR诱导的先天反应和DAMPS/ALARMIN结合，可激发强大的抗病毒获得性免疫反应。我们证明了这些新的佐剂具有与“黄金标准”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第二阶段的里程碑，这是优于IL-12的。我们随后发现，由这些新佐剂产生的I型干扰素严重减弱了由CMV启动子驱动的DNA疫苗质粒中疫苗抗原的表达。在这一后续的I期SBIR中，我们将确定一个铅干扰素不敏感启动子来驱动我们的疫苗抗原和佐剂表达，并在小鼠研究中测试该启动子，使用我们的领先RIG-1途径激活佐剂，比较其与IL-12的活性。我们完全预计，我们的主导RIG-1途径激活由干扰素不敏感启动子驱动的佐剂将产生我们最初预期的这种佐剂的结果，因此将达到或超过我们进入第二阶段的里程碑。在第二阶段，我们将在猕猴中将激活佐剂的主导RIG-1途径与我们的其他佐剂结合起来，以激发被认为最适合预防/抗击HIV感染的强大的抗病毒先天和获得性免疫反应。

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.