Improving the safety profile of DNA prime - protein boost HIV vaccinations

一种多价DMA初免-蛋白加强疫苗（DP 6 -001），由密码子优化的HIV-1 env（A，B，C， 我们的研究小组评估了QS-21佐剂中的gag（C）和gag（E）基因以及同源gp 120蛋白， 临床前研究和I期临床试验。临床试验的数据表明， 引发增强了Env蛋白加强后的抗Env抗体（Ab）应答（参见初步研究）。 这是第一次，这种疫苗的策略，引发抗体，称为'DNA总理/蛋白加强，'是 在人类中用于HIV疫苗的开发。特别令人鼓舞的是， 抗同源和异源原代分离株的中和抗体（NAb）。此外，T DP 6 -001疫苗接种也诱导了针对Gag和Env的细胞应答，表明DNA 引发蛋白加强策略有可能引发抗HIV NAb和细胞免疫。 虽然这些结果令人兴奋，但人体试验也揭示了意外的反应性并发症 在家兔临床前IND启用安全性/毒理学试验或非人 灵长类研究1例受试者一过性发生白细胞破碎性血管炎（LCV）， 接受最高的DNA引发剂量（7.2mg肌内），随后是单一蛋白免疫。 同样，来自该高剂量DNA预激组的所有其他5例受试者也表现出反应原性AE 如自我报告的肌痛、低烧和单一蛋白质加强后的头痛所证明的。 这些结果使我们意识到一种可接受的艾滋病毒疫苗的边界条件： 尽管免疫原性良好，但过度的反应原性可能限制这种疫苗的广泛部署。 由于这一经验，我们重新调整了项目2中的研究，以尽量减少 反应原性，因为我们优化免疫原性。目的1将使用小鼠比较细胞因子谱和TLR 当蛋白加强包括QS-21时，接受低和高DNA初免的小鼠之间的反应， 包括在DP 6 -001中。目标2将使用从目标1中获得的信息来测试其他佐剂的效果 （单磷酰脂质A、Montanide伊萨51和明矾）可能具有较低的反应原性， 保持高免疫原性。目标3将检查候选疫苗的反应原性， 当DNA疫苗通过电穿孔递送时，小鼠的免疫应答。Aim 4将测试下一代多价 Env制剂（包括优化的佐剂和DNA递送方法）在恒河猴中的应用，以评估其 免疫原性、安全性和保护免受病毒攻击的能力。

A polyvalent DMA prime-protein boost vaccine (DP6-001), consisting of codon optimized HIV-1 env (A, B, C, E) and gag (C) genes and homologous gp120 proteins in QS-21 adjuvant, was evaluated by our team in both preclinical studies and in a Phase I clinical trial. Data from the clinical trial demonstrated that DNA priming enhanced the anti-Env antibody (Ab) response following Env protein boost (see Preliminary Studies). This was the first time that this vaccine strategy for eliciting Ab, termed 'DNA prime/protein boost,' was demonstrated in humans for HIV vaccine development. Especially encouraging was the detection of neutralizing antibodies (NAbs) against both homologous and heterologous primary isolates. In addition, T cell responses against Gag and Env were also induced by DP6-001 vaccination, indicating that the DNA prime-protein boost strategy has the potential to elicit both anti-HIV NAbs and cellular immunity. While these results were exciting, the human trial also revealed unanticipated reactogenic complications that were not seen in either the preclinical, IND-enabling safety/toxicology testing in rabbits or the nonhuman primate studies. A single case of leukocytoclastic vasculitis (LCV) that transiently occurred in a subject who received the highest DNA priming dose (7.2 mg intramuscularly) followed by a single protein immunization. Similarly, all of the other five subjects from this high dose DNA priming group also exhibited reactogenic AEs as evidenced by self-reported myalgias, low grade fever and headaches following the single protein boost. These results have made us aware of a boundary condition for an acceptable HIV vaccine: while strong immunogenicity is good, excessive reactogenicity could limit the widespread deployment of such a vaccine. As a result of this experience, we have reconfigured our studies in Project 2 in an effort to minimize reactogenicity as we optimize immunogenicity. Aim 1 will use mice to compare the cytokine profile and TLR responses between mice receiving low and high DNA prime when protein boost includes QS-21 which was included in DP6-001. Aim 2 will use the information learned from Aim 1 to test the effect of other adjuvants (monophosphoryl lipid A, Montanide ISA 51 and alum) that may have lower potential for reactogenicity while maintaining the high immunogenicity. Aim 3 will examine the reactogenicity of the candidate vaccines in mice when DNA vaccine is delivered by electroporation. Aim 4 will test the next generation of polyvalent Env formulation (including optimized adjuvant and DNA delivery method) in rhesus macaques to assess their immunogenicity, safety, and ability to protect from a viral challenge.