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

一种由密码子优化的HIV-1 env(A，B，C， E)和Gag(C)基因以及QS-21佐剂中的同源gp120蛋白 包括临床前研究和I期临床试验。来自临床试验的数据表明，DNA 启动增强了Env蛋白增强后的抗Env抗体(Ab)反应(见初步研究)。 这是第一次有这样的疫苗策略来激发抗体，这种策略被称为DNA主/蛋白增强。 在人类身上展示了艾滋病毒疫苗的开发。特别令人鼓舞的是发现了 针对同源和异源初级分离株的中和抗体(NAB)。此外，T DP6-001疫苗也能诱导细胞对Gag和Env的免疫应答。 Prime-Protein Boost策略有可能同时诱导抗HIV nab和细胞免疫。 虽然这些结果令人兴奋，但人体试验也发现了意想不到的反应性并发症。 在对兔子或非人类的临床前、启用IND的安全/毒理学测试中都没有发现 灵长类研究。一例一过性白细胞破碎性血管炎(LCV)发生在一名 接受最高DNA预备量(7.2 mg肌肉注射)，然后进行单蛋白免疫。 同样，来自高剂量DNA引导组的所有其他五名受试者也都表现出反应性AEs 自我报告的肌痛、低烧和单一蛋白质增强后的头痛就是明证。 这些结果让我们意识到了可接受的艾滋病毒疫苗的边界条件：虽然 免疫原性很好，过度的反应性可能会限制这种疫苗的广泛应用。 由于这一经历，我们在项目2中重新配置了我们的研究，以努力将 在我们优化免疫原性的同时，也提高了反应性。AIM 1将使用小鼠来比较细胞因子谱和TLR 当蛋白质Boost包括QS-21时，接受低和高DNA刺激的小鼠之间的反应 包括在DP6-001中。目标2将使用从目标1学到的信息来测试其他佐剂的效果 (单磷酰脂A、蒙丹尼德ISA 51和明矾)，可能具有较低的反应性潜力，而 保持较高的免疫原性。目标3将检查候选疫苗的反应性 当DNA疫苗通过电穿孔传递给小鼠时。AIM 4将测试下一代多价 恒河猴环状病毒制剂(包括优化佐剂和DNA给药方法)的研究 免疫原性、安全性和抵御病毒挑战的能力。

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.