Comparison of Dendritic Cell-Based Therapeutic Vaccine Strategies for HIV Functional Cure

项目总结 以树突状细胞(DC)为基础的治疗性疫苗在控制HIV复制方面显示出最大的前景 没有抗逆转录病毒治疗(ART)。尽管两项开创性的临床试验显示， 与疫苗诱导的HIV特异性免疫反应相关的无ART的血浆病毒血症，其他 以DC为基础的疫苗研究表明，病毒学效果不明确或没有效果。以DC为基础的 疫苗的理论能力，得到了效应性T细胞启动的强大体外证据的支持，以及 临床试验的不同结果，突显了在理解DC疫苗决定因素方面的重要差距 体内药效。因此，我们建议进行比较分析，以确认DC疫苗的先前效力，并 测试新的、创新的DC疫苗，双重目标是提高病毒学效力和确定关键 DC疫苗效力的决定因素。具体地说，我们将进行第一阶段/第二阶段，随机，双重- 比较四种不同DC疫苗和两种不同DC疫苗安全性和抗HIV效果的盲法试点研究 相应的安慰剂。该试验将评估两种DC成熟技术(前列腺素E2成熟 DC，在两个开创性的临床试验中部分有效，以及阿尔法-1型DC，它有 在体外表现出更好的抗原提呈和T细胞启动功能)，两种HIV免疫原(完整的， 在两个试验中部分有效的灭活的自体艾滋病毒，以及覆盖 GAG和POL中最高度保守的区域与已知与控制白粉病相关的表位相结合 未经治疗的艾滋病毒感染者的病毒血症)和两种给药策略(3剂对6剂)。初见成效 结果将从接种前的可诱导艾滋病毒储存库改变为最终疫苗接种后的2周 剂量。我们还将进一步评估DC疫苗的体内抗HIV效果。 分析疫苗引起的病毒学和免疫学参数的变化，次要目标是 确定疫苗诱导的病毒学反应的免疫相关性。测量的参数将包括 残存血浆病毒血症、HIV感染细胞数量和转录活性、CD8T细胞抑制 自体病毒复制、免疫反应的大小、广度和多功能性，以及 免疫调节反应包括调节性T细胞和髓系来源的抑制细胞。我们提出了一个 第二次临床试验，以评估第一次试验的初步结果的重复性，并评估 进一步完善DC疫苗的效力设计。我们为以下目标制定了预先指定的通过/不通过标准 继续进行第二次审判。是否将在第二个月评估特定的DC疫苗 试验将基于第一次试验的主要和次要病毒学和免疫学终点。这 创新、顺序和迭代的方法将评估多种DC疫苗，阐明决定因素 疫苗效力，确定疫苗导致艾滋病毒宿主减少的免疫相关因素，并提供新的 对DC疫苗在没有抗逆转录病毒治疗的情况下实现艾滋病毒持久缓解的潜力的洞察。

PROJECT SUMMARY Dendritic cell (DC)-based therapeutic vaccines have shown the most promise for controlling HIV replication without antiretroviral therapy (ART). Although two seminal clinical trials demonstrated significant decreases in plasma viremia without ART that were associated with vaccine-induced HIV-specific immune responses, other DC-based vaccine studies have shown equivocal or no virologic efficacy. The disconnect between a DC-based vaccine's theoretical capability, supported by strong in vitro evidence of priming of effector T-cells, and the variable results of clinical trials, highlight important gaps in understanding the determinants of DC vaccine efficacy in vivo. We therefore propose a comparative analysis to confirm prior efficacy of DC vaccines and to test new, innovative DC vaccines with the dual goals of improving virological efficacy and identifying key determinants of DC vaccine efficacy. Specifically, we will conduct an initial phase I/II, randomized, double- blind, pilot study to compare safety and anti-HIV efficacy of four different DC-based vaccines and two corresponding placebos. The trial will evaluate two DC maturation techniques (the prostaglandin E2-matured DCs, which were partially effective in the two seminal clinical trials, and the alpha-type-1 DCs, which have shown improved antigen-presenting and T-cell priming function ex vivo), two HIV immunogens (whole, inactivated, autologous HIV that was partially effective in the two trials, and a pool of HIV peptides covering the most highly-conserved regions in Gag and Pol combined with epitopes known to be associated with control of viremia in untreated HIV-infected individuals), and two dosing strategies (3 vs 6 doses). The primary efficacy outcome will be change in the inducible HIV reservoir from pre-vaccination to 2 weeks after the final vaccine dose. We will also further evaluate the in vivo anti-HIV efficacy of the DC vaccines by performing an extensive analysis of vaccine-induced changes in virologic and immunologic parameters with the secondary goal of identifying immune correlates of vaccine-induced virologic responses. The parameters measured will include residual plasma viremia, the number and transcriptional activity of HIV-infected cells, CD8+ T-cell inhibition of autologous virus replication, the magnitude, breadth, and polyfunctionality of immune responses, and immunoregulatory responses including regulatory T-cells and myeloid-derived suppressor cells. We propose a second clinical trial to assess reproducibility of initial findings from the first trial and to assess the impact of further refinements of DC vaccine designs on efficacy. We have developed pre-specified Go/No-Go criteria for moving forward to a second trial. The decision whether a specific DC vaccine will be evaluated in the second trial will be based on the primary and secondary virologic and immunologic endpoints of the first trial. This innovative, sequential, and iterative approach will evaluate multiple DC vaccines, elucidate determinants of vaccine efficacy, identify immune correlates of vaccine-induced reductions in HIV reservoirs, and provide new insights into the potential for DC vaccines to achieve durable HIV remission without ART.