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

项目概要 基于树突状细胞 (DC) 的治疗性疫苗显示出最有希望控制 HIV 复制 未经抗逆转录病毒治疗（ART）。尽管两项开创性的临床试验表明， 未经 ART 治疗的血浆病毒血症与疫苗诱导的 HIV 特异性免疫反应相关，其他 基于 DC 的疫苗研究显示病毒学功效不明确或没有。基于直流电之间的断开 疫苗的理论能力，得到效应 T 细胞启动的强有力的体外证据的支持，以及 临床试验的不同结果凸显了在了解 DC 疫苗决定因素方面的重要差距 体内功效。因此，我们建议进行比较分析，以确认 DC 疫苗的先前功效并 测试新的、创新的 DC 疫苗，其双重目标是提高病毒学功效和确定关键 DC 疫苗功效的决定因素。具体来说，我们将进行初始 I/II 期、随机、双 盲法试点研究比较四种不同 DC 疫苗和两种疫苗的安全性和抗 HIV 功效 相应的安慰剂。该试验将评估两种 DC 成熟技术（前列腺素 E2 成熟技术） DC 在两项开创性临床试验中部分有效，而 α-1 型 DC 在 显示出改进的抗原呈递和离体 T 细胞启动功能），两种 HIV 免疫原（完整、 灭活的自体 HIV 在这两项试验中部分有效，并且涵盖了 HIV 肽库 Gag 和 Pol 中最高度保守的区域与已知与控制相关的表位相结合 未经治疗的 HIV 感染者的病毒血症），以及两种剂量策略（3 剂与 6 剂）。主要功效 从疫苗接种前到最终疫苗接种后 2 周，诱导型 HIV 病毒库的结果将发生变化 剂量。我们还将通过广泛的研究来进一步评估 DC 疫苗的体内抗 HIV 功效。 分析疫苗引起的病毒学和免疫学参数的变化，次要目标是 识别疫苗诱导的病毒学反应的免疫相关性。测量的参数将包括 残留血浆病毒血症、HIV 感染细胞的数量和转录活性、CD8 T 细胞抑制 自体病毒复制，免疫反应的程度、广度和多功能性，以及 免疫调节反应，包括调节性 T 细胞和骨髓源性抑制细胞。我们提出一个 第二次临床试验，评估第一次试验初步结果的可重复性，并评估 进一步完善 DC 疫苗设计的功效。我们已经制定了预先指定的通过/不通过标准 进入二审。决定是否在第二次评估特定 DC 疫苗 试验将基于第一项试验的主要和次要病毒学和免疫学终点。这个 创新、连续和迭代的方法将评估多种 DC 疫苗，阐明 疫苗功效，确定疫苗引起的艾滋病毒储存量减少的免疫相关性，并提供新的 深入了解 DC 疫苗在无需 ART 的情况下实现艾滋病毒持久缓解的潜力。

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.