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

项目摘要 基于树突状细胞（DC）的治疗性疫苗显示出控制HIV复制的最大希望 没有抗逆转录病毒治疗（ART）。尽管两项开创性的临床试验表明， 与疫苗诱导的HIV特异性免疫应答相关的血浆病毒血症，其他 基于DC的疫苗研究显示不明确或无病毒学疗效。基于DC的 疫苗的理论能力得到了效应T细胞引发的强有力的体外证据的支持，并且 临床试验的可变结果，突出了在理解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疫苗的既往疗效， 测试新的、创新的DC疫苗，其双重目标是提高病毒学疗效和确定关键的 DC疫苗效力的决定因素。具体而言，我们将进行初始I/II期，随机，双- 一项盲法初步研究，比较四种不同的DC疫苗和两种 相应的安慰剂。该试验将评估两种DC成熟技术（前列腺素E2成熟的DC成熟技术）。 在两项开创性临床试验中部分有效的DCs，以及α-1型DCs， 显示出改进的抗原呈递和离体T细胞引发功能），两种HIV免疫原（全， 灭活的自体HIV，在两项试验中部分有效，以及一组HIV肽， Gag和Pol中最高度保守的区域与已知与控制 未经治疗的HIV感染个体中的病毒血症）和两种给药策略（3剂vs 6剂）。主要疗效 结果将是从接种前到最终疫苗接种后2周诱导型HIV储库的变化 次给药结束我们还将进一步评估DC疫苗的体内抗HIV功效， 分析疫苗诱导的病毒学和免疫学参数变化，次要目标为 鉴定疫苗诱导的病毒学应答的免疫相关性。测量的参数将包括 残余血浆病毒血症，HIV感染细胞的数量和转录活性，CD 8 + T细胞抑制， 自体病毒复制，免疫应答的幅度、广度和多功能性，以及 免疫调节应答包括调节性T细胞和骨髓来源的抑制细胞。我们提出了一个 第二项临床试验，以评估第一项试验的初步结果的重现性，并评估 DC疫苗设计在功效上的进一步改进。我们制定了预先规定的Go/No-Go标准， 进行第二次审判决定是否在第二阶段评估特定的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 创新的、连续的和迭代的方法将评估多种DC疫苗，阐明 疫苗效力，确定疫苗诱导的HIV宿主减少的免疫相关性，并提供新的 深入了解DC疫苗在没有ART的情况下实现持久HIV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.