Therapeutic vaccination and PD-1 blockade in treated HIV disease

摘要 我们计划的中心前提是在没有抗逆转录病毒治疗的情况下持久控制艾滋病毒 (“缓解”)将需要产生新的有效和持续的艾滋病毒特异性CD8细胞反应， 靶标在进化上保守的表位。我们的计划灵感来自于最近成功的VGX-3100(Inovio)， 一种可导致人类癌前病变组织病理学消退的HPV DNA治疗性疫苗 并与对HPV特异性CD8 T细胞群的有效、持续的促进有关。一个密切相关的 多分支Gag/pol/env DNA疫苗(PENNVAX，Inovio)已被研究用于预防HIV，并已知 既安全又具有高度的免疫原性。这种新方法的治疗潜力是未知的，也将是 前两年的工作重点。然而，我们充分意识到，DNA疫苗的接种 单独使用(PENNVAX-GP)不太可能足以实现疾病缓解。预先存在的存在 已知在艾滋病治疗期间持续存在的逃逸突变和免疫失调将阻碍疫苗 有效性和辅助性方法可能是必需的。在头两年，我们将确定IL- 12可增强该疫苗的免疫原性。这项工作是基于对非人类的丰富经验 在灵长类动物和未感染艾滋病毒的成年人中，IL-12可增强DNA疫苗的免疫原性。在第三年到第三年 5，我们将确定用培溴利珠单抗(默克)阻断PD-1是否会增强疫苗效力。本研究 如果在主动疫苗接种期间阻断PD-1是否能改善免疫广度，可能会进行首次测试 并增加效应细胞的数量。我们的研究将利用我们的 建立多学科研究团队，寻求高度创新的疫苗测量方法 免疫原性和病毒库。如果我们成功了，我们将在这个项目结束时 可行的疫苗战略，具有可管理的安全概况，并已知具有高度免疫原性。

ABSTRACT The central premise of our program is that durable control of HIV in the absence of antiretroviral therapy (“remission”) will require the generation of de novo potent and sustained HIV-specific CD8+ cell responses that target evolutionarily conserved epitopes. Our program is inspired by the recent success of VGX-3100 (Inovio), a DNA therapeutic vaccine for HPV that leads to histopathologic regression of pre-malignant lesions in people and is associated with a potent, sustained boost to HPV-specific CD8+ T cell populations. A closely related multi-clade gag/pol/env DNA vaccine (PENNVAX, Inovio) has been studied for HIV prevention and is known to be both safe and highly immunogenic. The therapeutic potential of this novel approach is unknown and will be the focus of our work in the first two years. We are fully aware, however, that administration of a DNA vaccine alone (PENNVAX-GP) will unlikely be sufficient to achieve a disease remission. The presence of pre-existing escape mutations and immune dysregulation known to persist during treated HIV disease will hamper vaccine effectiveness, and adjuvant approaches will be likely be needed. In the first two years, we will determine if IL- 12 can enhance immunogenicity of this vaccine. This work is based on extensive experience in non-human primates and in HIV-uninfected adults showing IL-12 enhances immunogenicity of DNA vaccines. In Years 3 to 5, we will determine if PD-1 blockade with pembrolizumab (Merck) enhances vaccine effectiveness. This study will likely test for the first time if PD-1 blockade during active vaccination improves the breadth of the immune response and increases the numbers of effector cells. Our study will leverage the considerable strengths of our established multi-disciplinary research team to pursue highly innovative approaches to measuring vaccine immunogenicity and the viral reservoir. Should we be successful, we will have at the end of this program a viable vaccine strategy that has a manageable safety profile and is known to be highly immunogenic.