Therapeutic vaccination and PD-1 blockade in treated HIV disease

摘要 我们项目的核心前提是，在没有抗逆转录病毒治疗的情况下， 缓解（“缓解”）将需要重新产生有效和持续的HIV特异性CD 8+细胞应答， 靶向进化上保守的表位。我们的计划受到VGX-3100（Inovio）最近成功的启发， 一种HPV的DNA治疗性疫苗，可导致人类癌前病变的组织病理学消退 并与HPV特异性CD 8 + T细胞群的有效、持续的增强有关。一个密切相关 已经研究了多进化枝gag/pol/env DNA疫苗（PENNVAX，Inovio）用于HIV预防，并且已知其 既安全又具有高度免疫原性。这种新方法的治疗潜力是未知的， 这是我们前两年的工作重点。然而，我们充分意识到， 单独使用（PENNVAX-GP）不太可能足以实现疾病缓解。存在预先存在 已知在治疗HIV疾病期间持续存在的逃逸突变和免疫失调将阻碍疫苗接种 有效性和辅助方法可能是必要的。在头两年，我们将确定是否IL- 12可以增强该疫苗的免疫原性。这项工作是基于非人类的广泛经验 在灵长类动物和未感染HIV的成人中显示IL-12增强DNA疫苗的免疫原性。在第3年至 5，我们将确定使用pembrolizumab（Merck）阻断PD-1是否会增强疫苗的有效性。本研究 将可能首次测试在主动疫苗接种期间阻断PD-1是否会改善免疫广度， 反应并增加效应细胞的数量。我们的研究将利用我们的相当大的优势 建立了多学科研究小组，以寻求高度创新的方法来衡量疫苗 免疫原性和病毒库。如果我们成功了，我们将在这个节目结束时， 一种可行的疫苗策略，具有可管理的安全性特征，并且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.