Ad26 Based Therapeutic Vaccines for HIV

治疗性疫苗接种的目标是增加宿主对HIV-1的免疫控制，以实现持久的病毒学治疗。 在没有ART的情况下进行控制，其被定义为“功能性治愈”。然而，治疗性疫苗研究在 人类迄今为止基本上是不成功的。我们推测，这可能反映了这样一个事实，即先前的疫苗 (i)未能诱导足够广度的细胞免疫应答，和（ii）未有效激活或 瞄准了潜伏的病毒库我们假设一种治疗性疫苗， 免疫反应和激活潜伏的病毒库将减少复制的大小- 有能力的病毒储存库，并将在ART停药后加强病毒控制。 我们已经表明，Ad 26/MVA治疗性疫苗接种与TLR 7的先天免疫刺激一起， 激动剂导致病毒学控制在SIV感染的恒河猴的一个子集后，ART中断。 因此，我们建议评估Ad 26/MVA + TLR 7激动剂疫苗的免疫原性和有效性， HIV-1感染者，以确定其在停止ART后控制病毒复制的能力。 我们还假设，广泛中和抗体（bNAb）的加入可能会增强抗病毒作用。 治疗性疫苗的功效。为了优化主动和被动免疫，我们提出了一项后续研究 评价最佳治疗性疫苗与bNAb在HIV-1感染者中的作用。 因此，我们提出以下两个具体目标： 具体目标1。评价Ad 26/MVA治疗性免疫缺陷病毒的安全性、免疫原性和有效性， 在HIV-1感染的人中施用TLR 7激动剂的疫苗接种 具体目标2。评价Ad 26/MVA治疗性免疫缺陷病毒的安全性、免疫原性和有效性， 在HIV-1感染者中接种广泛中和抗体（bNAb）和TLR 7激动剂

The goal of therapeutic vaccination is to increase host immune control of HIV-1 to achieve durable virologic control in the absence of ART, which is defined as a “functional cure”. However, therapeutic vaccine studies in humans have to date been largely unsuccessful. We speculate that this may reflect the fact that prior vaccines (i) have failed to induce sufficient breadth of cellular immune responses and (ii) have not effectively activated or targeted the latent viral reservoir. We hypothesize that a therapeutic vaccine that induces potent and broad immune responses and that activates the latent viral reservoir will reduce the size of the replication- competent viral reservoir and will enhance virologic control following ART discontinuation. We have shown that Ad26/MVA therapeutic vaccination together with innate immune stimulation with a TLR7 agonist resulted in virologic control in a subset of SIV-infected rhesus monkeys following ART discontinuation. We therefore propose to evaluate the immunogenicity and efficacy of the Ad26/MVA + TLR7 agonist vaccine in HIV-1-infected humans to define its ability to control viral replication following discontinuation of ART. We also hypothesize that the addition of broadly neutralizing antibodies (bNAbs) may augment the antiviral efficacy of a therapeutic vaccine. To optimize both active and passive immunity, we propose a follow-up study to evaluate the optimal therapeutic vaccine together with bNAbs in HIV-1-infected humans. We therefore propose the following two Specific Aims: Specific Aim 1. To evaluate the safety, immunogenicity, and efficacy of Ad26/MVA therapeutic vaccination with TLR7 agonist administration in HIV-1-infected humans Specific Aim 2. To evaluate the safety, immunogenicity, and efficacy of Ad26/MVA therapeutic vaccination with broadly neutralizing antibodies (bNAbs) and a TLR7 agonist in HIV-1-infected humans