Ad26 Based Therapeutic Vaccines for HIV

治疗性疫苗接种的目标是加强对HIV-1的宿主免疫控制，以实现持久的病毒学 在没有抗逆转录病毒治疗的情况下进行控制，这被定义为“功能性治愈”。然而，中国的治疗性疫苗研究 到目前为止，人类在很大程度上没有成功。我们推测，这可能反映了以前的疫苗 (I)未能诱导足够广泛的细胞免疫反应；及(Ii)未有效地激活或 目标是潜伏的病毒库。我们假设一种治疗性疫苗能够诱导出强大而广泛的 免疫反应和激活潜伏的病毒库将减少复制的大小- 并将在ART停用后加强病毒学控制。 我们已经证明，AD26/MVA治疗性疫苗接种与TLR7先天免疫刺激相结合 在ART停用后，激动剂在SIV感染的恒河猴的子集中导致了病毒学控制。 因此，我们建议评估AD26/MVA+TLR7激动剂疫苗的免疫原性和效力。 确定停止抗逆转录病毒疗法后其控制病毒复制的能力。 我们还假设，广谱中和抗体(BNAbs)的加入可能会增强抗病毒作用。 治疗性疫苗的疗效。为了优化主动免疫和被动免疫，我们建议进行后续研究。 目的：评价HIV-1感染者的最佳治疗性疫苗和bNAbs。 因此，我们提出以下两个具体目标： 具体目的1.评价AD26/MVA治疗的安全性、免疫原性和疗效 用TLR7激动剂接种HIV-1感染者的疫苗 具体目的2.评价AD26/MVA治疗的安全性、免疫原性和疗效 广谱中和抗体和TLR7激动剂在HIV-1感染者中的免疫接种

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