HIV-1 Fusion Peptide-directed Vaccine Design Using Virus-like Particles

项目摘要 在HIV疫苗领域中，对于持续引发有效血清抗体的免疫原存在未满足的需求 中和了在世界范围内广泛传播的HIV-1变异体。最近我们发现了一个新的目标 对于人中和抗体（NAb）：在人抗体（NAb）上的融合肽（FP）的八个N-末端氨基酸。 融合前HIV-1包膜（Env）三聚体（Science 2016）。然后，我们创造了一种新的免疫策略：引发 用与载体蛋白钥孔血蓝蛋白（FP-KLH）结合的FP和HIV-1 Env加强免疫 三聚体。这种策略在涉及小鼠的多项研究中可重复地引发FP定向的交叉反应性NAb， 豚鼠和非人灵长类动物（NHP），但并非所有动物（Nat Med 2018，Cell 2019）。最好的 免疫NHP的单克隆抗体（mAb）中和58株野生型HIV-1菌株的98 序列匹配的免疫原，和59%的208株代表全球病毒，并含有 不同的FP序列因此，FP初免/Env加强是引发NAb应答的有前景的策略。到 为了进一步改进FP导向的疫苗设计，需要解决两个主要限制。第一，中立化 来自免疫动物的多克隆血清的广度仍然有限。二是交叉中和活动 仅在一小部分免疫动物中观察到，并且通常滴度较低。解决这些 局限性，在这项建议中，我们将开发新的FP免疫原和免疫策略，以改善 豚鼠和非豚鼠FP导向反应的宽度（目标1）、幅度（目标2）和质量（目标3） 人类灵长类动物

PROJECT SUMMARY There is an unmet need in the HIV vaccine field for immunogens that consistently elicit potent serum antibodies that neutralize a broad spectrum of HIV-1 variants in circulation worldwide. Recently, we identified a novel target for human neutralizing antibodies (NAbs): the eight N-terminal amino acids of the fusion peptide (FP) on prefusion HIV-1 envelope (Env) trimer (Science 2016). We then created a novel immunization strategy: priming with FP conjugated to the carrier protein keyhole limpet hemocyanin (FP-KLH) and boosting with HIV-1 Env trimer. This strategy has reproducibly elicited FP-directed cross-reactive NAbs in multiple studies involving mice, guinea pigs and non-human primates (NHPs), although not in every animal (Nat Med 2018, Cell 2019). The best monoclonal antibody (mAb) from an immunized NHP neutralized 98% of 58 wild-type HIV-1 strains with FP sequence matching the immunogen, and 59% of 208 strains that represent viruses worldwide and contain diverse FP sequences. Therefore, FP prime/Env boost is a promising strategy for eliciting NAb responses. To further improve FP-directed vaccine design, two main limitations need to be addressed. First, the neutralization breadth of the polyclonal sera from immunized animal is still limited. Second, the cross-neutralizing activities were only observed in a small subset of immunized animals and were generally low-titer. To address these limitations, in this proposal, we will develop novel FP immunogens and immunization strategies to improve the breadth (Aim 1), magnitude (Aim 2) and quality (Aim 3) of the FP-directed responses in guinea pigs and non- human primates.