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

项目总结 在艾滋病毒疫苗领域，对持续诱导有效血清抗体的免疫原的需求尚未得到满足。 这中和了在世界各地流通的广泛的HIV-1变种。最近，我们发现了一个新的目标 对于人中和抗体(NABS)：融合多肽(FP)的八个N末端氨基酸 HIV-1包膜(Env)三聚体(《科学》2016年版)。然后我们创造了一种新的免疫策略：预置 FP与载体蛋白锁孔帽状血蓝蛋白(FP-KLH)的结合及HIV-1 Env的增强作用 特里默。这一策略在涉及小鼠的多项研究中重复地引发了FP导向的交叉反应NAB， 豚鼠和非人类灵长类动物(NHP)，尽管不是在每种动物中(Nat Med 2018，Cell 2019)。最好的 免疫NHP的单抗对58株HIV-1野生型毒株中和率为98% 与免疫原匹配的序列，以及代表世界各地的病毒并含有 不同的FP序列。因此，FP Prime/Env Boost是一种很有前途的诱导NAB反应的策略。至 要进一步改进FP导向疫苗设计，需要解决两个主要限制。第一，中和 来自免疫动物的多克隆血清的广度仍然有限。第二，交叉中和活动 仅在一小部分免疫动物中观察到，且一般效价较低。要解决这些问题 限制，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定向反应的广度(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.