Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Nat Commun. 2023 Sep 13;14(1):5650. doi: 10.1038/s41467-023-41171-3.
The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.
裂谷热病毒（RVFV）具有人畜共患性，能引起人类的严重疾病，且具有大流行的潜力，但目前尚无获得批准的疫苗或疗法。在这里，我们描述了一种针对 RVFV 的双机制人源单克隆抗体（mAb）组合，在感染的致死性小鼠模型中，以最小剂量即可发挥作用。我们对一种典型的强效 Gn 结构域 A 结合抗体进行了结构分析和特征描述，该抗体能阻止病毒附着，另一种抗体则通过阻断融合过程来抑制感染，这与之前的研究结果一致。令人惊讶的是，通过竞争性测定，Gn 结构域 A 抗体并没有直接阻断 RVFV Gn 与宿主受体低密度脂蛋白受体相关蛋白 1（LRP1）的相互作用。这项研究确定了一种合理设计的人源 mAb 组合，值得进一步研究，以用于人类对抗 RVFV 感染。我们采用双管齐下的机制方法，证明了一种合理设计的组合 mAb 治疗方法具有强大的功效。
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