The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome
The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome
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DOI：
10.1128/aac.02457-15
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发表时间：
2016-04-01
影响因子：
4.9
通讯作者：
Govorkova, Elena A.
中科院分区：
文献类型：
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作者：
Baranovich, Tatiana;Jones, Jeremy C.;Govorkova, Elena A.
大多数严重流感病例与肺部并发症有关，如急性呼吸窘迫综合征（ARDS），目前尚无经证实有价值的抗病毒药物可用于治疗此类并发症。使用靶向流感病毒表面血凝素（HA）的茎的单克隆抗体是用于控制多种HA亚型的病毒的快速发展的策略。然而，这些抗体的作用机制尚未完全了解，其减轻流感严重并发症的能力研究甚少。我们评估了用VIS 410（一种靶向HA干区的人单克隆抗体）治疗对感染甲型流感（H7N9）病毒后BALB/c小鼠中ARDS发展的影响。预防性施用VIS 410导致小鼠完全保护免于致死性A（H7N9）病毒攻击。在病毒接种后24小时给予单次治疗剂量的VIS 410导致高达100%的接种有神经氨酸酶释放物敏感或耐药性A（H7N9）病毒的小鼠的剂量依赖性保护。与模拟治疗对照的结果相比，单次施用VIS 410改善了病毒从肺中的清除，以剂量依赖性方式减少了病毒在肺中的传播，导致较低的肺损伤评分，降低了肺血管通透性和支气管肺泡灌洗液中蛋白质积累的改变程度，并改善了肺生理功能。因此，靶向HA干细胞的抗体可以降低ARDS的严重程度，并显示出作为控制流感肺部并发症的药物的前景。
Most cases of severe influenza are associated with pulmonary complications, such as acute respiratory distress syndrome (ARDS), and no antiviral drugs of proven value for treating such complications are currently available. The use of monoclonal antibodies targeting the stem of the influenza virus surface hemagglutinin (HA) is a rapidly developing strategy for the control of viruses of multiple HA subtypes. However, the mechanisms of action of these antibodies are not fully understood, and their ability to mitigate severe complications of influenza has been poorly studied. We evaluated the effect of treatment with VIS410, a human monoclonal antibody targeting the HA stem region, on the development of ARDS in BALB/c mice after infection with influenza A(H7N9) viruses. Prophylactic administration of VIS410 resulted in the complete protection of mice against lethal A(H7N9) virus challenge. A single therapeutic dose of VIS410 given 24 h after virus inoculation resulted in dose-dependent protection of up to 100% of mice inoculated with neuraminidase inhibitor-susceptible or -resistant A(H7N9) viruses. Compared to the outcomes in mock-treated controls, a single administration of VIS410 improved viral clearance from the lungs, reduced virus spread in lungs in a dose-dependent manner, resulting in a lower lung injury score, reduced the extent of the alteration in lung vascular permeability and protein accumulation in bronchoalveolar lavage fluid, and improved lung physiologic function. Thus, antibodies targeting the HA stem can reduce the severity of ARDS and show promise as agents for controlling pulmonary complications in influenza.