Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that target the underside of the NA globular head domain, inhibit viral propagation of a wide range of human H3N2, swine-origin variant H3N2, and H2N2 viruses, and confer both pre- and post-exposure protection against lethal H3N2 infection in mice. Cryo-EM structures of two such antibodies in complex with NA reveal non-overlapping epitopes covering the underside of the NA head. These sites are highly conserved among N2 NAs yet inaccessible unless the NA head tilts or dissociates. Our findings help guide the development of effective countermeasures against ever-changing influenza viruses by identifying hidden conserved sites of vulnerability on the NA underside.

中文翻译：

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保护性人单克隆抗体针对流感病毒神经氨酸酶底部的保守脆弱位点

不断进化的流感病毒引起季节性流行并构成全球大流行威胁。尽管病毒神经氨酸酶 (NA) 是一种有效的药物和疫苗靶点，但我们对 NA 抗原状况的了解仍然不完整。在这里，我们描述了 NA 特异性人抗体，其靶向 NA 球状头结构域的下侧，抑制多种人 H3N2、猪源变异 H3N2 和 H2N2 病毒的病毒传播，并赋予暴露前和暴露后防止小鼠致命的 H3N2 感染。与 NA 复合的两种此类抗体的冷冻电镜结构揭示了覆盖 NA 头下侧的非重叠表位。这些位点在 N2 NA 中高度保守，但除非 NA 头部倾斜或解离，否则无法访问。我们的研究结果通过识别 NA 底部隐藏的保守脆弱位点，有助于指导针对不断变化的流感病毒制定有效的对策。