Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA.
Immunity. 2024 Mar 12;57(3):574-586.e7. doi: 10.1016/j.immuni.2024.02.003. Epub 2024 Mar 1.
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.
不断演变的流感病毒会引起季节性流行，并构成全球大流行的威胁。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 抗原表位的理解仍然不完整。在这里，我们描述了针对 NA 球形头部结构域底面的 NA 特异性人源抗体，这些抗体能够抑制广泛的人源 H3N2、猪源变异 H3N2 和 H2N2 病毒的复制，并在小鼠中提供针对致死性 H3N2 感染的预防和治疗效果。两种此类抗体与 NA 复合物的冷冻电镜结构揭示了非重叠的表位，覆盖了 NA 头部的底面。这些位点在 N2 NA 中高度保守，但除非 NA 头部倾斜或解离，否则无法接触到这些位点。我们的研究结果通过确定 NA 底面的隐藏保守脆弱性位点，有助于指导针对不断变化的流感病毒的有效对策的开发。
