Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Virol. 2019 Mar 5;93(6). doi: 10.1128/JVI.01696-18. Print 2019 Mar 15.
Protection from influenza virus infection is canonically associated with antibodies that neutralize the virus by blocking the interaction between the viral hemagglutinin and host cell receptors. However, protection can also be conferred by other mechanisms, including antibody-mediated effector functions. Here, we report the characterization of 22 broadly cross-reactive, nonneutralizing antibodies specific for influenza B virus hemagglutinin. The majority of these antibodies recognized influenza B viruses isolated over the period of 73 years and bind the conserved stalk domain of the hemagglutinin. A proportion of the characterized antibodies protected mice from both morbidity and mortality after challenge with a lethal dose of influenza B virus. Activity in an antibody-dependent cell-mediated cytotoxicity reporter assay correlated strongly with protection, suggesting that Fc-dependent effector function determines protective efficacy. The information regarding mechanism of action and epitope location stemming from our characterization of these antibodies will inform the design of urgently needed vaccines that could induce broad protection against influenza B viruses. While broadly protective antibodies against the influenza A virus hemagglutinin have been well studied, very limited information is available for antibodies that broadly recognize influenza B viruses. Similarly, the development of a universal or broadly protective influenza B virus vaccine lags behind the development of such a vaccine for influenza A virus. More information about epitope location and mechanism of action of broadly protective influenza B virus antibodies is required to inform vaccine development. In addition, protective antibodies could be a useful tool to treat or prevent influenza B virus infection in pediatric cohorts or in a therapeutic setting in immunocompromised individuals in conjugation with existing treatment avenues.
针对流感病毒感染的保护作用通常与能够通过阻断病毒血凝素与宿主细胞受体之间的相互作用来中和病毒的抗体有关。然而，保护作用也可以通过其他机制来实现，包括抗体介导的效应功能。在这里，我们报告了 22 种广谱交叉反应性、非中和性的针对乙型流感病毒血凝素的特异性抗体的特征。这些抗体中的大多数能够识别在 73 年期间分离的乙型流感病毒，并且与血凝素的保守茎部结构域结合。所鉴定的一部分抗体能够保护小鼠免受致死剂量乙型流感病毒攻击后的发病率和死亡率的影响。在抗体依赖性细胞介导的细胞毒性报告测定中的活性与保护作用密切相关，表明 Fc 依赖性效应功能决定了保护效果。我们对这些抗体的作用机制和表位位置的描述提供的信息将为急需的疫苗设计提供信息，这些疫苗可以诱导针对乙型流感病毒的广泛保护。虽然针对甲型流感病毒血凝素的广谱保护性抗体已经得到了很好的研究，但针对广泛识别乙型流感病毒的抗体的信息非常有限。同样，乙型流感病毒通用或广谱保护性疫苗的开发也落后于甲型流感病毒疫苗的开发。更多关于广谱保护性乙型流感病毒抗体的表位位置和作用机制的信息对于疫苗开发至关重要。此外，保护性抗体可能是一种有用的工具，可以在与现有治疗途径结合的情况下，针对儿科人群或免疫功能低下个体的治疗环境中，治疗或预防乙型流感病毒感染。
