State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, People's Republic of China.
Department of Poultry Diseases, National Veterinary Research Institute, Puławy, Poland.
J Virol. 2022 Sep 28;96(18):e0123822. doi: 10.1128/jvi.01238-22. Epub 2022 Aug 29.
The H7N9 subtype influenza A viruses pose a serious threat to public health, and there is still a lack of vaccines or drugs for humans against H7N9 influenza viruses. In this study, we screened two monoclonal antibodies (MAbs), 4H1E8 and 7H9A6, that specifically recognize the hemagglutinin (HA) protein of H7N9 influenza virus and display highly neutralizing activity against H7N9 virus. The epitopes recognized by two MAbs are nearly all conserved within all known H7 subtypes. Characteristic identification showed that two MAbs have high avidity for the HA protein but no hemagglutinin inhibition activity or antibody-dependent cellular cytotoxicity. Mechanistically, the 4H1E8 and 7H9A6 antibodies inhibit the pH-dependent conformational change of HA and block the HA-mediated membrane fusion. More importantly, 4H1E8 and 7H9A6 exhibit promising prophylactic and therapeutic effects against lethal challenge with H7N9 virus. Moreover, 4H1E8- and 7H9A6-treated mice displayed inhibition of pulmonary viral replication and reduced lung lesions after viral challenge. Together, these findings indicate that antibodies 4H1E8 and 7H9A6 recognize unique epitopes in the HA protein and possess the neutralizing activity and protective efficacy against the H7N9 influenza A viruses. In 2013, H7N9 influenza viruses appeared in China and other countries resulting in more than 1,500 individual infections or death. There are still limited studies on vaccines or drugs for humans against H7N9 influenza viruses. Alternative approaches against H7N9 virus infection need to be developed. Here, we identified two monoclonal antibodies (4H1E8 and 7H9A6) that possess neutralizing activity by blocking the pH-dependent HA-mediated membrane fusion. Additionally, the two monoclonal antibodies protect mice against the H7N9 virus challenge prophylactically or therapeutically. Therefore, our study demonstrates that 4H1E8 and 7H9A6 could be used for the prevention and treatment of the H7N9 influenza virus, and the conserved epitopes we identified may contribute to the development of a broad H7N9 vaccine and provide insights into unique antiviral approaches.
H7N9 亚型流感 A 病毒对公共卫生构成严重威胁，目前仍缺乏针对 H7N9 流感病毒的人类疫苗或药物。在本研究中，我们筛选了两种特异性识别 H7N9 流感病毒血凝素（HA）蛋白的单克隆抗体（MAb）4H1E8 和 7H9A6，它们具有高度中和 H7N9 病毒的活性。两种 MAb 识别的表位在所有已知的 H7 亚型中几乎全部保守。特征鉴定表明，两种 MAb 对 HA 蛋白具有高亲和力，但没有血凝抑制活性或抗体依赖性细胞毒性。在机制上，4H1E8 和 7H9A6 抗体抑制 HA 的 pH 依赖性构象变化，并阻断 HA 介导的膜融合。更重要的是，4H1E8 和 7H9A6 对 H7N9 病毒的致死性攻击表现出有前景的预防和治疗效果。此外，4H1E8 和 7H9A6 处理的小鼠在病毒攻击后显示出肺部病毒复制的抑制和肺损伤的减少。总之，这些发现表明抗体 4H1E8 和 7H9A6 识别 HA 蛋白中的独特表位，并具有中和活性和针对 H7N9 流感 A 病毒的保护效力。2013 年，H7N9 流感病毒在中国和其他国家出现，导致超过 1500 人感染或死亡。目前针对 H7N9 流感病毒的人类疫苗或药物的研究仍然有限。需要开发针对 H7N9 病毒感染的替代方法。在这里，我们鉴定了两种单克隆抗体（4H1E8 和 7H9A6），它们通过阻断 pH 依赖性 HA 介导的膜融合具有中和活性。此外，这两种单克隆抗体可预防或治疗地保护小鼠免受 H7N9 病毒的攻击。因此，我们的研究表明，4H1E8 和 7H9A6 可用于预防和治疗 H7N9 流感病毒，我们鉴定的保守表位可能有助于开发广泛的 H7N9 疫苗，并为独特的抗病毒方法提供思路。
