A Potent Germline-like Human Monoclonal Antibody Targets a pH-Sensitive Epitope on H7N9 Influenza Hemagglutinin

• Published in: Cell host & microbe Vol. 22; no. 4; pp. 471 - 483.e5
• Main Authors: Yu, Fei, Song, He, Wu, Yanling, Chang, So Young, Wang, Lili, Li, Wei, Hong, Binbin, Xia, Shuai, Wang, Chunyu, Khurana, Surender, Feng, Yang, Wang, Yanping, Sun, Zhiwu, He, Biao, Hou, Dongni, Manischewitz, Jody, King, Lisa R., Song, Yuanlin, Min, Ji-Young, Golding, Hana, Ji, Xinhua, Lu, Lu, Jiang, Shibo, Dimitrov, Dimiter S., Ying, Tianlei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.10.2017; Elsevier
• Subjects: ADCC; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Dogs; Epitopes - immunology; Female; germline; H7N9 influenza; HEK293 Cells; hemagglutinin; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Humans; Hydrogen-Ion Concentration; Influenza A Virus, H7N9 Subtype - chemistry; Influenza A Virus, H7N9 Subtype - immunology; Influenza Vaccines - immunology; Influenza, Human - immunology; Influenza, Human - therapy; Influenza, Human - virology; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred BALB C; Molecular Conformation; monoclonal antibody; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - therapy; Orthomyxoviridae Infections - virology; germline; monoclonal antibody; ADCC; hemagglutinin; H7N9 influenza
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2017.08.011

The H7N9 influenza virus causes high-mortality disease in humans but no effective therapeutics are available. Here we report a human monoclonal antibody, m826, that binds to H7 hemagglutinin (HA) and protects against H7N9 infection. m826 binds to H7N9 HA with subnanomolar affinity at acidic pH and 10-fold lower affinity at neutral pH. The high-resolution (1.9 Å) crystal structure of m826 complexed with H7N9 HA indicates that m826 binds an epitope that may be fully exposed upon pH-induced conformational changes in HA. m826 fully protects mice against lethal challenge with H7N9 virus through mechanisms likely involving antibody-dependent cell-mediated cytotoxicity. Interestingly, immunogenetic analysis indicates that m826 is a germline antibody, and m826-like sequences can be identified in H7N9-infected patients, healthy adults, and newborn babies. These m826 properties offer a template for H7N9 vaccine immunogens, a promising candidate therapeutic, and a tool for exploring mechanisms of virus infection inhibition by antibodies. [Display omitted] •Identification of human germline monoclonal antibody (m826) that binds H7N9 HA•Structure of H7N9 HA complexed with m826 antibody•Antibody recognizes a pH-sensitive epitope within H7N9 HA•Antibody fully protects mice against lethal challenge with H7N9 virus H7N9 influenza virus causes high-mortality disease in humans. Yu et al. identify a human germline monoclonal antibody recognizing a pH-sensitive epitope on H7N9 hemagglutinin globular head. This antibody is effective against H7N9 influenza in vivo, likely due to ADCC activity, and may facilitate the development of prophylactics and therapeutics.