Abstract
Passive administration of broadly neutralizing anti-influenza monoclonal antibodies (mAbs) before or after virus infection can prevent or alleviate disease. Unlike seasonal influenza, infection with zoonotic avian influenza viruses can lead to acute respiratory distress syndrome and high mortality in humans. Respiratory tract-targeting antibody delivery appears to be more clinically relevant and effective for zoonotic influenza treatment. In this study, the efficacy of an anti-H7N9 murine mAb 4B7 and its humanized form (chi4B7) against H7 subtype influenza viruses administered through the intranasal route was investigated in mice. 4B7 recognizes critical residues in the vestigial esterase domain and receptor-binding sites in the hemagglutinin of H7N9 virus. The antibody had cross-H7 binding, hemagglutination inhibition, and neutralizing activities. In particular, the dose of 4B7 required for prophylactic protection against H7N9 infection was significantly reduced in mice treated locally (intranasal) compared with those treated systemically (intraperitoneal). Intranasal delivery of the antibody also enhanced therapeutic efficacy against H7N9 infection compared to intraperitoneal administration. Chi4B7 generated by grafting the variable regions onto the human IgG1 backbone sustained cross-reactivity with different H7 viruses of the parental murine antibody. Airway-delivered chi4B7 provided broad prophylactic and therapeutic protection against divergent H7 viruses in mice. Moreover, intranasal administration of chi4B7 had a long effective prophylaxis window against H7N9 infection. Our results suggest that airway delivery of the humanized anti-H7 antibody is a favorable approach for broad-spectrum prophylaxis and therapy against the H7 subtype influenza.IMPORTANCEInfection of zoonotic H7 avian influenza viruses can cause severe respiratory symptoms and high mortality in humans. Monoclonal antibody administration is an effective approach for treatment of zoonotic influenza infection, while systematic routes of antibody administration (typically intravenous infusion) have several shortcomings. However, there are no approved anti-H7 antibody therapies, and the efficacy of antibodies administered through the airway route against H7 viruses has not been fully investigated. Herein, we report a murine broadly neutralizing monoclonal antibody against divergent H7 viruses and reveal that intranasal administration enhanced prophylactic and therapeutic efficacy of this antibody against H7N9 virus compared to systemic administration. Airway delivery of the humanized antibody conferred broad protection against diverse strains of H7 virus in mice. Our study presents new candidates of broad antiviral agents against H7 avian influenza viruses and highlights airway delivery as a more potent manner of administering antibodies for clinical treatment of influenza.