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Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine. These data provide a proof-of-concept for broad, pre-exposure protection against a potential future pandemic using the intranasal administration route. Studies in humans should assess if autonomous administration of a broadly-neutralizing monoclonal antibody is safe and effective and can thus contribute to pandemic preparedness.

Monoclonal antibodies have two core mechanisms of protection: an antibody’s antigen-binding fragment (Fab) can bind and neutralize viral pathogens and its fragment crystallizable domain (Fc) catalyzes effector functions. We investigated the relative contribution of Fab- versus Fc-mediated mechanisms of protection through passive administration of distinct forms of the pan-reactive anti-influenza antibody CR9114. We demonstrated that the contribution of Fc-independent (Fab-dependent) versus Fc-dependent mechanisms of protection is defined by the route of administration. We used CR9114 variants (wild-type, two Fc-silenced variants, or the bivalent antigen-binding fragment F(ab′) 2 ), administered either intravenously or intranasally. We found that intravenously-administered CR9114 requires the Fc domain to provide potent, pre-exposure protection against influenza A and B viral challenge. In contrast, when CR9114 was administered locally to the nasal mucosa, the main mode of protection was provided by F(ab′) 2 , and was largely Fc-independent. Importantly, this mode of protection following intranasal administration also applied to non-neutralized influenza B strains. Moreover, intranasal administration resulted in an increase in potency against influenza A/H1N1, A/H5N1, A/H3N2, B/Yam and B/Vic compared to intravenous administration up to 50-fold. These results shed new light on the application of monoclonal antibodies such as CR9114 to combat viral infection locally, and will help inform clinical strategies of pre-exposure prophylaxis. More fundamentally, this study uncovers distinct modes of protection for systemic versus intranasally-administered prophylactic antibodies.