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Here we use an<jats:italic>in vivo<\/jats:italic>plasmablast enrichment technique to isolate a human monoclonal antibody, 46B8 that neutralizes all IBVs tested<jats:italic>in vitro<\/jats:italic>and protects mice against lethal challenge of all IBVs tested when administered 72\u2009h post infection. 46B8 demonstrates a superior therapeutic benefit over Tamiflu and has an additive antiviral effect in combination with Tamiflu. 46B8 binds to a conserved epitope in the vestigial esterase domain of hemagglutinin (HA) and blocks HA-mediated membrane fusion. After passage of the B\/Brisbane\/60\/2008 virus in the presence of 46B8, we isolated three resistant clones, all harbouring the same mutation (Ser301Phe) in HA that abolishes 46B8 binding to HA at low pH. 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