Circulating subtypes of Influenza viruses seasonally change and therefore vaccines need to be matched to these strains each year, which is why there is a need for next-generation vaccines that can elicit broad and cross-type protection. Here, Li et al. generate a human-mouse chimeric antibody with broad neutralizing activity against seasonal and pandemic H1N1 and some H5N1 viruses in vivo and identify residues on hemagglutinin relevant for its broad neutralization activity.