Significance A small number of mutations to the viral hemagglutinin are sufficient to permit aerosol transmission, in a ferret model of human infection, of highly pathogenic avian H5N1 influenza A viruses. Here, we show how an antibody (H5.3) against hemagglutinin 5 (H5) recognizes both WT and variant H5 proteins. H5.3 retains germ-line characteristics, most remarkably a conformationally flexible combining site, consistent with an antibody that has not been through multiple cycles of affinity maturation. Many antibodies against H5 are lightly mutated and may arise from naive B cells, explaining the low antigenicity of H5N1 vaccines relative to seasonal influenza vaccines and supporting the idea that multiple exposures are necessary to develop a strong immune response to H5N1 strains.