Abstract Humans are frequently exposed to seasonal influenza viruses like H1N1, H3N2 and influenza B viruses. However, infections with avian influenza viruses like H5N1 or H7N9 are rare. So far it is unclear how the human immune system reacts to exposure to these viruses, specifically in the context of pre-existing immunity to seasonal influenza virus strains. Preliminary data has shown that in these rare cases antibodies to epitopes that are conserved between human seasonal and avian influenza viruses are boosted. In this collaborative effort between the Xu laboratory (Fudan University, Shanghai, China) and the Krammer laboratory (Icahn School of Medicine at Mount Sinai, New York, USA) we propose to investigate the human antibody response after natural infection with avian influenza viruses. Antibody responses will be characterized at three levels. Initially we will assess the reactivity and functionality of polyclonal serum responses of humans naturally infected with H7N9 viruses. Then, on an epidemiologic level, we will assess the cross-reactivity of 'at risk' cohorts (wet market vendors, bird handlers, farmers etc.) to get insights into the prevalence of exposure to avian influenza viruses. Finally, we will zoom in to characterize the epitope usage of monoclonal antibodies induced after infection with avian influenza viruses. The data obtained from this study will guide the design of novel broadly protective and pandemic influenza virus vaccines and will significantly enhance our pandemic preparedness.