The influenza virus infects millions of people worldwide on an annual basis. The worldwide pandemic of 1918 killed an estimated fifty million people and a future pandemic has the potential to kill hundreds of millions of people. Although vaccines and drugs are available, the virus continues to be a major health problem due to its abilities to change the antigenic makeup of hemagglutinin, and its zoonotic nature, allowing animal viruses to infect humans to which the human population has no preexisting immunity. There is a fundamental gap in understanding how the molecular structure and organization of influenza hemagglutinin affect influenza virus assembly and epitope display. Lack of such information represents important problems and until they are addressed the mechanisms by which neutralizing antibodies, immune effector molecules and drugs abrogate virus assembly and entry cannot be understood in molecular details. This hinders structure-guided approaches to design influenza immunogens and anti-viral compounds. In FY 2013, we have established significant milestones both in structural imaging of influenza viruses and hemagglutinin proteins by electron microscopy and in creating novel computational methods to analyze hemagglutinin and virus structures with the purpose of understanding the structure and epitope display of influenza hemagglutinin. In addition, we have established and utilized structural informatics methods to identify and characterize various influenza epitopes. Innovative accomplishments with high-impact from the last year include (i) Molecular characterization of epitopes of influenza viruses with pandemic potential (e.g. H1N1, H5N1, H7N9);(ii) Characterization of influenza hemagglutinin oligomeric scaffolds for broadly neutralizing epitope display;(iii) Design of protein oligomeric fragments for epitope display. These results are significant and relevant to public health because it is expected to expand understanding of the structure and epitope disposition of influenza hemagglutinin proteins that will aid immunogen design for universal influenza vaccines and provide targets for novel therapeutic agents.

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