Influenza viruses cause significant morbidity and mortality every year. Vaccines that protect from influenza virus infection are available but they have to be re-formulated annually because their effectiveness is limited to seasonal strains. The high mutation rate of influenza virus, specifically the highly variable antigenic structure of the viral surface protein hemagglutinin (HA) is at the core of this problem. The influenza virus vaccine is reliant on an antibody response to HA and vaccines are manufactured based on predictions of which strains are the most likely to circulate in a given season. These predictions can be inaccurate, leading to ineffective vaccines. Moreover, they do not account for the emergence of pandemic strains as exemplified by the H1N1 "swine flu" outbreak in 2009. Annual vaccination campaigns are also costly and there is increasing resistance to vaccination in a significant segment of the population. A universal influenza virus vaccine that affords lifetime protection against seasonal and pandemic strains would be a solution to these problems. We propose a novel strategy to develop such a universal influenza virus vaccine. The strategy is based on the recent discovery of a broadly neutralizing epitope in the influenza HA. We plan to graft this epitope onto the surface of a virus-like particle (VLP) platform that is based on the insect virus Flock House virus (FHV). FHV VLPs allow presentation of foreign epitopes in a polyvalent manner and induce a potent antibody response. Chimeric FHV particles displaying the HA epitope will be structurally characterized by cryoEM and image reconstruction as well as binding assays using the broadly neutralizing monoclonal antibodies. The particles will then be used to vaccinate mice and their antibody response will be characterized by ELISA and microneutralization assays. It is expected that immunized mice generate neutralizing antibodies and this will be confirmed by challenge studies with live virus. If successful, the proposed research could lead to a transformation in flu vaccination by eliminating the challenges currently associated with this endeavor. PUBLIC HEALTH RELEVANCE: In this application we propose to develop a new influenza virus vaccine that needs to be administered only once and then protects for a lifetime against all seasonal and pandemic strains. The strategy that we will use is based on a recent discovery that there is a region in the influenza hemagglutinin protein that does not mutate and can give rise to antibodies that neutralize many different influenza viruses. We will isolate this region of the hemagglutinin protein and graft it on a carrier particle that is known to induce a very potent immune response.