Broadly Protective Influenza Vaccines: Protection Against Mismatched Strains Ted M. Ross1,2, Hyusen Jang1, James D. Allen1 1Center for Vaccines and Immunology, 2Department of Infectious Diseases, University of Georgia, Athens, GA, USA The vast majority of people already have pre-existing immune responses to influenza viruses from one or more subtypes. However, almost all preclinical studies evaluate new influenza vaccine candidates in immunologically naïve animals. Recently, our group demonstrated that priming naive ferrets with broadly reactive H1 COBRA HA based vaccines boosted pre-existing antibodies induced by wild-type H1N1 virus infections. These H1 COBRA HA antigens induced antibodies with HAI activity against multiple antigenically different H1N1 viral variants. In this study, ferrets, preimmune to the historical H3N2 virus, A/Panama/2007/1999, were vaccinated with virus-like particle (VLP) vaccines expressing either an HA from a wild-type H3 influenza virus or a COBRA H3 HA antigen. The elicited antisera had the ability to neutralize virus infection against a panel of viruses representing vaccine strains selected by the World Health Organization (WHO) between 1995 and 2016 or a set of viral variants that co-circulated during the same time period. Preimmune animals vaccinated with H3 COBRA T10 HA antigen elicited sera with higher HAI antibody titers than antisera elicited by VLP vaccines with wild-type HA proteins in preimmune ferrets. However, while the T11 COBRA vaccine did not elicit HAI activity, the elicited antibodies did neutralize antigenically distinct H3N2 influenza viruses. Overall, H3 COBRA-based HA vaccines were able to neutralize both historical H3 and comtemporary, as well as future, H3N2 viruses with higher titers than vaccines with wild-type H3 HA antigens. This is the first report demonstrating the effectiveness of a broadly reactive H3N2 vaccine in a preimmune ferret model.