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Enterovirus A (EV-A) has been responsible for recent outbreaks of hand-foot-mouth disease (HFMD); however, there is no vaccine or effective antiviral treatment. The goal of our project is to develop broad vaccines targeting the diverse EV-A serotype viruses that cause HFMD. We used the EV-A viral capsid protein 1 (VP1) as the vaccine antigenic target, because of its genetic diversity across EV-A serotypes, and prior work that showed VP1 has linear neutralizing antibody epitopes. We computationally designed VP1 proteins to create mosaic antigens that optimize B and T cell epitopes among diverse EV-A viral sequences. We identified that a hexavalent mosaic vaccine cocktail had the highest EV-A sequence coverage. We then immunized mice in three groups with recombinant VP1 proteins in adjuvant; Group 1 was given the EV-A Consensus VP1 (Consensus), Group 2 was given the EV-A strain EVA-71 VP1 protein (EVA-71, strain specific) and Group 3 was given our newly designed hexavalent vaccine (EV-A Consensus + 5 mosaic VP1). We measured the antibody binding levels to 9 EV-A VP1 antigens after immunization and found that the EV-A hexavalent vaccine resulted in improved antibody binding breadth during in vivo vaccination. Our results demonstrate the feasibility of using polyvalent VP1 proteins to increase the breath of antibody epitopes among EV-A serotypes. Our approach has the potential to treat and block EV-A infection and serve as a model for responding to other emerging viral diseases.

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Design and testing of mosaic enterovirus vaccine to prevent hand, foot and mouth disease