Despite the past and present successes of vaccination for the control of infectious diseases, new vaccines need to be developed that respond to the societal demands for improving disease prevention. Vaccines that are efficient in one administration, that protect against a variety of rapidly mutating pathogen variants, and that cure chronic infections and cancers are major pursued goals. New strategies from basic immunological research in the mouse revealed that antigenized immunoglobulin-based vaccines that target dendritic cells (DC)- the key cell that orchestrate immunity- generate an unequaled quality of immunogenicity. Furthermore, the specific targeting of DC subsets resulted in eliciting specific arms of immunity i.e. either strong antibody or cytotoxic responses. However given the limited predictive value of mouse results, the translation of this approach to “real” species, such as human and domestic animals, requires further demonstration. DC subsets are well represented in the skin that appears as a convenient and efficient site for vaccine delivery. Pig is a model of choice for skin delivery, as human and swine skin structures and their DC compositions share a high degree of similarities. In addition, pig and human are both sensitive to zoonotic pathogens, with influenza representing a permanent threat as demonstrated by the 2009 pandemic. The goal of “DCVacFlu” is to generate Flu-antigenized antibody-based vaccines that target swine skin DC subsets (Flu-DCVacAb), in order to provide novel veterinary vaccines and solid preclinical information for developing corresponding human vaccines. The French coordinator has identified the conservation of DC subset organization across mammals based on functional and transcriptomic comparative analyses. This led to the selection of molecular candidates that could allow (1) targeting the “antibody promoting” DC type with the c-type lectins DECTIN2, MANNOSE R and ASGPR2 and (2) targeting the “cytotoxic T cell promoting” DC type, with the c-type lectins DEC205, CLEC9A, CLEC12A and the chemokine receptor XCR1. Interestingly, the Mexican coordinator has already developed the anti porcine DEC205 (not published), what represents the first and unique anti-DC Ab in pig. Both partners will share the development of complementary DCVacAb. Two strategies will be compared for associating the Flu antigens (FluAG) to the DCVacAb. The Mexican teams will molecularly clone a selection of DCVacAb as Single Chain Fragment variables (ScFv) fused to the Flu antigens. The French partners will exploit their novel patented strategy which consists in expressing the FluAG in fusion with streptavidin (SA) for making complexes with biotinylated DCVacAb, thus providing a simple and flexible way to antigenize DCVacAb. The selected FluAG will be the nucleoprotein (induces cytotoxic T cells) and the external ion channel M2e (induces protective antibodies) that can both induce protective immunity against a large array of Flu strains. Finally a virulent challenge with influenza A H1N1 2009 will be done in the pigs vaccinated with the most immunogenic DCVacAb structures. In total, the expectations of “DCVacFlu” are the: - Demonstration of the proof of concept of DC targeting by DCVacAb in a relevant target species (pig) for efficient vaccination via skin, - Evaluation of novel molecular targets such as XCR1, DECTIN2 and ASGPR2, not yet fully tested in the mouse, for DCVacAb strategies, - Challenge the concept of biasing the immune response types by targeting specific DC subsets in a relevant species, - Comparison of efficacy between 2 strategies to antigenize the DCVacAb, i.e. FluAG fused to ScFV and Streptavidin-FluAG linked to DCVAcAb. DCVacFlu shall provide cutting edge vaccines for veterinary medicine and convincing preclinical date useful for translation to humans, validated for influenza and transposable to other pathogens.