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We evaluated the performance of split swine influenza A virus (SwIAV) H1N2 antigens with a plant-derived nanoparticle adjuvant alone (Nano-11) [Nano11-SwIAV] or in combination with the synthetic stimulator of interferon genes (STING) agonist ADU-S100 (NanoS100-SwIAV). Specific pathogen free (SPF) pigs were vaccinated twice via intramuscular (IM) or intradermal (ID) routes and challenged with a virulent heterologous SwIAV H1N1-OH7 virus.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Animals vaccinated IM or ID with NanoS100-SwIAV had significantly increased cross-reactive IgG and IgA titers in serum, nasal secretion and bronchoalveolar lavage fluid at day post challenge 6 (DPC6). Furthermore, NanoS100-SwIAV ID vaccinates, even at half the vaccine dose compared to their IM vaccinated counterparts, had significantly increased frequencies of CXCL10<jats:sup>+<\/jats:sup> myeloid cells in the tracheobronchial lymph nodes (TBLN), and IFN\u03b3<jats:sup>+<\/jats:sup> effector memory T-helper\/memory cells, IL-17A<jats:sup>+<\/jats:sup> total T-helper\/memory cells, central and effector memory T-helper\/memory cells, IL-17A<jats:sup>+<\/jats:sup> total cytotoxic T-lymphocytes (CTLs), and early effector CTLs in blood compared with the Nano11-SwIAV group demonstrating a potential dose-sparing effect and induction of a strong IL-17A<jats:sup>+<\/jats:sup> T-helper\/memory (Th17) response in the periphery. However, the frequencies of IFN\u03b3<jats:sup>+<\/jats:sup> late effector CTLs and effector memory T-helper\/memory cells, IL-17A<jats:sup>+<\/jats:sup> total CTLs, late effector CTLs, and CXCL10<jats:sup>+<\/jats:sup> myeloid cells in blood, as well as lung CXCL10<jats:sup>+<\/jats:sup> plasmacytoid dendritic cells were increased in NanoS100-SwIAV IM vaccinated pigs. Increased expression of IL-4 and IL-6 mRNA was observed in TBLN of Nano-11 based IM vaccinates following challenge. Furthermore, the challenge virus load in the lungs and nasal passage was undetectable in NanoS100-SwIAV IM vaccinates by DPC6 along with reduced macroscopic lung lesions and significantly higher virus neutralization titers in lungs at DPC6. However, NanoS100-SwIAV ID vaccinates exhibited significant reduction of challenge virus titers in nasal passages and a remarkable reduction of challenge virus in lungs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Despite vast genetic difference (77% HA gene identity) between the H1N2 and H1N1 SwIAV, the NanoS100 adjuvanted vaccine elicited cross protective cell mediated immune responses, suggesting the potential role of this combination adjuvant in inducing cross-protective immunity in pigs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12951-022-01677-2","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T21:03:18Z","timestamp":1668200598000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A split influenza vaccine formulated with a combination adjuvant composed of alpha-d-glucan nanoparticles and a STING agonist elicits cross-protective immunity in pigs"],"prefix":"10.1186","volume":"20","author":[{"given":"V.","family":"Patil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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All the pigs were maintained, samples collected and euthanized, and all efforts were made to minimize the suffering of pigs as per the approved institutional, state and federal regulations and policies regarding animal care and use at The Ohio State University on the Ethics for Animal Experiments (Protocol Number: 2014A00000099).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests\" in this section.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"477"}}