Swine influenza A replicon particle and live attenuated influenza virus vaccines induce differential systemic and mucosal antibody and T cell responses

Authors: Wymore Brand, Meghan; Kaplan, Bryan; Kunzler Souza, Carine; Wiarda, Jayne; Kimble, James; Arruda, Bailey; PEREZ, DANIEL - University Of Georgia; Baker, Amy

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/22/2025
Publication Date: 1/30/2026
Citation: Wymore Brand, M.J., Kaplan, B.S., Kunzler Souza, C., Wiarda, J.E., Kimble, J.B., Arruda, B.L., Perez, D.R., Baker, A.L. 2026. Swine influenza A replicon particle and live attenuated influenza virus vaccines induce differential systemic and mucosal antibody and T cell responses. Frontiers in Veterinary Science. https://doi.org/10.3389/fvets.2025.1690418.
DOI: https://doi.org/10.3389/fvets.2025.1690418

Interpretive Summary: Influenza A virus (IAV) is a significant economic concern in the swine industry. Swine IAV viruses are incredibly diverse, and there is a critical need to improve swine IAV vaccines against divergent viruses. Cellular immunity and antibody responses in the respiratory tract are not well understood as potential correlates of protection for swine IAV vaccines, and may be critical in vaccine protection against divergent viruses. This study evaluated live attenuated influenza A virus (LAIV) vaccines and IAV replicon particle (RP) vaccines in swine against a divergent virus. Additionally, the study assessed antibody and cellular immune responses to vaccine virus and the divergent challenge virus in the blood and in the lung. LAIV vaccine is given into the nose, while RP is given in the muscle, and these different vaccine platforms and locations of vaccination impact the immune response. This work demonstrated LAIV reduced viral shedding and viral lung load, while RP reduced lung lesions after challenge with the divergent virus. Both vaccines induced similar antibody in blood to the challenge virus. Both vaccines induced IgG antibody in the lung to challenge virus, but only LAIV induced high levels of lung IgA antibody. Both vaccines stimulated T cell responses to IAV, but the magnitude and type differed based on the vaccine, with greater CD8+ T cell responses in blood and the lungs and CD4+ T cells in the blood induced by LAIV but higher lung CD4+ T cell responses were noted in one assay from the RP vaccine. These data demonstrate LAIV and RP induce different immune responses that are likely impacted by type and location of vaccination. Additionally, as the increased CD8+ T cell responses with LAIV vaccination corresponded to decreased viral load, enhanced CD8+ T cell responses may represent a correlate of protection against divergent viruses. A better understanding of these immune responses that may represent correlates of protection will help develop improved swine IAV vaccination strategies.

Technical Abstract: Influenza A virus (IAV) in swine is a significant economic concern and there is a critical need to improve vaccine efficacy. Commercial and experimental vaccine platforms are effective against homologous infection but may not reliably provide protection against drifted or heterologous viruses. Live attenuated influenza A virus (LAIV) vaccines induce mucosal antibody and localized cellular immune responses that may provide partial protection from drifted IAV. However, limited data exists on the induction of mucosal antibody and cellular immune responses and heterologous protection induced by RNA-based vaccines in swine. In this work, experimental, non-adjuvanted hemagglutinin-based replicon particle (RP-HA) and live attenuated influenza A virus (LAIV) vaccines were assessed for induction of mucosal antibody, cellular immune responses, and heterologous protection. LAIV reduced viral shedding and viral lung load while RP-HA limited macroscopic lung lesions. Both vaccines induced similar homologous systemic antibody and mucosal IgG, while only LAIV induced high levels of mucosal IgA. Both vaccines stimulated ex vivo virus-specific T cell proinflammatory cytokine production and proliferation. LAIV induced greater CD8+ T cell responses in blood and the lungs and CD4+ T cells in the blood, though RP-HA induced higher lung CD4+ T cell cytokine responses. Together these results demonstrate LAIV and RP-HA IAV vaccines induce differential antibody and T cell responses that are likely impacted by vaccine platform and route of exposure. A better understanding of correlates of protection including cellular immunity and mucosal antibody induction will aid in the development of improved swine IAV vaccination strategies.