Development of Bacteroides thetaiotaomicron outer membrane vesicles as a universal, mucosal vaccine for Influenza A virus

Influenza A Virus (IAV) is a zoonotic pathogen which causes seasonal epidemics worldwide, resulting in significant morbidity and mortality. Due to rapid virus evolution, available vaccines/antiviral drugs must be re-formulated and re-administered in most years. There is therefore an unmet need for a ‘universal’ vaccine to provide long-lasting, adaptive immunity to multiple strains of IAV. The aim of this study was to assess outer membrane vesicles (OMVs) produced by Bacteroides thetaiotaomicron (Bt) containing IAV antigens as a candidate universal mucosal vaccine. First, using intranasally-delivered fluorescently-labelled OMVs and FACS we demonstrated good uptake of OMVs by dendritic cells in both secondary and tertiary lymphoid tissue, showing OMVs are efficiently trafficked from the mucosa to the lymphatic system. Immunohistology confirmed this and showed expansion of lymphoid tissues and lymphoid follicles after OMV delivery. The stem/stalk of IAV HA is less variable and will generate antibodies that are cross-protective. Thus, we produced OMVs (termed H5F) that contained the stalk region of HA from strain A/VietNam/1203/04 (H5N1). We inoculated mice intranasally with H5F expressing OMVs or wild type OMVs and assessed antibody production and protection from challenge using a lethal dose of a different strain of influenza (PR8; H1N1). OMV-H5F-inoculted mice produced IgG and IgA in the respiratory tract that recognised both H5 HA and H1 HA. OMV-H5F inoculated mice were also protected from lethal challenge and supported lower virus titres. Our results indicate a strong potential for this approach to generate a universal IAV vaccine.