The vast majority of infectious agents enter the body via mucosal sites yet there are very few licensed mucosal vaccines able to generate protective immunity at the sites of pathogen entry. A major obstacle in developing mucosal vaccine is delivering biologically active vaccine antigens (Ag) to mucosa-associated lymphoid tissues to prime protective immune responses. To address these issues we have developed a drug delivery technology platform to deliver intact antigens to the respiratory and gastrointestinal tract using outer membrane vesicles (OMV) naturally produced by Bacteroides thetaiotaomicron (Bt), a non-pathogenic human commensal gut bacterium. We have developed the capability of engineering Bt to express antigens of interest in their OMVs which we have shown are stable for long periods of time across a wide temperatures range. They also have inherent adjuvanticity as shown by the ability of native OMVs to elicit the formation of organised lymphoid follicles comprising dendritic cells and T and B cells in both the upper and lower respiratory tract after intranasal administration. The intransal administration of Bt OMVs expressing the pre-fusion headless hemagglutinin mini-stem protein of influenza type A virus (IAV) subtype, H5N1, induced high titre antigen-specific antibodies in the respiratory mucosa (IgA) and serum (IgG) that conferred heterotypic protection to infection by a H1N1 IAV. Collectively, our data demonstrates the feasibility of using Bt OMVs in mucosal vaccine formulations for respiratory infections.


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