Despite important success in protecting individuals against many pathogenic infections, parenteral vaccination is not optimal to induce immunity at the site of pathogen entry, i.e. mucosal surfaces. Moreover, designing adequate delivery systems and safe adjuvants to overcome the inherent tolerogenic environment of the mucosal tissue is challenging, in particular in the gastrointestinal tract prone to antigen degradation. We recently demonstrated that intranasal administration of a Salmonella-derived antigen associated with gas-filled microbubbles induced specific Ab and T cell responses in the gut and was associated with a reduction in local and systemic bacterial load after oral Salmonella infection. Building on these promising data, the adequate choice of antigen(s) to be administered and how to make it suitable for possible human application are discussed. We additionally present novel data dealing with oral administration of microbubbles and describe research strategies to direct them to mucosal sampling/inductive sites.