Innovative strategies for non-invasive vaccines administration

The development of vaccines administered in a non-invasive way is considered a great goal to improve their safety and ease of administration, especially for children vaccination and during pandemic situations. Recently, mucosal tissues have received great attention as target sites for vaccination due to their ability to elicit both local and systemic immune responses. With this in mind, in the present work fluorescent dextrans, of different molecular weight, were used as model polysaccharide antigens to investigate the possibility to administer vaccines through the buccal mucosal tissue; chemical enhancers, such as fatty acids and bile salts, and physical methods, i.e. microneedles arrays, were used to improve tissue penetration. Among chemicals enhancers tested, caprylic acid pre-treatment and sodium taurocholate co-administration resulted the best absorption strategies: dextrans of molecular weight higher than 40 kDa were able to cross the tissue only in the presence of enhancers. The use of two photon microscopy, an innovative technique allowing three-dimensional and deep tissue imaging, enabled dextrans visualization in the tissue. Chitosan, hydroxypropyl methyl cellulose (HPMC) and anionic type nanofibrillar cellulose (ANFC) were used to produce and test suitable buccal delivery systems in the form of gel or film. The chitosan/HPMC gel formulation in association with chemical enhancers can deliver dextran with 20 kDa m.w. but the film with the same composition allows dextran transport exclusively after tissue pre-treatment. ANFC film instead is surprisingly able to deliver dextrans with m.w. smaller than 20 kDa without any treatment. Finally, a minimally invasive approach was applied: fluorescent dextrans were loaded in dissolving microneedles, of different length, and applied to buccal mucosa. Two photon microscopy imaging revealed that only microneedles of appropriate length (500 and 800 µm) were able to penetrate the tissue; in these cases, dextran permeation was very high and quick. The data reported in this work show that it is possible to increase buccal permeation of high molecular weight dextrans by applying certain enhancing strategies, such as the pre-treatment of tissue, co-administration of absorption enhancers and/or production of particular formulation and devices suitable for buccal delivery. Besides this non-invasive approach, a minimally invasive strategy, based on the use of dissolving microneedles guaranteed, with a very short application time (10 minutes), a considerable permeation of dextran.