Traditionally, vaccines are administered intramuscularly using conventional hypodermic needles, which cause pain and distress. Microneedles are very short needles (smaller than 1 mm) that are... Show moreTraditionally, vaccines are administered intramuscularly using conventional hypodermic needles, which cause pain and distress. Microneedles are very short needles (smaller than 1 mm) that are practically invisible to the naked eye. Microneedles may administer vaccine into the skin in a pain-free manner. By using the intradermal route for immunization, a high number of immune cells in the skin are targeted, which may result in more efficient immunization. In this thesis, several aspects of intradermal immunization were investigated by using hollow microneedles. As differently specialized immune cells reside at different depths in skin, immunization outcomes as function of injection depth in skin were investigated to determine effects of injection depth. Furthermore, as prolonged antigen exposure may enhance immune responses, immunization outcomes resulting from repeated fractional intradermal dosing schedules were compared to those resulting from bolus dosing schedules. Finally, a layer-by-layer coating approach was developed for solid microneedle arrays. In the layer-by-layer coating approach, alternating layers of antigen and polymer are coated onto the surface of microneedle arrays. This approach enabled coating and intradermal delivery of a precise amount of antigen. Intradermal immunization using layer-by-layer coated microneedle arrays resulted in effective immunization. In conclusion, these studies provide important insights towards controlled microneedle-mediated intradermal immunization. Show less
In summary, the collective results described in this thesis show that nanoparticulate vaccines can be delivered intradermally by coated and hollow microneedles and evoke antigen-specific immune... Show moreIn summary, the collective results described in this thesis show that nanoparticulate vaccines can be delivered intradermally by coated and hollow microneedles and evoke antigen-specific immune responses. The choice of both the nanoparticles and the microneedle(s) could have important influences on the immune responses. Microneedle arrays coated with antigen loaded and lipid bilayer fused mesoporous silica nanoparticles (MSNs) could be a promising system for convenient and fast intradermal delivery of protein antigen, although our results indicate that the system needs to be improved in order to obtain optimal immune responses. Moreover, antigen and adjuvant loaded nanoparticles can increase IgG2a (Th1) and CD8+ responses after intradermal delivery by hollow microneedles. This effect depends on the type and the physicochemical characteristics of the nanoparticles, in which smaller size and controlled release properties of antigen and adjuvant were found to correlate with the stronger effect. Finally, the combination of separate antigen loaded and adjuvant loaded nanoparticles may be as efficient as the antigen and adjuvant co-encapsulated nanoparticles for modification of the immune responses following intradermal immunization. Show less
In the Netherlands, children receive within the National Vaccination Program, 14 injections against 12 diseases. This number will only increase in the future. Since needles and syringes have... Show moreIn the Netherlands, children receive within the National Vaccination Program, 14 injections against 12 diseases. This number will only increase in the future. Since needles and syringes have several drawbacks, such as needle stick injuries and needle fear, alternatives have been assessed to deliver vaccines. The aim of the thesis was to identify and evaluate methods suitable for minimally invasive delivery of vaccines in order to become more flexible in complex pediatric immunization programs. Access to these delivery methods would facilitateincorporation of new vaccines in the program. Three alternatives are assessed in this thesis: -Bioneedles for s.c delivery -Elastic vesicles for topical application -Liquid jet injector for i.d delivery Show less
