Abstract
The skin is immunologically very potent because of the high number of antigen-presenting cells in the dermis and epidermis, and is therefore considered to be very suitable for vaccination. However, the skin’s physical barrier, the stratum corneum, prevents foreign substances, including vaccines, from entering the skin. Microneedles, which are needle-like structures with dimensions in the micrometer range, form a relatively new approach to circumvent the stratum corneum, allowing for minimally invasive and pain-free vaccination. In this study, we tested ceramic nanoporous microneedle arrays (npMNAs), representing a novel microneedle-based drug delivery technology, for their ability to deliver the subunit vaccines diphtheria toxoid (DT) and tetanus toxoid (TT) intradermally. First, the piercing ability of the ceramic (alumina) npMNAs, which contained over 100 microneedles per array, a length of 475 µm, and an average pore size of 80 nm, was evaluated in mouse skin. Then, the hydrodynamic diameters of DT and TT and the loading of DT, TT, and imiquimod into, and subsequent release from the npMNAs were assessed in vitro. It was shown that DT and TT were successfully loaded into the tips of the ceramic nanoporous microneedles, and by using near-infrared fluorescently labeled antigens, we found that DT and TT were released following piercing of the antigen-loaded npMNAs into ex vivo murine skin. Finally, the application of DT- and TT-loaded npMNAs onto mouse skin in vivo led to the induction of antigen-specific antibodies, with titers similar to those obtained upon subcutaneous immunization with a similar dose. In conclusion, we show for the first time, the potential of npMNAs for intradermal (ID) immunization with subunit vaccines, which opens possibilities for future ID vaccination designs.
Highlights
The skin has great potential for vaccine delivery, because it is a large organ that is easy to reach
It was shown that diphtheria toxoid (DT) and tetanus toxoid (TT) were successfully loaded into the tips of the ceramic nanoporous microneedles, and by using near-infrared fluorescently labeled antigens, we found that DT and TT were released following piercing of the antigen-loaded nanoporous microneedle arrays (npMNA) into ex vivo murine skin
Nanoporous microneedle arrays fabricated from alumina nanoparticles as previously reported [10], were characterized for geometry and dimensions via surface Bruker analysis, which showed that the ceramic microneedles had an average length of 475 μm and a needle shaft diameter of 275 μm (Figure 2A)
Summary
The skin has great potential for vaccine delivery, because it is a large organ that is easy to reach. To circumvent the barrier function of the stratum corneum and reach antigen-presenting cells for vaccination purposes, microneedles can be used. Microneedles are needlelike structures with a length in the micrometer range and are a promising tool to deliver drugs and vaccines across the barrier. They represent a possible painless vaccination method [5], they present reduced contamination risks compared with traditional needles, they allow for injection by less trained personnel and even have potential for self-administration [6]. Multiple strategies have been investigated for the delivery of vaccine antigens into the skin, as reviewed by van der Maaden et al [10]
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