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Skin is more potent than the muscle for vaccination, but it is not a common site for immunization to date owing, in part, to a relatively high rate of pains and skin irritation and difficulty of administration. Here, we show effective and lesion free cutaneous vaccination by a combination of a biodegradable microneedle array (MNs) and an FDA-approved nonablative fractional laser (NAFL). Delivering a vaccine into many micropores, instead of a single “big” pore in the skin, effectively segregated vaccine-induced inflammation into many microzones and resulted in quick resolution of the inflammation, provided that distances between any two micropores were far enough. When the inoculation site was treated by NAFL prior to insertion of the MNs comprised of PR8 model influenza vaccine, the mice displayed vigorous antigen-uptake, giving rise to strong, Th1-biased immunity. The mice were protected from a challenge of homologous influenza virus at a high dose as well as heterologous H1N1 and H3N2 viruses. The adjuvant effect of NAFL was ascribed primarily to activation of the dsDNA sensing pathway by dsDNA released from laser-damaged skin cells. Thus, mice deficient in the dsDNA sensing pathway, but not toll like receptor (TLR) or inflammasome pathways, showed poor response to NAFL. Importantly, both mice and swine exhibited strong, protective immunity, but no overt skin reactions with this approach, in sharp contrast to intradermal injections that caused severe, overt skin reactions. The effective lesion-free transcutaneous vaccination merits further clinical studies.
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