PNAS – Proceedings of the National Academy of Sciences of the United States of America
http://www.pnas.org/content/early/
(Accessed 11 April 2015)

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Effective and lesion-free cutaneous influenza vaccination
Ji Wang1, Bo Li1, and Mei X. Wu2
Author Affiliations
Significance
Skin is more potent than muscle for vaccination, but it is not yet a common site for immunization, in part owing to relatively high rates of pain and skin irritation and difficulty of administration. We resolve this dilemma by delivering vaccines into many micropores in the skin, which constrains vaccine-induced inflammation, leading to fast healing and lesion-free. Moreover, combination of microfractional vaccine delivery with nonablative fractional laser (NAFL), not only significantly augmented vaccine efficiency but also broadened cross-protection against homologous and heterologous influenza viral infections. Cross-protective immunity is pivotal for influenza vaccines because mismatches occur frequently between vaccine viral strains and circulating viruses. To the best of our knowledge, this represents the first strategy for lesion-free efficient cutaneous vaccination.

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Abstract
The current study details efficient lesion-free cutaneous vaccination via vaccine delivery into an array of micropores in the skin, instead of bolus injection at a single site. Such delivery effectively segregated vaccine-induced inflammation, resulting in rapid resolution of the inflammation, provided that distances between any two micropores were sufficient. When the inoculation site was treated by FDA-approved nonablative fractional laser (NAFL) before insertion of a PR8 model influenza vaccine-packaged, biodegradable microneedle array (MNs), mice displayed vigorous antigen-uptake, eliciting strong Th1-biased immunity. These animals were completely protected from homologous viral challenges, and fully or partially protected from heterologous H1N1 and H3N2 viral challenges, whereas mice receiving MNs alone suffered from severe illnesses or died of similar viral challenges. NAFL-mediated adjuvanicity was ascribed primarily to dsDNA and other “danger” signals released from laser-damaged skin cells. Thus, mice deficient in dsDNA-sensing pathway, but not Toll like receptor (TLR) or inflammasome pathways, showed poor responses to NAFL. Importantly, with this novel approach both mice and swine exhibited strong protective immunity without incurring any appreciable skin irritation, in sharp contrast to the overt skin irritation caused by intradermal injections. The effective lesion-free cutaneous vaccination merits further clinical studies.