title: Effective and lesion-free cutaneous influenza vaccination.
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.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Boston, MA 02114.
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Boston, MA 02114.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Boston, MA 02114 mwu5@mgh.harvard.edu.
authors.forename: Mei X
authors.initials: MX
authors.lastname: Wu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D056738:Cross Protection / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D007109:Immunity / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007271:Injections, Intradermal; D007834:Lasers; D008807:Mice, Inbred BALB C; D009339:Needles; D015203:Reproducibility of Results; D012867:Skin / Q000473:pathology*; D034421:Sus scrofa; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; D004247:DNA
keywords: biodegradable microneedle; dsDNA; nonablative fractional laser
references.citation: PLoS One. 2014;9(3):e92153
references.pmid: 24667168
references.citation: Vaccine. 2008 Dec 2;26(51):6614-9
references.pmid: 18930093
references.citation: Annu Rev Immunol. 2014;32:461-88
references.pmid: 24655297
references.citation: FASEB J. 2012 Mar;26(3):1272-9
references.pmid: 22106367
references.citation: Annu Rev Chem Biomol Eng. 2010;1:175-201
references.pmid: 22432578
references.citation: Nat Commun. 2014;5:4447
references.pmid: 25033973
references.citation: Vaccine. 2012 Dec 17;31(1):159-64
references.pmid: 23123021
references.citation: J Burn Care Res. 2014 Jan-Feb;35(1):46-53
references.pmid: 24270084
references.citation: Drug Deliv Transl Res. 2011 Feb 1;1(1):7-12
references.pmid: 21799951
references.citation: Nat Commun. 2013;4:1702
references.pmid: 23591869
references.citation: Bull World Health Organ. 2011 Mar 1;89(3):221-6
references.pmid: 21379418
references.citation: J Pharm Sci. 2013 Nov;102(11):4100-8
references.pmid: 24027112
references.citation: Vaccine. 2013 Jul 25;31(34):3392-5
references.pmid: 23176978
references.citation: Nat Med. 2010 Aug;16(8):915-20
references.pmid: 20639891
references.citation: J Control Release. 2012 Apr 10;159(1):43-51
references.pmid: 22261281
references.citation: Science. 2013 Feb 15;339(6121):786-91
references.pmid: 23258413
references.citation: Clin J Pain. 2008 Sep;24(7):585-94
references.pmid: 18716497
references.citation: Nature. 2009 Oct 8;461(7265):788-92
references.pmid: 19776740
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3041-6
references.pmid: 23386724
references.citation: Nat Med. 2011 Aug;17(8):996-1002
references.pmid: 21765404
references.citation: Sci Transl Med. 2011 Mar 9;3(73):73ra19
references.pmid: 21389263
references.citation: J Exp Med. 2010 Dec 20;207(13):2921-30
references.pmid: 21115688
references.citation: Expert Rev Vaccines. 2013 Nov;12(11):1313-23
references.pmid: 24127871
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):E1122-31
references.pmid: 23447566
references.citation: Int J Pharm. 2010 May 31;391(1-2):7-12
references.pmid: 20188808
references.citation: Immunity. 2013 May 23;38(5):870-80
references.pmid: 23706668
references.citation: Blood. 2012 Nov 1;120(18):3699-707
references.pmid: 22927244
references.citation: Adv Drug Deliv Rev. 2012 Nov;64(14):1547-68
references.pmid: 22575858
references.citation: Nat Rev Immunol. 2007 Mar;7(3):179-90
references.pmid: 17318230
references.citation: Science. 2013 Feb 15;339(6121):826-30
references.pmid: 23258412
references.citation: BMC Med. 2009;7:13
references.pmid: 19341446
references.citation: Nature. 2007 Oct 4;449(7162):564-9
references.pmid: 17873860
references.citation: J Immunol. 2003 Jun 1;170(11):5583-9
references.pmid: 12759437
references.citation: Small. 2010 Aug 16;6(16):1776-84
references.pmid: 20665754
references.citation: J Invest Dermatol. 2014 Sep;134(9):2361-70
references.pmid: 24714201
references.citation: J Control Release. 2014 Oct 28;192:310-6
references.pmid: 25135790
references.citation: N Engl J Med. 2009 Nov 12;361(20):1945-52
references.pmid: 19745214
references.citation: Immunity. 2014 Nov 20;41(5):830-42
references.pmid: 25517615
references.citation: Expert Rev Vaccines. 2011 Oct;10(10):1397-403
references.pmid: 21988305
references.citation: PLoS One. 2010;5(10):e13776
references.pmid: 21048884
references.citation: Lasers Surg Med. 2004;34(5):426-38
references.pmid: 15216537