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Understanding the basis of transcutaneous vaccine delivery

    Carlos Gamazo

    *Author for correspondence: Tel.: +34 948 255 400; Fax: +34 948 296 500;

    E-mail Address: cgamazo@unav.es

    Department of Microbiology, University of Navarra, 31008-Pamplona, Spain

    ,
    Yadira Pastor

    Department of Microbiology, University of Navarra, 31008-Pamplona, Spain

    ,
    Eneko Larrañeta

    School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK

    ,
    Melibea Berzosa

    Department of Microbiology, University of Navarra, 31008-Pamplona, Spain

    ,
    Juan M Irache

    Department of Pharmacy & Pharmaceutical Technology, University of Navarra, 31008-Pamplona, Spain

    &
    Ryan F Donnelly

    School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK

    Published Online:https://doi.org/10.4155/tde-2018-0054

    Under many circumstances, prophylactic immunizations are considered as the only possible strategy to control infectious diseases. Considerable efforts are typically invested in immunogen selection but, erroneously, the route of administration is not usually a major concern despite the fact that it can strongly influence efficacy. The skin is now considered a key component of the lymphatic system with tremendous potential as a target for vaccination. The purpose of this review is to present the immunological basis of the skin-associated lymphoid tissue, so as to provide understanding of the skin vaccination strategies. Several strategies are currently being developed for the transcutaneous delivery of antigens. The classical, mechanical or chemical disruptions versus the newest approaches based on microneedles for antigen delivery through the skin are discussed herein.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Shenefelt PD. Herbal treatment for dermatologic disorders. Arch. Dermatol. 138(2), 232–242 (2002).
    • 2 Streilein JW. Skin-associated lymphoid tissues (SALT): origins and functions. J. Invest. Dermatol. 80(Suppl), 12s–16s (1983). •• Seminal work on understanding the role of the skin-associated lymphoid tissue.
    • 3 Global Commission for the Certification of Smallpox Eradication & World Health Organization. The global eradication of smallpox: final report of the Global Commission for the Certification of Smallpox Eradication, Geneva, December 1979 (1980). http://apps.who.int/iris/handle/10665/68258.
    • 4 Baxter AL, Cohen LL, Burton M, Mohammed A, Lawson ML. The number of injected same-day preschool vaccines relates to preadolescent needle fear and HPV uptake. Vaccine 35(33), 4213–4219 (2017).
    • 5 Guo X, Zhong J-Y, Li J-W. Hepatitis C virus infection and vaccine development. J. Clin. Exp. Hepatol. 8(2), 195–204 (2018).
    • 6 Tomljenovic L, Shaw CA. Aluminum vaccine adjuvants: are they safe? Curr. Med. Chem. 18(17), 2630–2637 (2011).
    • 7 van der Laan JW, Gould S, Tanir JY. Safety of vaccine adjuvants: focus on autoimmunity. Vaccine 33(13), 1507–1514 (2015).
    • 8 Jung EC, Maibach HI. Animal models for percutaneous absorption. J. Appl. Toxicol. 35(1), 1–10 (2015).
    • 9 Lavker RM, Sun TT. Heterogeneity in epidermal basal keratinocytes: morphological and functional correlations. Science 215(4537), 1239–1241 (1982).
    • 10 Menon GK. New insights into skin structure: scratching the surface. Adv. Drug Deliv. Rev. 54(Suppl.), S3–S7 (2002).
    • 11 Nemes Z, Steinert PM. Bricks and mortar of the epidermal barrier. Exp. Mol. Med. 31(1), 5–19 (1999).
    • 12 Kalinin AE, Kajava AV, Steinert PM. Epithelial barrier function: assembly and structural features of the cornified cell envelope. Bioessays 24(9), 789–800 (2002).
    • 13 Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14(5), 289–301 (2014).
    • 14 Tong PL, Roediger B, Kolesnikoff N et al. The skin immune atlas: three-dimensional analysis of cutaneous leukocyte subsets by multiphoton microscopy. J. Invest. Dermatol. 135(1), 84–93 (2015).
    • 15 Lambert PH, Laurent PE. Intradermal vaccine delivery: will new delivery systems transform vaccine administration? Vaccine 26(26), 3197–3208 (2008).
    • 16 Gniadecka M, Jamec G. Quantitative evaluation of chronological aging and photoaging in vivo: studies on skin echogenicity and thickness. Br. J. Dermatol. 139, 815–821 (1998).
    • 17 Waller JM, Maibach HI. Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. Ski. Res. Technol. 11(4), 221–235 (2005).
    • 18 Shuster S, Black MM, McVitie E. The influence of age and sex on skin thickness, skin collagen and density. Br. J. Dermatol. 93(6), 639–643 (1975).
    • 19 Sandby-Møller J, Poulsen T, Wulf HC. Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits. Acta Derm. Venereol. 83(6), 410–413 (2003).
    • 20 Laurent A, Mistretta F, Bottigioli D et al. Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines. Vaccine 25(34), 6423–6430 (2007).
    • 21 Groswasser J, Kahn A, Bouche B et al. Needle length and injection technique for efficient intramuscular vaccine delivery in infants and children evaluated through an ultrasonographic determination of subcutaneous and muscle layer thickness. Pediatrics 100(3 Pt 1), 400–403 (1997).
    • 22 Marples M. In: Chapter 1. The Ecology of the Human Skin. Thomas CC (Ed.). Bannerstone House, IL, USA (1965).
    • 23 Kearney JN, Harnby D, Gowland G, Holland KT. The follicular distribution and abundance of resident bacteria on human skin. J. Gen. Microbiol. 130(4), 797–801 (1984).
    • 24 Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat. Rev. Immunol. 12(7), 503–516 (2012).
    • 25 Christensen GJM, Scholz CFP, Enghild J et al. Antagonism between Staphylococcus epidermidis and Propionibacterium acnes and its genomic basis. BMC Genomics 17(1), 1–14 (2016).
    • 26 Nakatsuji T, Chen TH, Narala S et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci. Transl. Med. 9(378), eaah4680 (2017).
    • 27 Chehoud C, Rafail S, Tyldsley AS, Seykora JT, Lambris JD, Grice EA. Complement modulates the cutaneous microbiome and inflammatory milieu. Proc. Natl Acad. Sci. USA 110(37), 15061–15066 (2013).
    • 28 Naik S, Bouladoux N, Wilhelm C et al. Compartmentalized control of skin immunity by resident commensals. Science 337(6098), 1115–1119 (2012).
    • 29 Naik S, Bouladoux N, Linehan JL et al. Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520(7545), 104–108 (2015).
    • 30 Brandtzaeg P. Mucosal immunity: induction, dissemination, and effector functions. Scand. J. Immunol. 70(6), 505–515 (2009).
    • 31 Salinas I. The mucosal immune system of teleost fish. Biology (Basel). 4, 525–539 (2015).
    • 32 Chen YE, Fischbach MA, Belkaid Y. Skin microbiota–host interactions. Nature 553(7689), 427–436 (2018). • Presents an overview on the interaction between skin microbes and the host, and the consequences on health, including the immune response.
    • 33 Thaiss CA, Levy M, Itav S, Elinav E. Integration of innate immune signaling. Trends Immunol. 37(2), 84–101 (2016).
    • 34 Belyakov IM, Hammond SA, Ahlers JD, Glenn GM, Berzofsky JA. Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells. J. Clin. Invest. 113(7), 998–1007 (2004).
    • 35 Glenn GM, Kenney RT, Ellingsworth LR, Frech SA, Hammond SA, Zoeteweij JP. Transcutaneous immunization and immunostimulant strategies: capitalizing on the immunocompetence of the skin. Expert Rev. Vaccines 2(2), 253–267 (2003).
    • 36 Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9(10), 679–691 (2009).
    • 37 Miller LS, Modlin RL. Human keratinocyte toll-like receptors promote distinct immune responses. J. Invest. Dermatol. 127(2), 262–263 (2007).
    • 38 Lebre MC, Van Der Aar AMG, Van Baarsen L et al. Human keratinocytes express functional toll-like receptor 3, 4, 5, and 9. J. Invest. Dermatol. 127(2), 331–341 (2007).
    • 39 Black APB, Ardern-Jones MR, Kasprowicz V et al. Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells. Eur. J. Immunol. 37(6), 1485–1493 (2007).
    • 40 Brodell LA, Ã B, Rosenthal KS. Skin structure and function the body's primary defense against infection. Infect. Dis. Clin. Pract. 16(2), 113–117 (2008).
    • 41 Kobayashi M, Yoshiki R, Sakabe J, Kabashima K, Nakamura M, Tokura Y. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes. Br. J. Dermatol. 160(2), 297–304 (2009).
    • 42 Partidos CD, Beignon AS, Semetey V, Briand JP, Muller S. The bare skin and the nose as non-invasive routes for administering peptide vaccines. Vaccine 19(17–19), 2708–2715 (2001).
    • 43 Kubo A, Nagao K, Yokouchi M, Sasaki H, Amagai M. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J. Exp. Med. 206(13), 2937–2946 (2009).
    • 44 Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat. Rev. Immunol. 8(12), 935–947 (2008).
    • 45 Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nat. Rev. Immunol. 14(6), 417–428 (2014).
    • 46 Kerstan A, Bröcker EB, Trautmann A. Decisive role of tumor necrosis factor-α for spongiosis formation in acute eczematous dermatitis. Arch. Dermatol. Res. 303(9), 651–658 (2011).
    • 47 Ebner S, Nguyen VA, Forstner M et al. Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells. J. Allergy Clin. Immunol. 119(4), 982–990 (2007).
    • 48 Gasque P, Jaffar-Bandjee MC. The immunology and inflammatory responses of human melanocytes in infectious diseases. J. Infect. 71(4), 413–421 (2015).
    • 49 Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).
    • 50 Gorvel L, Korenfeld D, Tung T, Klechevsky E. Dendritic cell-derived IL-32α: a novel inhibitory cytokine of NK cell function. J. Immunol. 199(4), 1290–1300 (2017).
    • 51 Lalor SJ, McLoughlin RM. Memory γδ T Cells – newly appreciated protagonists in infection and immunity. Trends Immunol. 37(10), 690–702 (2016).
    • 52 Gordon S. Alternative activation of macrophages. Nat. Rev. Immunol. 3(1), 23–25 (2003).
    • 53 Sica AM. Macrophage plasticity and polarization. J. Clin. Invest. 122(3), 787–795 (2012).
    • 54 Heib V, Becker M, Taube C, Stassen M. Advances in the understanding of mast cell function. Br. J. Haematol. 142(5), 683–694 (2008).
    • 55 Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ. Mast cell-derived IL-10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat. Immunol. 8(10), 1095–104 (2007).
    • 56 Clark RA. Skin-resident T cells: the ups and downs of on site immunity. J. Invest. Dermatol. 130(2), 362–370 (2010).
    • 57 Holtmeier W, Kabelitz D. gammadelta T cells link innate and adaptive immune responses. Chem. Immunol. Allergy 86, 151–183 (2005).
    • 58 O'Brien RL, Born WK. Dermal γδ T cells - what have we learned? Cell. Immunol. 296(1), 62–69 (2015).
    • 59 Mehling A, Loser K, Varga G et al. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J. Exp. Med. 194(5), 615–628 (2001).
    • 60 Chen D, Maa YF, Haynes JR. Needle-free epidermal powder immunization. Expert Rev. Vaccin. 1(3), 265–276 (2002).
    • 61 Logomasini MA, Stout RR. Jet injection devices for the needle-free administration of compounds, vaccines, and other agents. Int. J. Pharm. Compd. 17(4), 270–280 (2013).
    • 62 Chen X, Kositratna G, Zhou C, Manstein D, Wu MX. Micro-fractional epidermal powder delivery for improved skin vaccination. J. Control. Rel. 192, 310–316 (2014).
    • 63 Baxter J, Mitragotri S. Needle-free liquid jet injections: mechanisms and applications. Expert Rev. Med. Devices 3(5), 565–574 (2006).
    • 64 Frerichs DM, Ellingsworth LR, Frech SA et al. Controlled, single-step, stratum corneum disruption as a pretreatment for immunization via a patch. Vaccine 26(22), 2782–2787 (2008).
    • 65 Seid RC, Look JL, Ruiz C et al. Transcutaneous immunization with Intercell's vaccine delivery system. Vaccine 30(29), 4349–4354 (2012).
    • 66 Glenn GM, Villar CP, Flyer DC et al. Safety and immunogenicity of an enterotoxigenic Escherichia coli vaccine patch containing heat-labile toxin: use of skin pretreatment to disrupt the stratum corneum. Infect. Immun. 75(5), 2163–2170 (2007).
    • 67 Gill HS, Andrews SN, Sakthivel SK et al. Selective removal of stratum corneum by microdermabrasion to increase skin permeability. Eur. J. Pharm. Sci. 38(2), 95–103 (2009).
    • 68 Apitz I, Vogel A. Material ejection in nanosecond Er:YAG laser ablation of water, liver, and skin. Appl. Phys. A Mater. Sci. Process. 81(2), 329–338 (2005).
    • 69 Bramson J, Dayball K, Evelegh C, Wan YH, Page D, Smith A. Enabling topical immunization via microporation: a novel method for pain-free and needle-free delivery of adenovirus-based vaccines. Gene Ther. 10(3), 251–260 (2003).
    • 70 Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int. J. Pharm. 364(2), 227–236 (2008).
    • 71 Tezel A, Paliwal S, Shen Z, Mitragotri S. Low-frequency ultrasound as a transcutaneous immunization adjuvant. Vaccine 23(29), 3800–3807 (2005).
    • 72 Dahlan A, Alpar HO, Stickings P, Sesardic D, Murdan S. Transcutaneous immunisation assisted by low-frequency ultrasound. Int. J. Pharm. 368(1–2), 123–128 (2009).
    • 73 Foldvari M, Babiuk S, Badea I. DNA delivery for vaccination and therapeutics through the skin. Curr. Drug Deliv. 3(1), 17–28 (2006).
    • 74 Broderick KE, Khan AS, Sardesai NY. DNA vaccination in skin enhanced by electroporation. Methods Mol. Biol. 1143, 123–130 (2014).
    • 75 Todorova B, Adam L, Culina S et al. Electroporation as a vaccine delivery system and a natural adjuvant to intradermal administration of plasmid DNA in macaques. Sci. Rep. 7(1), 4122 (2017).
    • 76 Storni T, Kündig TM, Senti G, Johansen P. Immunity in response to particulate antigen-delivery systems. Adv. Drug Deliv. Rev. 57(3), 333–355 (2005).
    • 77 Trovato M, De Berardinis P. Novel antigen delivery systems. World J. Virol. 4(3), 156–168 (2015).
    • 78 Mishra D, Dubey V, Asthana A, Saraf DK, Jain NK. Elastic liposomes mediated transcutaneous immunization against Hepatitis B. Vaccine 24(22), 4847–4855 (2006).
    • 79 Mahor S, Rawat A, Dubey PK et al. Cationic transfersomes based topical genetic vaccine against hepatitis B. Int. J. Pharm. 340(1–2), 13–19 (2007).
    • 80 Mishra V, Mahor S, Rawat A et al. Development of novel fusogenic vesosomes for transcutaneous immunization. Vaccine 24(27–28), 5559–5570 (2006).
    • 81 Vyas SP, Singh RP, Jain S et al. Non-ionic surfactant based vesicles (niosomes) for non-invasive topical genetic immunization against hepatitis B. Int. J. Pharm. 296(1–2), 80–86 (2005).
    • 82 Tamayo I, Gamazo C, de Souza Rebouças J, Irache JM. Topical immunization using a nanoemulsion containing bacterial membrane antigens. J. Drug Deliv. Sci. Technol. 42, 207–214 (2017).
    • 83 Karande P, Mitragotri S. Transcutaneous immunization: an overview of advantages, disease targets, vaccines, and delivery technologies. Annu. Rev. Chem. Biomol. Eng. 1, 175–201 (2010).
    • 84 Cevc G. Transferosomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery. Crit. Rev. Ther. Drug Carr. Syst. 13(3–4), 257–388 (1996).
    • 85 Chen J, Lu W-L, Gu W, Lu S-S, Chen Z-P, Cai B-C. Skin permeation behavior of elastic liposomes: role of formulation ingredients. Expert Opin. Drug Deliv. 10(6), 845–856 (2013).
    • 86 Benson HAE. Elastic liposomes for topical and transdermal drug delivery. Methods Mol. Biol. 605, 77–86 (2010).
    • 87 Duangjit S, Opanasopit P, Rojanarata T, Ngawhirunpat T. Effect of edge activator on characteristic and in vitro skin permeation of meloxicam loaded in elastic liposomes. Adv. Mater. Res. Vols. 194–196, 537–540 (2011).
    • 88 Garg V, Singh H, Bimbrawh S et al. Ethosomes and transfersomes: principles, perspectives and practices. Curr. Drug Deliv. 14(5), 613–633 (2016).
    • 89 Prausnitz MR. Microneedles for transdermal drug delivery. Adv. Drug Deliv. Rev. 56(5), 581–587 (2004).
    • 90 Donnelly RF, Singh TRR, Morrow DIJ, Woolfson AD. Microneedle-Mediated Transdermal and Intradermal Drug Delivery. Hoboken, Wiley–Blackwell, Oxford, UK (2012).
    • 91 Larrañeta E, Lutton REM, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Mater. Sci. Eng. R Reports. 104, 1–32 (2016). •• Identifies the relevance of microneedles as delivery systems. Contains key perspectives for manufacture and commercial development.
    • 92 Lutton REM, Moore J, Larrañeta E, Ligett S, Woolfson AD, Donnelly RF. Microneedle characterisation: the need for universal acceptance criteria and GMP specifications when moving towards commercialisation. Drug Deliv. Transl. Res. 5(4), 313–331 (2015). • Contains an interesting discussion on commercial development of microneedles.
    • 93 Tuan-Mahmood TM, McCrudden MTC, Torrisi BM et al. Microneedles for intradermal and transdermal drug delivery. Eur. J. Pharm. Sci. 50(5), 623–637 (2013).
    • 94 Indermun S, Luttge R, Choonara YE et al. Current advances in the fabrication of microneedles for transdermal delivery. J. Control. Rel. 185, 130–138 (2014).
    • 95 Ripolin A, Quinn J, Larrañeta E, Vicente-Perez EM, Barry J, Donnelly RF. Successful application of large microneedle patches by human volunteers. Int. J. Pharm. 521(1–2), 92–101 (2017).
    • 96 Lutton REM, Larrañeta E, Kearney MC, Boyd P, Woolfson AD, Donnelly RF. A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays. Int. J. Pharm. 494(1), 417–429 (2015).
    • 97 Kommareddy S, Baudner BC, Oh S, Kwon SY, Singh M, O'Hagan DT. Dissolvable microneedle patches for the delivery of cell-culture-derived influenza vaccine antigens. J. Pharm. Sci. 101(3), 1021–1027 (2012).
    • 98 Raphael AP, Prow TW, Crichton ML, Chen X, Fernando GJP, Kendall MAF. Targeted, needle-free vaccinations in skin using multilayered, densely-packed dissolving microprojection arrays. Small 6(16), 1785–1793 (2010).
    • 99 Sullivan SP, Koutsonanos DG, Del Pilar Martin M et al. Dissolving polymer microneedle patches for influenza vaccination. Nat. Med. 16(8), 915–920 (2010).
    • 100 Rouphael NG, Paine M, Mosley R et al. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, Phase I trial. Lancet 390(10095), 649–658 (2017).
    • 101 Matsuo K, Hirobe S, Yokota Y et al. Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza. J. Control. Rel. 160(3), 495–501 (2012).
    • 102 Matsuo K, Okamoto H, Kawai Y et al. Vaccine efficacy of transcutaneous immunization with amyloid β using a dissolving microneedle array in a mouse model of Alzheimer's disease. J. Neuroimmunol. 266(1–2), 1–11 (2014).
    • 103 Kommareddy S, Baudner BC, Bonificio A et al. Influenza subunit vaccine coated microneedle patches elicit comparable immune responses to intramuscular injection in guinea pigs. Vaccine 31(34), 3435–3441 (2013).
    • 104 Zhu Q, Zarnitsyn VG, Ye L et al. Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge. Proc. Natl Acad. Sci. USA 106(19), 7968–7973 (2009).
    • 105 Wang BZ, Gill HS, He C et al. Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity. J. Control. Rel. 178, 1–7 (2014).
    • 106 Edens C, Collins ML, Ayers J, Rota PA, Prausnitz MR. Measles vaccination using a microneedle patch. Vaccine 31(34), 3403–3409 (2013).
    • 107 Vrdoljak A, McGrath MG, Carey JB et al. Coated microneedle arrays for transcutaneous delivery of live virus vaccines. J. Control. Rel. 159(1), 34–42 (2012).
    • 108 Kim NW, Lee MS, Kim KR et al. Polyplex-releasing microneedles for enhanced cutaneous delivery of DNA vaccine. J. Control. Rel. 179, 11–17 (2014).
    • 109 Donnelly RF, Larrañeta E. Microarray patches: potentially useful delivery systems for long-acting nanosuspensions. Drug Discov. Today 23(5), 1026–1033 (2018). •• Recent review on micropatches. Explore the key considerations in the development of combined drug-delivery systems.
    • 110 Demuth PC, Moon JJ, Suh H, Hammond PT, Irvine DJ. Releasable layer-by-layer assembly of stabilized lipid nanocapsules on microneedles for enhanced transcutaneous vaccine delivery. ACS Nano. 6(9), 8041–8051 (2012).
    • 111 Burton SA, Ng CY, Simmers R et al. Rapid intradermal delivery of liquid formulations using a hollow microstructured array. Pharm. Res. 28(1), 31–40 (2011).
    • 112 Laurent PE, Bonnet S, Alchas P et al. Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. Vaccine 25(52), 8833–8842 (2007).
    • 113 Mikszta JA, Dekker JP, Harvey NG et al. Microneedle-based intradermal delivery of the anthrax recombinant protective antigen vaccine. Infect. Immun. 74(12), 6806–6810 (2006).
    • 114 Laurent PE, Bourhy H, Fantino M, Alchas P, Mikszta JA. Safety and efficacy of novel dermal and epidermal microneedle delivery systems for rabies vaccination in healthy adults. Vaccine 28(36), 5850–5856 (2010).
    • 115 Morefield GL, Tammariello RF, Purcell BK et al. An alternative approach to combination vaccines: intradermal administration of isolated components for control of anthrax, botulism, plague and staphylococcal toxic shock. J. Immune Based Ther. Vaccines 6, 5 (2008).
    • 116 Larrañeta E, McCrudden MTC, Courtenay AJ, Donnelly RF. Microneedles: a new frontier in nanomedicine delivery. Pharm. Res. 33(5), 1055–1073 (2016).
    • 117 Zaric M, Lyubomska O, Touzelet O et al. Skin dendritic cell targeting via microneedle arrays laden with antigen-encapsulated poly-D, l-Lactide-Co-Glycolide nanoparticles induces efficient antitumor and antiviral immune responses. ACS Nano. 7(3), 2042–2055 (2013).
    • 118 Zaric M, Lyubomska O, Poux C et al. Dissolving microneedle delivery of nanoparticle-encapsulated antigen elicits efficient cross-priming and th1 immune responses by murine langerhans cells. J. Invest. Dermatol. 135(2), 425–434 (2015).
    • 119 Zhang Y, Ng Weibeng, Feng X, Cao F, Xu Huaxi. Lipid vesicular nanocarrier: quick encapsulation efficiency determination and transcutaneous application. Int. J. Pharm. 516(1–2), 225–230 (2017). • Highlights the immune mechanisms underlying effective immunization by using micronneedles.
    • 120 Bussio JI, Molina-Perea C, González-Aramundiz JV. Lower-size chitosan nanocapsules for transcutaneous antigen delivery. Nanomaterials (Basel). 8(9), doi: 10.3390/nano8090659 (2018) (Epub ahead of print).
    • 121 Bernardi DS, Bitencourt C, da Silveira DS et al. Effective transcutaneous immunization using a combination of iontophoresis and nanoparticles. Nanomedicine 12(8), 2439–2448 (2016). • The authors illustrate the effectiveness of using nanoparticles as antigen-delivery systems through the skin.
    • 122 Leone M, Mönkäre J, Bouwstra JA, Kersten G. Dissolving microneedle patches for dermal vaccination. Pharm. Res. 34(11), 2223–2240 (2017).
    • 123 Warrell MJ. Current rabies vaccines and prophylaxis schedules: preventing rabies before and after exposure. Travel Med. Infect. Dis. 10(1), 1–15 (2012).
    • 124 Millar JD, Roberto RR, Wulff H, Wenner HA, Henderson DA. Smallpox vaccination by intradermal jet injection. I. Introduction, background and results of pilot studies. Bull. World Health Organ. 41(6), 749–760 (1969).
    • 125 Mohammed AJ, AlAwaidy S, Bawikar S et al. Fractional doses of inactivated poliovirus vaccine in Oman. N. Engl. J. Med. 362(25), 2351–2359 (2010).
    • 126 Resik S, Tejeda A, Lago PM et al. Randomized controlled clinical trial of fractional doses of inactivated poliovirus vaccine administered intradermally by needle-free device in Cuba. J. Infect. Dis. 201(9), 1344–1352 (2010).
    • 127 Resik S, Tejeda A, Mach O et al. Needle-free jet injector intradermal delivery of fractional dose inactivated poliovirus vaccine: association between injection quality and immunogenicity. Vaccine 33(43), 5873–5877 (2015).
    • 128 Dean HJ, Chen D. Epidermal powder immunization against influenza. Vaccine 23(5), 681–686 (2004).
    • 129 Jones S, Evans K, McElwaine-Johnn H et al. DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled Phase Ib clinical trial. Vaccine 27(18), 2506–2512 (2009).
    • 130 Frech SA, DuPont HL, Bourgeois AL et al. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a Phase II, randomised, double-blind, placebo-controlled field trial. Lancet 371(9629), 2019–2025 (2008).
    • 131 Behrens RH, Cramer JP, Jelinek T et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a Phase III, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect. Dis. 14(3), 197–204 (2014).
    • 132 Kwon KM, Lim S-M, Choi S et al. Microneedles: quick and easy delivery methods of vaccines. Clin. Exp. Vaccine Res. 6(2), 156–159 (2017).
    • 133 Leroux-Roels I, Weber F. Intanza® 9 μg intradermal seasonal influenza vaccine for adults 18 to 59 years of age. Hum. Vaccin. Immunother. 9(1), 115–121 (2013).
    • 134 Arnou R, Icardi G, De Decker M et al. Intradermal influenza vaccine for older adults: a randomized controlled multicenter Phase III study. Vaccine 27(52), 7304–7312 (2009).
    • 135 Troy SB, Kouiavskaia D, Siik J et al. Comparison of the immunogenicity of various booster doses of inactivated polio vaccine delivered intradermally versus intramuscularly to HIV-infected adults. J. Infect. Dis. 211(12), 1969–1976 (2015).
    • 136 Anand A, Zaman K, Estívariz CF et al. Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: a randomized controlled trial. Vaccine 33(48), 6816–6822 (2015).
    • 137 Vescovo P, Rettby N, Ramaniraka N et al. Safety, tolerability and efficacy of intradermal rabies immunization with DebioJect. Vaccine 35(14), 1782–1788 (2017).
    • 138 Laurent PE, Bourhy H, Fantino M, Alchas P, Mikszta JA. Safety and efficacy of novel dermal and epidermal microneedle delivery systems for rabies vaccination in healthy adults. Vaccine 28(36), 5850–5856 (2010).
    • 139 Rouphael NG, Paine M, Mosley R et al. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, Phase I trial. Lancet 390(10095), 649–658 (2017).
    • 140 Hirobe S, Azukizawa H, Hanafusa T et al. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Biomaterials 57, 50–58 (2015).
    • 141 Marshall S, Sahm LJ, Moore AC. The success of microneedle-mediated vaccine delivery into skin. Hum. Vaccin. Immunother. 12(11), 2975–2983 (2016). •• Compares primary scientific literature pertaining to micronneedle-mediated in vivo vaccination programs.
    • 142 Haidari G, Cope A, Miller A et al. Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial. Sci. Rep. 7(1), 1–11 (2017).
    • 143 Kim H, Theogarajan LS, Pennathur S. A repeatable and scalable fabrication method for sharp, hollow silicon microneedles. J. Micromech. Microeng. 28, 035007 (2018).
    • 144 McCrudden MTC, Alkilani AZ, Courtenay AJ et al. Considerations in the sterile manufacture of polymeric microneedle arrays. Drug Deliv. Transl. Res. 5(1), 3–14 (2014).
    • 145 Donnelly RF, Singh TRR, Tunney MM et al. Microneedle arrays allow lower microbial penetration than hypodermic needles in vitro. Pharm. Res. 26(11), 2513–2522 (2009).
    • 146 Donnelly RF, Majithiya R, Singh TRR et al. Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding techniques. Pharm. Res. 28, 41–57 (2010).