Targeting the Skin for Microneedle Delivery of Influenza Vaccine

  • Dimitrios G. Koutsonanos
  • Richard W. Compans
  • Ioanna SkountzouEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 785)


Influenza infection represents a major socioeconomic burden worldwide. Skin represents a new target that has gained much attention in recent years for delivery of influenza vaccine as an alternative to the conventional intramuscular route of immunization. In this review we describe different microneedle vaccination approaches used in vivo, including metal and dissolving microneedle patches that have demonstrated promising results. Additionally we analyze the immunological basis for microneedle skin immunization and targeting of the skin’s dense population of antigen presenting cells, their role, characterization, and function. Additionally we analyze the importance of inflammatory signaling in the skin after microneedle delivery.


Microneedles Skin immunization Influenza Dendritic cells Langerhans cells 



We thank for the collaboration Dr. Mark R. Prausnitz, Dr. Vladimyr G. Zarnitsyn, Dr. Harvinder Singh Gill and Dr. Sean P. Sullivan, School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA.

Research was supported by 1U01 AI074579-01/NIH and 1U01 EB012495/NIBIB grants.


  1. 1.
    Fiore, A.E., et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 57, 1–60 (2008).PubMedGoogle Scholar
  2. 2.
    Monto, A.S. Seasonal influenza and vaccination ­coverage. Vaccine 28 Suppl 4, D33–44 (2010).PubMedCrossRefGoogle Scholar
  3. 3.
    Osterholm, M.T. Preparing for the next pandemic. N Engl J Med 352, 1839–1842 (2005).PubMedCrossRefGoogle Scholar
  4. 4.
    Thompson, W.W., et al. Influenza-associated ­hospitalizations in the United States. JAMA 292, 1333–1340 (2004).PubMedCrossRefGoogle Scholar
  5. 5.
    Beigel, J.H. Influenza. Crit Care Med 36, 2660–2666 (2008).CrossRefGoogle Scholar
  6. 6.
    Dushoff, J., Plotkin, J.B., Viboud, C., Earn, D.J. & Simonsen, L. Mortality due to influenza in the United States--an annualized regression approach using multiple-cause mortality data. Am J Epidemiol 163, 181–187 (2006).PubMedCrossRefGoogle Scholar
  7. 7.
    Heron, M. Deaths: leading causes for 2007. Natl Vital Stat Rep 59, 1–95 (2011).PubMedGoogle Scholar
  8. 8.
    Simonsen, L. The global impact of influenza on morbidity and mortality. Vaccine 17 Suppl 1, S3–10 (1999).PubMedCrossRefGoogle Scholar
  9. 9.
    Palese, P. Influenza: old and new threats. Nat Med 10, S82–87 (2004).PubMedCrossRefGoogle Scholar
  10. 10.
    Cox, N.J. & Subbarao, K. Influenza. Lancet 354, 1277–1282 (1999).CrossRefGoogle Scholar
  11. 11.
    WHO. Immunization, Vaccines and Biologicals-Influenza. (2008).Google Scholar
  12. 12.
    Zhou, H., et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993–2008. Clin Infect Dis 54, 1427–1436 (2012).PubMedCrossRefGoogle Scholar
  13. 13.
    Longini, I.M., Jr. & Halloran, M.E. Strategy for distribution of influenza vaccine to high-risk groups and children. Am J Epidemiol 161, 303–306 (2005).PubMedCrossRefGoogle Scholar
  14. 14.
    Ompad, D.C., Galea, S. & Vlahov, D. Distribution of influenza vaccine to high-risk groups. Epidemiol Rev 28, 54–70 (2006).PubMedCrossRefGoogle Scholar
  15. 15.
    Loerbroks, A., Stock, C., Bosch, J.A., Litaker, D.G. & Apfelbacher, C.J. Influenza vaccination coverage among high-risk groups in 11 European countries. Eur J Public Health (2011).Google Scholar
  16. 16.
    O’Brien, M.A., et al. Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics 113, 585–593 (2004).PubMedCrossRefGoogle Scholar
  17. 17.
    Izurieta, H.S., et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 342, 232–239 (2000).PubMedCrossRefGoogle Scholar
  18. 18.
    Nolan, T., et al. Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial. JAMA 303, 37–46 (2010).PubMedCrossRefGoogle Scholar
  19. 19.
    Avelino-Silva, V.I., et al. Campaign, counseling and compliance with influenza vaccine among older persons. Clinics (Sao Paulo) 66, 2031–2035 (2011).Google Scholar
  20. 20.
    Miraglia, J.L., et al. Immunogenicity and reactogenicity of 2009 influenza A (H1N1) inactivated monovalent non-adjuvanted vaccine in elderly and immunocompromised patients. PloS one 6, e27214 (2011).PubMedCrossRefGoogle Scholar
  21. 21.
    Mullooly, J.P., et al. Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization. Ann Intern Med 121, 947–952 (1994).PubMedGoogle Scholar
  22. 22.
    Nichol, K.L., et al. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 348, 1322–1332 (2003).PubMedCrossRefGoogle Scholar
  23. 23.
    Reber, A.J., et al. Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population. Aging Dis 3, 68–90 (2012).PubMedGoogle Scholar
  24. 24.
    Myers, E.R., Misurski, D.A. & Swamy, G.K. Influence of timing of seasonal influenza vaccination on effectiveness and cost-effectiveness in pregnancy. Am J Obstet Gynecol 204, S128–140 (2011).PubMedCrossRefGoogle Scholar
  25. 25.
    Blanchard-Rohner, G. & Siegrist, C.A. Vaccination during pregnancy to protect infants against influenza: why and why not? Vaccine 29, 7542–7550 (2011).PubMedCrossRefGoogle Scholar
  26. 26.
    Ford, E.S., Mannino, D.M. & Williams, S.G. Asthma and influenza vaccination: findings from the 1999–2001 National Health Interview Surveys. Chest 124, 783–789 (2003).PubMedCrossRefGoogle Scholar
  27. 27.
    Ford, E.S., Williams, S.G., Mannino, D.M. & Redd, S.C. Influenza vaccination coverage among adults with asthma: findings from the 2000 Behavioral Risk Factor Surveillance System. Am J Med 116, 555–558 (2004).PubMedCrossRefGoogle Scholar
  28. 28.
    Plans-Rubio, P. Prevention and control of influenza in persons with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2, 41–53 (2007).PubMedGoogle Scholar
  29. 29.
    Hsu, A.C., See, H.V. & Wark, P.A. Innate immunity to influenza in chronic airways diseases. Respirology (2012).Google Scholar
  30. 30.
    Iorio, A.M., et al. Influenza vaccination in patients on long-term anticoagulant therapy. Vaccine 24, 6624–6628 (2006).PubMedCrossRefGoogle Scholar
  31. 31.
    Shaw, S.M., Williams, S.G., Yonan, N. & Fildes, J.E. Decreased immune responses to influenza vaccination in patients with heart failure. J Card Fail 15, 549; author reply 549–551 (2009).Google Scholar
  32. 32.
    Ott, S.R., et al. [The impact of viruses in lower respiratory tract infections of the adult. Part II: acute bronchitis, acute exacerbated COPD, pneumonia, and influenza]. Pneumologie 64, 18–27 (2010).PubMedCrossRefGoogle Scholar
  33. 33.
    Hakim, H., et al. Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults. Vaccine 30, 879–885 (2012).PubMedCrossRefGoogle Scholar
  34. 34.
    Bickel, M., et al. Low rate of seroconversion after vaccination with a split virion, adjuvanted pandemic H1N1 influenza vaccine in HIV-1-infected patients. AIDS 24, F31–35 (2010).PubMedCrossRefGoogle Scholar
  35. 35.
    Cooper, C., et al. Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults. PloS one 6, e17758 (2011).PubMedCrossRefGoogle Scholar
  36. 36.
    Jain, S. & Chaves, S.S. Obesity and influenza. Clin Infect Dis 53, 422–424 (2011).CrossRefGoogle Scholar
  37. 37.
    Camilloni, B., et al. An influenza B outbreak during the 2007/2008 winter among appropriately immunized elderly people living in a nursing home. Vaccine 28, 7536–7541 (2010).PubMedCrossRefGoogle Scholar
  38. 38.
    Potter, J.M., O’Donnel, B., Carman, W.F., Roberts, M.A. & Stott, D.J. Serological response to influenza vaccination and nutritional and functional status of patients in geriatric medical long-term care. Age Ageing 28, 141–145 (1999).PubMedCrossRefGoogle Scholar
  39. 39.
    Clarke, C.E. & McComas, K. Seeking and processing influenza vaccine information: a study of health care workers at a large urban hospital. Health Commun 27, 244–256 (2012).PubMedCrossRefGoogle Scholar
  40. 40.
    Potter, J., et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. J Infect Dis 175, 1–6 (1997).PubMedCrossRefGoogle Scholar
  41. 41.
    Carman, W.F., et al. Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 355, 93–97 (2000).PubMedCrossRefGoogle Scholar
  42. 42.
    Music, T. Protecting patients, protecting healthcare workers: a review of the role of influenza vaccination. Int Nurs Rev 59, 161–167 (2012).PubMedCrossRefGoogle Scholar
  43. 43.
    Medina, R.A. & Garcia-Sastre, A. Influenza A viruses: new research developments. Nat Rev Microbiol 9, 590–603 (2011).PubMedCrossRefGoogle Scholar
  44. 44.
    Guan, R., et al. Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus. Proc Natl Acad Sci USA 108, 13468–13473 (2011).PubMedCrossRefGoogle Scholar
  45. 45.
    Sridharan, H., Zhao, C. & Krug, R.M. Species specificity of the NS1 protein of influenza B virus: NS1 binds only human and non-human primate ubiquitin-like ISG15 proteins. J Biol Chem 285, 7852–7856 (2010).PubMedCrossRefGoogle Scholar
  46. 46.
    Higgins, R.R., et al. Recovery of Influenza B Virus with the H273Y Point Mutation in the neuraminidase Active site from a Human Patient. J Clin Microbiol (2012).Google Scholar
  47. 47.
    Ak, O., et al. Influenza B-associated encephalopathy in two adults. J Infect Chemother (2012).Google Scholar
  48. 48.
    Rath, B., et al. Virus Load Kinetics and Resistance Development during Oseltamivir Treatment in Infants and Children Infected with Influenza A (H1N1) 2009 and Influenza B Viruses. Pediatr Infect Dis J (2012).Google Scholar
  49. 49.
    Steininger, C., et al. Acute encephalopathy associated with influenza A virus infection. Clin Infect Dis 36, 567–574 (2003).PubMedCrossRefGoogle Scholar
  50. 50.
    Baccam, P., Beauchemin, C., Macken, C.A., Hayden, F.G. & Perelson, A.S. Kinetics of influenza A virus infection in humans. J Virol 80, 7590–7599 (2006).PubMedCrossRefGoogle Scholar
  51. 51.
    Canini, L. & Carrat, F. Population modeling of influenza A/H1N1 virus kinetics and symptom dynamics. J Virol 85, 2764–2770 (2011).PubMedCrossRefGoogle Scholar
  52. 52.
    Russell, C.A. The global circulation of seasonal influenza A (H3N2) viruses. Science 320, 340–346 (2008).PubMedCrossRefGoogle Scholar
  53. 53.
    Russell, R.J., Stevens, D.J., Haire, L.F., Gamblin, S.J. & Skehel, J.J. Avian and human receptor binding by hemagglutinins of influenza A viruses. Glycoconj. J. 23, 85–92 (2006).PubMedCrossRefGoogle Scholar
  54. 54.
    Skountzou, I. Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus. J. Immunol. 185, 1642–1649 (2010).PubMedCrossRefGoogle Scholar
  55. 55.
    Xu, R. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328, 357–360 (2010).PubMedCrossRefGoogle Scholar
  56. 56.
    Perez, D.R. Fitness of pandemic H1N1 and seasonal influenza A viruses during co-infection: evidence of competitive advantage of pandemic H1N1 influenza versus seasonal influenza. PLoS Curr. 1, RRN1011 (2009).Google Scholar
  57. 57.
    Chen, R. & Holmes, E.C. The evolutionary dynamics of human influenza B virus. J Mol Evol 66, 655–663 (2008).PubMedCrossRefGoogle Scholar
  58. 58.
    Hampson, A.W. & Mackenzie, J.S. The influenza viruses. Med J Aust 185, S39–43 (2006).PubMedGoogle Scholar
  59. 59.
    Racaniello, V.R. & Palese, P. Isolation of influenza C virus recombinants. J Virol 32, 1006–1014 (1979).PubMedGoogle Scholar
  60. 60.
    Fouchier, R.A. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J. Virol. 79, 2814–2822 (2005).PubMedCrossRefGoogle Scholar
  61. 61.
    Tong, S., et al. A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci USA 109, 4269–4274 (2012).PubMedGoogle Scholar
  62. 62.
    Krauss, S., Walker, D. & Webster, R.G. Influenza virus isolation. Methods Mol Biol 865, 11–24 (2012).PubMedCrossRefGoogle Scholar
  63. 63.
    CDC. Influenza Type A Viruses and Subtypes. (2011).Google Scholar
  64. 64.
    Khiabanian, H., Farrell, G.M., St George, K. & Rabadan, R. Differences in patient age distribution between influenza A subtypes. PloS one 4, e6832 (2009).Google Scholar
  65. 65.
    Pica, N., Chou, Y.Y., Bouvier, N.M. & Palese, P. Transmission of influenza B viruses in the guinea pig. J Virol 86, 4279–4287 (2012).PubMedCrossRefGoogle Scholar
  66. 66.
    Sandbulte, M.R., et al. Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses. Proc Natl Acad Sci USA 108, 20748–20753 (2011).PubMedCrossRefGoogle Scholar
  67. 67.
    Stray, S.J. & Pittman, L.B. Subtype- and antigenic site-specific differences in biophysical influences on evolution of influenza virus hemagglutinin. Virol J 9, 91 (2012).PubMedCrossRefGoogle Scholar
  68. 68.
    Yewdell, J.W. Viva la revolucion: rethinking influenza a virus antigenic drift. Curr Opin Virol 1, 177–183 (2011).PubMedCrossRefGoogle Scholar
  69. 69.
    Salazar, M.I., Lopez-Ortega, O., Leon-Avila, G., Ramirez-Gonzalez, J.E. & Castro-Mussot, M.E. [The origin of the genetic variability of influenza viruses]. Gac Med Mex 146, 199–206 (2010).PubMedGoogle Scholar
  70. 70.
    Epstein, S.L. & Price, G.E. Cross-protective immunity to influenza A viruses. Expert Rev Vaccines 9, 1325–1341 (2010).PubMedCrossRefGoogle Scholar
  71. 71.
    Bouvier, N.M. & Palese, P. The biology of influenza viruses. Vaccine 26 Suppl 4, D49–53 (2008).PubMedCrossRefGoogle Scholar
  72. 72.
    Grebe, K.M., Yewdell, J.W. & Bennink, J.R. Heterosubtypic immunity to influenza A virus: where do we stand? Microbes Infect 10, 1024–1029 (2008).PubMedCrossRefGoogle Scholar
  73. 73.
    Szucs, T. The socio-economic burden of influenza. J Antimicrob Chemother 44 Suppl B, 11–15 (1999).Google Scholar
  74. 74.
    Molinari, N.A. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25, 5086–5096 (2007).PubMedCrossRefGoogle Scholar
  75. 75.
    Monto, A.S. Seasonal influenza vaccinations: specialized products for different target groups. Vaccine 28 Suppl 4, D14–23 (2010).PubMedCrossRefGoogle Scholar
  76. 76.
    Hannoun, C., Megas, F. & Piercy, J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 103, 133–138 (2004).PubMedCrossRefGoogle Scholar
  77. 77.
    Fiore, A.E., et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep 59, 1–62 (2010).PubMedGoogle Scholar
  78. 78.
    Hanon, E. Vaccination strategies against influenza. Bull Mem Acad R Med Belg 164, 283–287 (2009).PubMedGoogle Scholar
  79. 79.
    Nichol, K.L. & Treanor, J.J. Vaccines for seasonal and pandemic influenza. J Infect Dis 194 Suppl 2, S111–118 (2006).PubMedCrossRefGoogle Scholar
  80. 80.
    CDC. Seasonal Influenza (Flu). (2011).Google Scholar
  81. 81.
    Beyer, W.E., Nauta, J.J., Palache, A.M., Giezeman, K.M. & Osterhaus, A.D. Immunogenicity and safety of inactivated influenza vaccines in primed populations: a systematic literature review and meta-­analysis. Vaccine 29, 5785–5792 (2011).PubMedCrossRefGoogle Scholar
  82. 82.
    Gross, P.A. & Ennis, F.A. Influenza vaccine: split-product versus whole-virus types--How do they differ. N Engl J Med 296, 567–568 (1977).PubMedCrossRefGoogle Scholar
  83. 83.
    Gross, P.A., et al. A controlled double-blind comparison of reactogenicity, immunogenicity, and protective efficacy of whole-virus and split-product influenza vaccines in children. J Infect Dis 136, 623–632 (1977).PubMedCrossRefGoogle Scholar
  84. 84.
    Johansson, B.E. & Brett, I.C. Changing perspective on immunization against influenza. Vaccine 25, 3062–3065 (2007).PubMedCrossRefGoogle Scholar
  85. 85.
    Cook, I.F., Barr, I., Hartel, G., Pond, D. & Hampson, A.W. Reactogenicity and immunogenicity of an inactivated influenza vaccine administered by intramuscular or subcutaneous injection in elderly adults. Vaccine 24, 2395–2402 (2006).PubMedCrossRefGoogle Scholar
  86. 86.
    Schwartz, B. & Wortley, P. Mass vaccination for annual and pandemic influenza. Current topics in microbiology and immunology 304, 131–152 (2006).PubMedCrossRefGoogle Scholar
  87. 87.
    Fredrickson, K., et al. Influenza vaccination coverage among children aged 6-23 months - six immunization information system sentinel sites, United States, 2005-06 influenza season. MMWR Morb Mortal Wkly Rep 55, 1329–1330 (2006).PubMedGoogle Scholar
  88. 88.
    McElhaney, J.E. Influenza vaccine responses in older adults. Ageing Res Rev 10, 379–388 (2011).PubMedCrossRefGoogle Scholar
  89. 89.
    Ellebedy, A.H. & Webby, R.J. Influenza vaccines. Vaccine 27 Suppl 4, D65–68 (2009).PubMedCrossRefGoogle Scholar
  90. 90.
    Marcelin, G., et al. Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic influenza A(H1N1) 2009 virus in an age-dependent manner. J Infect Dis 202, ­1634–1638 (2010).PubMedCrossRefGoogle Scholar
  91. 91.
    Coudeville, L., et al. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model. BMC Med Res Methodol 10, 18 (2010).PubMedCrossRefGoogle Scholar
  92. 92.
    CDC. Vaccine Effectiveness - How Well Does the Flu Vaccine Work? (2011).Google Scholar
  93. 93.
    CDC. Flu Vaccine Effectiveness: Questions and Answers for Health Professionals. (2011).Google Scholar
  94. 94.
    Kim, Y.C. & Prausnitz, M.R. Enabling skin vaccination using new delivery technologies. Drug Deliv Transl Res 1, 7–12 (2011).PubMedCrossRefGoogle Scholar
  95. 95.
    Jepps, O.G., Dancik, Y., Anissimov, Y.G. & Roberts, M.S. Modeling the human skin barrier - Towards a better understanding of dermal absorption. Adv Drug Deliv Rev (2012).Google Scholar
  96. 96.
    Skountzou, I. & Kang, S.M. Transcutaneous immunization with influenza vaccines. Current topics in microbiology and immunology 333, 347–368 (2009).PubMedCrossRefGoogle Scholar
  97. 97.
    Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).PubMedCrossRefGoogle Scholar
  98. 98.
    Romani, N., et al. Morphological and phenotypical characterization of bone marrow-derived dendritic Thy-1-positive epidermal cells of the mouse. J Invest Dermatol 85, 91 s-95 s (1985).PubMedCrossRefGoogle Scholar
  99. 99.
    Itano, A.A., et al. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19, 47–57 (2003).PubMedCrossRefGoogle Scholar
  100. 100.
    Valladeau, J., et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 12, 71–81 (2000).PubMedCrossRefGoogle Scholar
  101. 101.
    Allavena, P., et al. The chemokine receptor switch paradigm and dendritic cell migration: its significance in tumor tissues. Immunol Rev 177, 141–149 (2000).PubMedCrossRefGoogle Scholar
  102. 102.
    Sozzani, S., Allavena, P., Vecchi, A. & Mantovani, A. Chemokines and dendritic cell traffic. J Clin Immunol 20, 151–160 (2000).PubMedCrossRefGoogle Scholar
  103. 103.
    Locati, M., Allavena, P., Sozzani, S. & Mantovanii, A. Shaping and tuning of the chemokine system by regulation of receptor expression and signaling: dendritic cells as a paradigm. J Neuroimmunol 107, 174–177 (2000).PubMedCrossRefGoogle Scholar
  104. 104.
    Sozzani, S., et al. In vitro and in vivo regulation of chemokine receptors. Eur Cytokine Netw 11, 502–503 (2000).PubMedGoogle Scholar
  105. 105.
    Romani, N., et al. Targeting skin dendritic cells to improve intradermal vaccination. Current topics in microbiology and immunology 351, 113–138 (2012).PubMedCrossRefGoogle Scholar
  106. 106.
    Miller, L.S. Toll-like receptors in skin. Adv Dermatol 24, 71–87 (2008).PubMedCrossRefGoogle Scholar
  107. 107.
    Abdelsadik, A. & Trad, A. Toll-like receptors on the fork roads between innate and adaptive immunity. Hum Immunol 72, 1188–1193 (2011).PubMedCrossRefGoogle Scholar
  108. 108.
    Dupasquier, M., Stoitzner, P., van Oudenaren, A., Romani, N. & Leenen, P.J. Macrophages and dendritic cells constitute a major subpopulation of cells in the mouse dermis. J Invest Dermatol 123, 876–879 (2004).PubMedCrossRefGoogle Scholar
  109. 109.
    Debenedictis, C., Joubeh, S., Zhang, G., Barria, M. & Ghohestani, R.F. Immune functions of the skin. Clin Dermatol 19, 573–585 (2001).PubMedCrossRefGoogle Scholar
  110. 110.
    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, 2937–2946 (2009).PubMedCrossRefGoogle Scholar
  111. 111.
    Flacher, V., et al. Epidermal Langerhans cells rapidly capture and present antigens from C-type lectin-targeting antibodies deposited in the dermis. J Invest Dermatol 130, 755–762 (2010).PubMedCrossRefGoogle Scholar
  112. 112.
    Romani, N., Brunner, P.M. & Stingl, G. Changing views of the role of Langerhans cells. J Invest Dermatol 132, 872–881 (2012).PubMedCrossRefGoogle Scholar
  113. 113.
    Flacher, V., et al. Skin Langerin(+) dendritic cells transport intradermally injected anti-DEC-205 antibodies but are not essential for subsequent cytotoxic CD8(+) T cell responses. J Immunol 188, 2146–2155 (2012).PubMedCrossRefGoogle Scholar
  114. 114.
    del Pilar Martin, M., et al. Local response to microneedle-based influenza immunization in the skin. MBio 3, e00012–00012 (2012).Google Scholar
  115. 115.
    Raz, E., et al. Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. Proc Natl Acad Sci USA 91, 9519–9523 (1994).PubMedCrossRefGoogle Scholar
  116. 116.
    Koutsonanos, D.G., et al. Serological memory and long-term protection to novel H1N1 influenza virus after skin vaccination. J Infect Dis 204, 582–591 (2011).PubMedCrossRefGoogle Scholar
  117. 117.
    Prausnitz, M.R. Microneedles for transdermal drug delivery. Adv Drug Deliv Rev 56, 581–587 (2004).PubMedCrossRefGoogle Scholar
  118. 118.
    Prausnitz, M.R., Mitragotri, S. & Langer, R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov 3, 115–124 (2004).PubMedCrossRefGoogle Scholar
  119. 119.
    Kim, Y.C., Park, J.H. & Prausnitz, M.R. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev (2012).Google Scholar
  120. 120.
    Kim, Y.C., Jarrahian, C., Zehrung, D., Mitragotri, S. & Prausnitz, M.R. Delivery systems for intradermal vaccination. Current topics in microbiology and immunology 351, 77–112 (2012).PubMedCrossRefGoogle Scholar
  121. 121.
    Koutsonanos, D.G., et al. Delivery of subunit influenza vaccine to skin with microneedles improves immunogenicity and long-lived protection. Sci Rep 2, 357 (2012).PubMedCrossRefGoogle Scholar
  122. 122.
    Koutsonanos, D.G., et al. Transdermal influenza immunization with vaccine-coated microneedle arrays. PloS one 4, e4773 (2009).PubMedCrossRefGoogle Scholar
  123. 123.
    Sullivan, S.P., et al. Dissolving polymer microneedle patches for influenza vaccination. Nat Med 16, 915v920 (2010).PubMedCrossRefGoogle Scholar
  124. 124.
    Kim, Y.C., Quan, F.S., Compans, R.W., Kang, S.M. & Prausnitz, M.R. Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity. Journal of controlled release : official journal of the Controlled Release Society 142, 187v195 (2010).CrossRefGoogle Scholar
  125. 125.
    Gill, H.S. & Prausnitz, M.R. Coating formulations for microneedles. Pharm Res 24, 1369–1380 (2007).PubMedCrossRefGoogle Scholar
  126. 126.
    Gill, H.S. & Prausnitz, M.R. Coated microneedles for transdermal delivery. Journal of controlled release : official journal of the Controlled Release Society 117, 227–237 (2007).CrossRefGoogle Scholar
  127. 127.
    Koyama, S., et al. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Sci Transl Med 2, 25ra24 (2010).Google Scholar
  128. 128.
    Chu, L.Y., Choi, S.O. & Prausnitz, M.R. Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: Bubble and pedestal microneedle designs. J Pharm Sci 99, 4228–4238 (2010).PubMedCrossRefGoogle Scholar
  129. 129.
    Lee, J.W., Park, J.H. & Prausnitz, M.R. Dissolving microneedles for transdermal drug delivery. Biomaterials 29, 2113–2124 (2008).PubMedCrossRefGoogle Scholar
  130. 130.
    Chu, L.Y. & Prausnitz, M.R. Separable arrowhead microneedles. Journal of controlled release : official journal of the Controlled Release Society 149, 242–249 (2011).CrossRefGoogle Scholar
  131. 131.
    Prausnitz, M.R., Mikszta, J.A., Cormier, M. & Andrianov, A.K. Microneedle-based vaccines. Current topics in microbiology and immunology 333, 369–393 (2009).PubMedCrossRefGoogle Scholar
  132. 132.
    Choi, H.J., et al. Stability of influenza vaccine coated onto microneedles. Biomaterials 33, 3756–3769 (2012).PubMedCrossRefGoogle Scholar
  133. 133.
    Patel, S.R., Lin, A.S., Edelhauser, H.F. & Prausnitz, M.R. Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharm Res 28, 166–176 (2011).PubMedCrossRefGoogle Scholar
  134. 134.
    Gupta, J., Denson, D.D., Felner, E.I. & Prausnitz, M.R. Rapid local anesthesia in humans using minimally invasive microneedles. Clin J Pain 28, 129–135 (2012).PubMedCrossRefGoogle Scholar
  135. 135.
    Wang, P.M., Cornwell, M., Hill, J. & Prausnitz, M.R. Precise microinjection into skin using hollow microneedles. J Invest Dermatol 126, 1080–1087 (2006).PubMedCrossRefGoogle Scholar
  136. 136.
    Gupta, J., Felner, E.I. & Prausnitz, M.R. Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. Diabetes Technol Ther 11, 329–337 (2009).PubMedCrossRefGoogle Scholar
  137. 137.
    Banks, S.L., et al. Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs. J Pharm Sci 99, 3072–3080 (2010).PubMedGoogle Scholar
  138. 138.
    Gupta, J., Felner, E.I. & Prausnitz, M.R. Rapid pharmacokinetics of intradermal insulin administered using microneedles in type 1 diabetes subjects. Diabetes Technol Ther 13, 451–456 (2011).PubMedCrossRefGoogle Scholar
  139. 139.
    Lee, J.W., Choi, S.O., Felner, E.I. & Prausnitz, M.R. Dissolving microneedle patch for transdermal delivery of human growth hormone. Small 7, 531–539 (2011).PubMedCrossRefGoogle Scholar
  140. 140.
    Andrews, S., Lee, J.W., Choi, S.O. & Prausnitz, M.R. Transdermal insulin delivery using microdermabrasion. Pharm Res 28, 2110–2118 (2011).PubMedCrossRefGoogle Scholar
  141. 141.
    Tas, C., et al. Delivery of salmon calcitonin using a microneedle patch. Int J Pharm 423, 257–263 (2012).PubMedCrossRefGoogle Scholar
  142. 142.
    Song, J.M., et al. DNA Vaccination in the Skin Using Microneedles Improves Protection Against Influenza. Mol Ther (2012).Google Scholar
  143. 143.
    Kim, Y.C., et al. Increased immunogenicity of avian influenza DNA vaccine delivered to the skin using a microneedle patch. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (2012).Google Scholar
  144. 144.
    Prow, T.W., et al. Nanopatch-targeted skin ­vaccination against West Nile Virus and Chikungunya virus in mice. Small 6, 1776–1784 (2010).PubMedCrossRefGoogle Scholar
  145. 145.
    Fernando, G.J., et al. Nanopatch targeted delivery of both antigen and adjuvant to skin synergistically drives enhanced antibody responses. Journal of controlled release : official journal of the Controlled Release Society 159, 215–221 (2012).CrossRefGoogle Scholar
  146. 146.
    FDA. Influenza Virus Vaccine, Trivalent, Types A and B. (2012).Google Scholar
  147. 147.
    Norman, J.J. & Prausnitz, M.R. Improving patient acceptance of insulin therapy by improving ­needle design. J Diabetes Sci Technol 6, 336–338 (2012).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Dimitrios G. Koutsonanos
    • 1
  • Richard W. Compans
    • 1
  • Ioanna Skountzou
    • 1
    Email author
  1. 1.Department of Microbiology and Immunology and Emory Vaccine CenterEmory University School of Medicine, Influenza Pathogenesis and Research Center (Emory University-UGA)AtlantaUSA

Personalised recommendations