Microneedles for Intradermal Vaccination: Immunopotentiation and Formulation Aspects

  • Alexander K. Andrianov


Microneedle systems can open ample possibilities for the development of new generation vaccines and even revolutionize the practice of vaccination [1]. Ease of administration, improved immune protection, antigen dose sparing, and independence of cold-chain distribution are among the many potential benefits that the technology can introduce in the field [2]. Due to the same advantages, microneedle-based vaccines, and intradermal vaccination in general can also open new prospects for the development of low cost vaccines for the developing countries [3, 4].


Polyelectrolyte Complex Vaccine Formulation Microneedle Array Muramyl Dipeptide Microfabrication Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Plotkin SA (2005) Vaccines: past, present and future. Nat Med 11:S5–S11PubMedCrossRefGoogle Scholar
  2. 2.
    Prausnitz MR, Mikszta JA, Cormier M, Andrianov AK (2009) Microneedle-based vaccines. In: Compans RW, Orenstein WA (eds) Curr Top Microbiol Immunol vol 333: vaccines for pandemic influenza. Springer, pp 369–393, BerlinGoogle Scholar
  3. 3.
    Hickling JK, Jones KR, Friede M, Zehrung D, Chenc D, Kristensenc D (2011) Intradermal delivery of vaccines: potential benefits and current challenges. Bull World Health Org 89:221–226PubMedCrossRefGoogle Scholar
  4. 4.
    Kristensen D, Zaffran M (2010) Designing vaccines for developing-country populations: ideal attributes, delivery devices, and presentation formats. Procedia Vaccinol 2:119–123CrossRefGoogle Scholar
  5. 5.
    Mikszta JA, Laurent PE (2008) Cutaneous delivery of prophylactic and therapeutic vaccines: historical perspective and future outlook. Expert Rev Vaccines 7:1329–1339PubMedCrossRefGoogle Scholar
  6. 6.
    Glenn GM, Kenney RT (2006) Mass vaccination: solutions in the skin. Curr Top Microbiol Immunol 304:247–268PubMedCrossRefGoogle Scholar
  7. 7.
    Larregina AT, Falo LD Jr (2004) Changing paradigms in cutaneous immunology: adapting with dendritic cells. J Investig Dermatol 124:1–12CrossRefGoogle Scholar
  8. 8.
    Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotechnol 26:1261–1268PubMedCrossRefGoogle Scholar
  9. 9.
    Prausnitz MR, McAllister DV, Kaushik S, Patel PN, Mayberry JL, Allen MG (1999) Microfabricated microneedles for transdermal drug delivery. American society of mechanical engineers, bioengineering division (publication). BED 42:89–90Google Scholar
  10. 10.
    Arora A, Prausnitz MR, Mitragotri S (2008) Micro-scale devices for transdermal drug delivery. Int J Pharm 364:227–236PubMedCrossRefGoogle Scholar
  11. 11.
    Kendall MAF (2010) Needle-free vaccine injection. In: Schäfer-Korting M (ed) Drug delivery. Springer, Berlin, pp 193–219CrossRefGoogle Scholar
  12. 12.
    Andrianov AK, DeCollibus DP, Gillis HA, Kha HH, Marin A, Prausnitz MR, Babiuk LA, Townsend H, Mutwiri G (2009) Poly[di(carboxylatophenoxy)phosphazene] is a potent adjuvant for intradermal immunization. Proc Natl Acad Sci USA 106:18936–18941. doi: 10.1073/pnas.0908842106 PubMedCrossRefGoogle Scholar
  13. 13.
    Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, Nyam K, Daddona PE (2002) Macroflux® microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm Res 19:63–70PubMedCrossRefGoogle Scholar
  14. 14.
    Vogelbruch M, Nuss B, Korner M, Kapp A, Kiehl P, Bohm W (2000) Aluminium-induced granulomas after inaccurate intradermal hyposensitization injections of aluminium-adsorbed depot preparations. Allergy 55:883–887PubMedGoogle Scholar
  15. 15.
    Glenn GM, Taylor DN, Li X, Frankel S, Montemarano A, Alving CR (2000) Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nat Med 6:1403–1406PubMedCrossRefGoogle Scholar
  16. 16.
    Mikszta JA, Sullivan VJ, Dean C, Waterston AM, Alarcon JB, Dekker Iii JP, Brittingham JM, Huang J, Hwang CR, Ferriter M, Jiang G, Mar K, Saikh KU, Stiles BG, Roy CJ, Ulrich RG, Harvey NG (2005) Protective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms. J Infect Dis 191:278–288PubMedCrossRefGoogle Scholar
  17. 17.
    Laurent PE, Bonnet S, Alchas P, Regolini P, Mikszta JA, Pettis R, Harvey NG (2007) Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. Vaccine 25:8833–8842PubMedCrossRefGoogle Scholar
  18. 18.
    Frey SE, Couch RB, Tacket CO, Treanor JJ, Wolff M, Newman FK, Atmar RL, Edelman R, Nolan CM, Belshe RB (2002) Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 346:1265–1274PubMedCrossRefGoogle Scholar
  19. 19.
    Holland D, Booy R, De Looze F, Eizenberg P, McDonald J, Karrasch J, McKeirnan M, Salem H, Mills G, Reid J (2008) Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 198:650–658PubMedCrossRefGoogle Scholar
  20. 20.
    Mitragotri S (2006) Current status and future prospects of needle-free liquid jet injectors. Nat Rev Drug Discov 5:543–548PubMedGoogle Scholar
  21. 21.
    Kendall M, Mitchell T, Wrighton-Smith P (2004) Intradermal ballistic delivery of micro-particles into excised human skin for pharmaceutical applications. J Biomech 37:1733–1741PubMedCrossRefGoogle Scholar
  22. 22.
    Raju PA, McSloy N, Truong NK, Kendall MAF (2006) Assessment of epidermal cell viability by near infrared multi-photon microscopy following ballistic delivery of gold micro-particles. Vaccine 24:4644–4647PubMedCrossRefGoogle Scholar
  23. 23.
    Glenn GM, Kenney RT, Hammond SA, Ellingsworth LR (2003) Transcutaneous immunization and immunostimulant strategies. Immunol Allergy Clin North Am 23:787–813PubMedCrossRefGoogle Scholar
  24. 24.
    Kim YC (2010) Enhanced memory responses to seasonal H1N1 influenza vaccination of the skin with the use of vaccine-coated microneedles. J Infect Dis 201:190–198PubMedCrossRefGoogle Scholar
  25. 25.
    Kim YC, Quan FS, Compans RW, Kang SM, Prausnitz MR (2010) Formulation of microneedles coated with influenza virus-like particle vaccine. AAPS PharmSciTech 11(3):1–9Google Scholar
  26. 26.
    Kim YC, Quan FS, Compans RW, Kang SM, Prausnitz MR (2010) Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity. J Control Release 142:187–195PubMedCrossRefGoogle Scholar
  27. 27.
    Zhu Q (2009) Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge. Proc Natl Acad Sci USA 106:7968–7973PubMedCrossRefGoogle Scholar
  28. 28.
    Kim YC, Quan FS, Yoo DG, Compans RW, Kang SM, Prausnitz MR (2009) Improved influenza vaccination in the skin using vaccine coated microneedles. Vaccine 27:6932–6938PubMedCrossRefGoogle Scholar
  29. 29.
    Koutsonanos DG (2009) Transdermal influenza immunization with vaccine-coated microneedle arrays. PLoS One 4:e4773PubMedCrossRefGoogle Scholar
  30. 30.
    Singh M (2006) Vaccine adjuvants and delivery systems. Wiley-Interscience, Hoboken, p 449Google Scholar
  31. 31.
    Lodmell DL, Ray NB, Ulrich JT, Ewalt LC (2000) DNA vaccination of mice against rabies virus: effects of the route of vaccination and the adjuvant monophosphoryl lipid A (MPL®). Vaccine 18:1059–1066PubMedCrossRefGoogle Scholar
  32. 32.
    Baldwin SL, Bertholet S, Kahn M, Zharkikh I, Ireton GC, Vedvick TS, Reed SG, Coler RN (2009) Intradermal immunization improves protective efficacy of a novel TB vaccine candidate. Vaccine 27:3063–3071PubMedCrossRefGoogle Scholar
  33. 33.
    Weiner GJ, Liu HM, Wooldridge JE, Dahle CE, Krieg AM (1997) Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc Natl Acad Sci USA 94:10833–10837PubMedCrossRefGoogle Scholar
  34. 34.
    McGowen AL, Hale LP, Shelburne CP, Abraham SN, Staats HF (2009) The mast cell activator compound 48/80 is safe and effective when used as an adjuvant for intradermal immunization with Bacillus anthracis protective antigen. Vaccine 27:3544–3552PubMedCrossRefGoogle Scholar
  35. 35.
    Disis ML, Bernhard H, Shiota FM, Hand SL, Gralow JR, Huseby ES, Gillis S, Cheever MA (1996) Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 88:202–210PubMedGoogle Scholar
  36. 36.
    Vandermeulen G, Daugimont L, Richiardi H, Vanderhaeghen ML, Lecouturier N, Ucakar B, Préat V (2009) Effect of tape stripping and adjuvants on immune response after intradermal DNA electroporation. Pharm Res 26:1745–1751PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang L, Widera G, Rabussay D (2004) Enhancement of the effectiveness of electroporation-augmented cutaneous DNA vaccination by a particulate adjuvant. Bioelectrochemistry 63:369–373PubMedCrossRefGoogle Scholar
  38. 38.
    Huang J, D’Souza AJ, Alarcon JB, Mikszta JA, Ford BM, Ferriter MS, Evans M, Stewart T, Amemiya K, Ulrich RG (2009) Protective immunity in mice achieved with dry powder formulation and alternative delivery of plague F1-V vaccine. Clin Vaccine Immunol 16:719–725PubMedCrossRefGoogle Scholar
  39. 39.
    Mikszta JA, Sullivan VJ, Dean C, Waterston AM, Alarcon JB, Dekker JP, Brittingham JM, Huang J, Hwang CR, Ferriter M (2005) Protective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms. J Infect Dis 191:278PubMedCrossRefGoogle Scholar
  40. 40.
    Bal SM, Ding Z, Kersten GFA, Jiskoot W, Bouwstra JA (2010) Microneedle-based transcutaneous immunisation in mice with N-trimethyl chitosan adjuvanted diphtheria toxoid formulations. Pharm Res 27:1–11CrossRefGoogle Scholar
  41. 41.
    Ding Z, Van Riet E, Romeijn S, Kersten GFA, Jiskoot W, Bouwstra JA (2009) Immune modulation by adjuvants combined with diphtheria toxoid administered topically in BALB/c mice after microneedle array pretreatment. Pharm Res 26:1635–1643PubMedCrossRefGoogle Scholar
  42. 42.
    Cui Z, Baizer L, Mumper RJ (2003) Intradermal immunization with novel plasmid DNA-coated nanoparticles via a needle-free injection device. J Biotechnol 102:105–115PubMedCrossRefGoogle Scholar
  43. 43.
    Zuber AK, Bråve A, Engström G, Zuber B, Ljungberg K, Fredriksson M, Benthin R, Isaguliants MG, Sandström E, Hinkula J, Wahren B (2004) Topical delivery of imiquimod to a mouse model as a novel adjuvant for human immunodeficiency virus (HIV) DNA. Vaccine 22:1791–1798PubMedCrossRefGoogle Scholar
  44. 44.
    Matyas GR, Friedlander AM, Glenn GM, Little S, Yu J, Alving CR (2004) Needle-free skin patch vaccination method for anthrax. Infect Immun 72:1181–1183PubMedCrossRefGoogle Scholar
  45. 45.
    Kenney RT, Yu J, Guebre-Xabier M, Frech SA, Lambert A, Heller BA, Ellingsworth LR, Eyles JE, Williamson ED, Glenn GM (2004) Induction of protective immunity against lethal anthrax challenge with a patch. J Infect Dis 190:774–782PubMedCrossRefGoogle Scholar
  46. 46.
    Frech SA, Kenney RT, Spyr CA, Lazar H, Viret JF, Herzog C, Gluck R, Glenn GM (2005) Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch. Vaccine 23:946–950PubMedCrossRefGoogle Scholar
  47. 47.
    Tierney R, Beignon AS, Rappuoli R, Muller S, Sesardic D, Partidos CD (2003) Transcutaneous immunization with tetanus toxoid and mutants of Escherichia coli heat-labile enterotoxin as adjuvants elicits strong protective antibody responses. J Infect Dis 188:753–758PubMedCrossRefGoogle Scholar
  48. 48.
    Guerena-Burgueno F, Hall ER, Taylor DN, Cassels FJ, Scott DA, Wolf MK, Roberts ZJ, Nesterova GV, Alving CR, Glenn GM (2002) Safety and immunogenicity of a prototype enterotoxigenic Escherichia coli vaccine administered transcutaneously. Infect Immun 70:1874–1880PubMedCrossRefGoogle Scholar
  49. 49.
    Andrianov AK, Langer R (2009) Polyphosphazenes for biology and medicine: current status and future prospects. In: Andrianov AK (ed) Polyphosphazenes for biomedical applications. Wiley, Hoboken, pp 3–13CrossRefGoogle Scholar
  50. 50.
    Andrianov AK, DeCollibus DP, Gillis HA, Kha HH, Marin A (2009) Polyphosphazene immunoadjuvants for intradermal vaccine delivery. In: Andrianov AK (ed) Polyphosphazenes for biomedical applications. Wiley, Hoboken, pp 101–116CrossRefGoogle Scholar
  51. 51.
    Andrianov AK, Marin A, Chen J (2006) Synthesis, properties, and biological activity of Poly[di(sodium carboxylatoethylphenoxy)phosphazene]. Biomacromolecules 7:394–399PubMedCrossRefGoogle Scholar
  52. 52.
    Andrianov AK, Chen J, LeGolvan MP (2004) Poly(dichlorophosphazene) as a precursor for biologically active polyphosphazenes: synthesis, characterization, and stabilization. Macromolecules 37:414–420CrossRefGoogle Scholar
  53. 53.
    Andrianov AK, Svirkin YY, LeGolvan MP (2004) Synthesis and biologically relevant properties of polyphosphazene polyacids. Biomacromolecules 5:1999–2006PubMedCrossRefGoogle Scholar
  54. 54.
    Marin A, DeCollibus DP, Andrianov AK (2010) Protein stabilization in aqueous solutions of polyphosphazene polyelectrolyte and non-ionic surfactants. Biomacromolecules 11:2268–2273. doi:10.1021/bm100603pPubMedCrossRefGoogle Scholar
  55. 55.
    Andrianov AK, Decollibus DP, Marin A, Webb A, Griffin Y, Webby RJ (2011) PCPP-formulated H5N1 influenza vaccine displays improved stability and dose-sparing effect in lethal challenge studies. J Pharm Sci 100:1436–1443. doi:10.1002/jps.22367CrossRefGoogle Scholar
  56. 56.
    Payne LG, Jenkins SA, Woods AL, Grund EM, Geribo WE, Loebelenz JR, Andrianov AK, Roberts BE (1998) Poly[di(carboxylatophenoxy)phosphazene] (PCPP) is a potent immunoadjuvant for an influenza vaccine. Vaccine 16:92–98PubMedCrossRefGoogle Scholar
  57. 57.
    Payne LG, Van Nest G, Barchfeld GL, Siber GR, Gupta RK, Jenkins SA (1998) PCPP as a parenteral adjuvant for diverse antigens. Dev Biol Stand 92:79–87PubMedGoogle Scholar
  58. 58.
    Mutwiri G, Benjamin P, Soita H, Townsend H, Yost R, Roberts B, Andrianov AK, Babiuk LA (2007) Poly[di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP) is a potent enhancer of mixed Th1/Th2 immune responses in mice immunized with influenza virus antigens. Vaccine 25:1204–1213PubMedCrossRefGoogle Scholar
  59. 59.
    Lu Y, Salvato MS, Pauza CD, Li J, Sodroski J, Manson K, Wyand M, Letvin N, Jenkins S, Touzjian N, Chutkowski C, Kushner N, LeFaile M, Payne LG, Roberts B (1996) Utility of SHIV for testing HIV-1 vaccine candidates in macaques. J Acquir Immune Defic Syndr Hum Retrovirol 12:99–106PubMedCrossRefGoogle Scholar
  60. 60.
    Wu JY, Wade WF, Taylor RK (2001) Evaluation of cholera vaccines formulated with toxin-coregulated pilin peptide plus polymer adjuvant in mice. Infect Immun 69:7695–7702PubMedCrossRefGoogle Scholar
  61. 61.
    Bouveret Le Cam NN, Ronco J, Francon A, Blondeau C, Fanget B (1998) Adjuvants for influenza vaccine. Res Immunol 149:19–23CrossRefGoogle Scholar
  62. 62.
    Ison MG, Mills J, Openshaw P, Zambon M, Osterhaus A, Hayden F (2002) Current research on respiratory viral infections: fourth international symposium. Antiviral Res 55:227–278PubMedCrossRefGoogle Scholar
  63. 63.
    Kim JH, Kirsch EA, Gilliam B, Michael NL, VanCott TC, Ratto-Kim S, Cox J, Nielsen R, Robb ML, Caudrelier P, El Habib R, McNeil J (1999) A phase I, open label, dose ranging trial of The Pasteur Merieux Connaught (PMC) oligomeric HIV-1 Gp160mn/LAI-2 vaccine in HIV seronegative adults. In: Abstracts of the 37th annual meeting of the infectious diseases society of America, Philadelphia, PA, pp. 1028Google Scholar
  64. 64.
    Mutwiri G, Benjamin P, Soita H, Babiuk LA (2008) Co-administration of polyphosphazenes with CpG oligodeoxynucleotides strongly enhances immune responses in mice immunized with Hepatitis B virus surface antigen. Vaccine 26:2680–2688PubMedCrossRefGoogle Scholar
  65. 65.
    Andrianov AK, Sargent JR, Sule SS, Le Golvan MP, Woods AL, Jenkins SA, Payne LG (1998) Synthesis, physico-chemical properties and immunoadjuvant activity of water-soluble phosphazene polyacids. J Bioact Compat Polym 13:243–256Google Scholar
  66. 66.
    Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 15:297–322PubMedCrossRefGoogle Scholar
  67. 67.
    Andrianov AK, Marin A, Roberts BE (2005) Polyphosphazene polyelectrolytes: a link between the formation of noncovalent complexes with antigenic proteins and immunostimulating activity. Biomacromolecules 6:1375–1379PubMedCrossRefGoogle Scholar
  68. 68.
    Kabanov VA (2004) From synthetic polyelectrolytes to polymer-subunit vaccines. Pure Appl Chem 76:1659–1677CrossRefGoogle Scholar
  69. 69.
    Gill HS, Prausnitz MR (2007) Coating formulations for microneedles. Pharm Res 24:1369–1380PubMedCrossRefGoogle Scholar
  70. 70.
    Andrianov AK, Chen J, Payne LG (1998) Preparation of hydrogel microspheres by coacervation of aqueous polyphosphazene solutions. Biomaterials 19:109–115PubMedCrossRefGoogle Scholar
  71. 71.
    Andrianov AK, Chen J (2006) Polyphosphazene microspheres: preparation by ionic complexation of phosphazene polyacids with spermine. J Appl Polymer Sci 101:414–419CrossRefGoogle Scholar
  72. 72.
    Gill HS, Prausnitz MR (2007) Coated microneedles for transdermal delivery. J Control Release 117:227–237PubMedCrossRefGoogle Scholar
  73. 73.
    Monteiro-Riviere NA (1991) Comparative anatomy, physiology, and biochemistry of mammalian skin. In: Hobson D (ed) Dermal and ocular toxicology: fundamentals and methods. CRC, Boca Raton, pp 3–71Google Scholar
  74. 74.
    Andrianov A, Marin A, DeCollibus D (2011) Microneedles with intrinsic immunoadjuvant properties: microfabrication, protein stability, and modulated release. Pharm Res 28:58–65. doi:10.1007/s11095-010-0133-7PubMedCrossRefGoogle Scholar
  75. 75.
    Quan F-S, Kim Y-C, Yoo D-G, Compans RW, Prausnitz MR, Kang S-M (2009) Stabilization of influenza vaccine enhances protection by microneedle delivery in the mouse skin. PLoS One 4:e7152PubMedCrossRefGoogle Scholar
  76. 76.
    Heinig K, Vogt C (1997) Determination of Triton X-100 in influenza vaccine by high-performance liquid chromatography and capillary electrophoresis. Anal Bioanal Chem 359:202–206Google Scholar
  77. 77.
    Cohen S, Bano MC, Visscher KB, Chow M, Allcock HR, Langer R (1990) Ionically crosslinkable polyphosphazene: a novel polymer for microencapsulation. J Am Chem Soc 112:7832–7833CrossRefGoogle Scholar
  78. 78.
    Allcock HR, Kwon S (1989) An ionically cross-linkable polyphosphazene: poly[bis(carboxylatophenoxy)phosphazene] and its hydrogels and membranes. Macromolecules 22:75–79CrossRefGoogle Scholar
  79. 79.
    Andrianov AK, Cohen S, Visscher KB, Payne LG, Allcock HR, Langer R (1993) Controlled release using ionotropic polyphosphazene hydrogels. J Control Release 27:69–77CrossRefGoogle Scholar
  80. 80.
    Andrianov AK (2007) Polyphosphazenes as vaccine adjuvants. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, Hoboken, pp 355–378CrossRefGoogle Scholar
  81. 81.
    Mutwiri G, Benjamin P, Andrianov AK, Babiuk LA (2009) Potential of polyphosphazenes in modulating vaccine-induced immune responses: I. Investigations in mice. In: Andrianov AK (ed) Polyphosphazenes for Biomedical Applications. Wiley, Hoboken, pp 65–75Google Scholar
  82. 82.
    Marin A, Andrianov AK (2011) Carboxymethylcellulose–chitosan-coated microneedles with modulated hydration properties. J Appl Polymer Sci 121:395–401. doi:10.1002/app. 33608CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Apogee Technology Inc.NorwoodUSA

Personalised recommendations