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Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature

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Abstract

Prevention of seasonal influenza epidemics and pandemics relies on widespread vaccination coverage to induce protective immunity. In addition to a good antigenic match with the circulating viruses, the effectiveness of individual strains represented in the trivalent vaccines depends on their immunogenicity. In this study, we evaluated the immunogenicity of H1N1, H3N2, and B seasonal influenza virus vaccine strains delivered individually with a novel dissolving microneedle patch and the stability of this formulation during storage at 25 °C. Our data demonstrate that all strains retained their antigenic activity after incorporation in the dissolving patches as measured by single radial diffusion (SRID) assay and immune responses to vaccination in BALB/c mice. After a single immunization, all three antigens delivered with microneedle patches induced superior neutralizing antibody titers compared to intramuscular immunization. Cutaneous antigen delivery was especially beneficial for the less immunogenic B strain. Mice immunized with dissolving microneedle patches encapsulating influenza A/Brisbane/59/07 (H1N1) vaccine were fully protected against lethal challenge by homologous mouse-adapted influenza virus. All vaccine components retained activity during storage at room temperature for at least 3 months as measured in vitro by SRID assay and in vivo by mouse immunization studies. Our data demonstrate that dissolving microneedle patches are a promising advance for influenza cutaneous vaccination due to improved immune responses using less immunogenic influenza antigens and enhanced stability.

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References

  1. del Pilar Martin M, Weldon WC, Zarnitsyn VG, Koutsonanos DG, Akbari H, Skountzou I, et al. Local response to microneedle-based influenza immunization in the skin. mBio. 2012;3(2):e00012–12. doi:10.1128/mBio.00012-12.

    PubMed  PubMed Central  Google Scholar 

  2. Chen X, Fernando GJ, Raphael AP, Yukiko SR, Fairmaid EJ, Primiero CA, et al. Rapid kinetics to peak serum antibodies is achieved following influenza vaccination by dry-coated densely packed microprojections to skin. J Control Release Off J Control Release Soc. 2012;158(1):78–84. doi:10.1016/j.jconrel.2011.10.026.

    Article  CAS  Google Scholar 

  3. Pulit-Penaloza JA, Esser ES, Vassilieva EV, Lee JW, Taherbhai MT, Pollack BP, et al. A protective role of murine langerin(+) cells in immune responses to cutaneous vaccination with microneedle patches. Sci Rep. 2014;4:6094. doi:10.1038/srep06094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Quinn HL, Kearney MC, Courtenay AJ, McCrudden MT, Donnelly RF. The role of microneedles for drug and vaccine delivery. Expert Opin Drug Deliv. 2014;11(11):1769–80. doi:10.1517/17425247.2014.938635.

    Article  CAS  PubMed  Google Scholar 

  5. Skountzou I, Compans RW. Skin immunization with influenza vaccines. Curr Top Microbiol Immunol. 2015;386:343–69. doi:10.1007/82_2014_407.

    PubMed  Google Scholar 

  6. Levin Y, Kochba E, Hung I, Kenney R. Intradermal vaccination using the novel microneedle device MicronJet600: past, present and future. Hum Vaccines Immunother. 2015. doi:10.1080/21645515.2015.1010871.

    Google Scholar 

  7. Barkam S, Saraf S, Seal S. Fabricated micro-nano devices for in vivo and in vitro biomedical applications. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2013;5(6):544–68. doi:10.1002/wnan.1236.

    Article  CAS  PubMed  Google Scholar 

  8. Jin J, Reese V, Coler R, Carter D, Rolandi M. Chitin microneedles for an easy-to-use tuberculosis skin test. Adv Healthcare Mater. 2014;3(3):349–53. doi:10.1002/adhm.201300185.

    Article  CAS  Google Scholar 

  9. Paliwal S, Hwang BH, Tsai KY, Mitragotri S. Diagnostic opportunities based on skin biomarkers. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2013;50(5):546–56. doi:10.1016/j.ejps.2012.10.009.

    CAS  Google Scholar 

  10. Koutsonanos DG, Compans RW, Skountzou I. Targeting the skin for microneedle delivery of influenza vaccine. Adv Exp Med Biol. 2013;785:121–32. doi:10.1007/978-1-4614-6217-0_13.

    Article  CAS  PubMed  Google Scholar 

  11. Qiu Y, Guo L, Zhang S, Xu B, Gao Y, Hu Y et al. DNA-based vaccination against hepatitis B virus using dissolving microneedle arrays adjuvanted by cationic liposomes and CpG ODN. Drug Delivery. 2015:1–8. doi:10.3109/10717544.2014.992497.

  12. Carey JB, Vrdoljak A, O’Mahony C, Hill AV, Draper SJ, Moore AC. Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route. Sci Rep. 2014;4:6154. doi:10.1038/srep06154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. van der Maaden K, Trietsch SJ, Kraan H, Varypataki EM, Romeijn S, Zwier R, et al. Novel hollow microneedle technology for depth-controlled microinjection-mediated dermal vaccination: a study with polio vaccine in rats. Pharm Res. 2014;31(7):1846–54. doi:10.1007/s11095-013-1288-9.

    PubMed  Google Scholar 

  14. Prow TW, Chen X, Prow NA, Fernando GJ, Tan CS, Raphael AP, et al. Nanopatch-targeted skin vaccination against West Nile virus and Chikungunya virus in mice. Small. 2010;6(16):1776–84. doi:10.1002/smll.201000331.

    Article  CAS  PubMed  Google Scholar 

  15. Suh H, Shin J, Kim YC. Microneedle patches for vaccine delivery. Clin Exp Vaccine Res. 2014;3(1):42–9. doi:10.7774/cevr.2014.3.1.42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hirobe S, Azukizawa H, Matsuo K, Zhai Y, Quan YS, Kamiyama F, et al. Development and clinical study of a self-dissolving microneedle patch for transcutaneous immunization device. Pharm Res. 2013;30(10):2664–74. doi:10.1007/s11095-013-1092-6.

    Article  CAS  PubMed  Google Scholar 

  17. Gill HS, Prausnitz MR. Pocketed microneedles for drug delivery to the skin. J Phys Chem Solids. 2008;69(5–6):1537–41. doi:10.1016/j.jpcs.2007.10.059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haq MI, Smith E, John DN, Kalavala M, Edwards C, Anstey A, et al. Clinical administration of microneedles: skin puncture, pain and sensation. Biomed Microdevices. 2009;11(1):35–47. doi:10.1007/s10544-008-9208-1.

    Article  CAS  PubMed  Google Scholar 

  19. Gupta J, Gill HS, Andrews SN, Prausnitz MR. Kinetics of skin resealing after insertion of microneedles in human subjects. J Control Release Off J Control Release Soc. 2011;154(2):148–55. doi:10.1016/j.jconrel.2011.05.021.

    Article  CAS  Google Scholar 

  20. Norman JJ, Arya JM, McClain MA, Frew PM, Meltzer MI, Prausnitz MR. Microneedle patches: usability and acceptability for self-vaccination against influenza. Vaccine. 2014. doi:10.1016/j.vaccine.2014.01.076.

    PubMed Central  Google Scholar 

  21. Zhu Q, Zarnitsyn VG, Ye L, Wen Z, Gao Y, Pan L, et al. Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge. Proc Natl Acad Sci U S A. 2009;106(19):7968–73. doi:10.1073/pnas.0812652106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Koutsonanos DG, del Pilar MM, Zarnitsyn VG, Jacob J, Prausnitz MR, Compans RW, et al. Serological memory and long-term protection to novel H1N1 influenza virus after skin vaccination. J Infec Dis. 2011;204(4):582–91. doi:10.1093/infdis/jir094.

    Article  CAS  Google Scholar 

  23. Weldon WC, Martin MP, Zarnitsyn V, Wang B, Koutsonanos D, Skountzou I, et al. Microneedle vaccination with stabilized recombinant influenza virus hemagglutinin induces improved protective immunity. Clin Vaccine Immunol CVI. 2011;18(4):647–54. doi:10.1128/CVI.00435-10.

    Article  CAS  PubMed  Google Scholar 

  24. Koutsonanos DG, Vassilieva EV, Stavropoulou A, Zarnitsyn VG, Esser ES, Taherbhai MT, et al. Delivery of subunit influenza vaccine to skin with microneedles improves immunogenicity and long-lived protection. Sci Rep. 2012;2:357. doi:10.1038/srep00357.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Song JM, Kim YC OE, Compans RW, Prausnitz MR, Kang SM. DNA vaccination in the skin using microneedles improves protection against influenza. Mol Ther J Am Soc Gene Ther. 2012;20(7):1472–80. doi:10.1038/mt.2012.69.

    Article  CAS  Google Scholar 

  26. Quan FS, Kim YC, Vunnava A, Yoo DG, Song JM, Prausnitz MR, et al. Intradermal vaccination with influenza virus-like particles by using microneedles induces protection superior to that with intramuscular immunization. J Virol. 2010;84(15):7760–9. doi:10.1128/JVI.01849-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fernando GJ, Chen X, Primiero CA, Yukiko SR, Fairmaid EJ, Corbett HJ, et al. Nanopatch targeted delivery of both antigen and adjuvant to skin synergistically drives enhanced antibody responses. J Control Release Off J Control Release Soc. 2012;159(2):215–21. doi:10.1016/j.jconrel.2012.01.030.

    Article  CAS  Google Scholar 

  28. Xie H, Jing X, Li X, Lin Z, Plant E, Zoueva O, et al. Immunogenicity and cross-reactivity of 2009–2010 inactivated seasonal influenza vaccine in US adults and elderly. PLoS ONE. 2011;6(1):e16650. doi:10.1371/journal.pone.0016650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Belongia EA, Sundaram ME, McClure DL, Meece JK, Ferdinands J, VanWormer JJ. Waning vaccine protection against influenza A (H3N2) illness in children and older adults during a single season. Vaccine. 2015;33(1):246–51. doi:10.1016/j.vaccine.2014.06.052.

    Article  CAS  PubMed  Google Scholar 

  30. Kang SM, Song JM, Kim YC. Microneedle and mucosal delivery of influenza vaccines. Expert Rev Vaccines. 2012;11(5):547–60. doi:10.1586/erv.12.25.

    Article  CAS  PubMed  Google Scholar 

  31. Holland D, Booy R, De Looze F, Eizenberg P, McDonald J, Karrasch J, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198(5):650–8. doi:10.1086/590434.

    Article  PubMed  Google Scholar 

  32. Duggan ST, Plosker GL. Intanza 15 microg intradermal seasonal influenza vaccine: in older adults (aged > or = 60 years). Drugs Aging. 2010;27(7):597–605. doi:10.2165/11203880-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  33. Sugimura T, Ito Y, Tananari Y, Ozaki Y, Maeno Y, Yamaoka T, et al. Improved antibody responses in infants less than 1 year old using intradermal influenza vaccination. Vaccine. 2008;26(22):2700–5. doi:10.1016/j.vaccine.2008.03.016.

    Article  CAS  PubMed  Google Scholar 

  34. Wong YL, Sampson S, Germishuizen WA, Goonesekera S, Caponetti G, Sadoff J, et al. Drying a tuberculosis vaccine without freezing. Proc Natl Acad Sci U S A. 2007;104(8):2591–5. doi:10.1073/pnas.0611430104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ohtake S, Martin RA, Yee L, Chen D, Kristensen DD, Lechuga-Ballesteros D, et al. Heat-stable measles vaccine produced by spray drying. Vaccine. 2010;28(5):1275–84. doi:10.1016/j.vaccine.2009.11.024.

    Article  CAS  PubMed  Google Scholar 

  36. Chen D, Kapre S, Goel A, Suresh K, Beri S, Hickling J, et al. Thermostable formulations of a hepatitis B vaccine and a meningitis A polysaccharide conjugate vaccine produced by a spray drying method. Vaccine. 2010;28(31):5093–9. doi:10.1016/j.vaccine.2010.04.112.

    Article  CAS  PubMed  Google Scholar 

  37. Soema PC, Willems GJ, van Twillert K, van de Wijdeven G, Boog CJ, Kersten GF, et al. Solid bioneedle-delivered influenza vaccines are highly thermostable and induce both humoral and cellular immune responses. PLoS ONE. 2014;9(3), e92806. doi:10.1371/journal.pone.0092806.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Frolov VG, Seid Jr RC, Odutayo O, Al-Khalili M, Yu J, Frolova OY, et al. Transcutaneous delivery and thermostability of a dry trivalent inactivated influenza vaccine patch. Influenza Other Respir Viruses. 2008;2(2):53–60. doi:10.1111/j.1750-2659.2008.00040.x.

    Article  CAS  PubMed  Google Scholar 

  39. Raphael AP, Prow TW, Crichton ML, Chen X, Fernando GJ, Kendall MA. Targeted, needle-free vaccinations in skin using multilayered, densely-packed dissolving microprojection arrays. Small. 2010;6(16):1785–93. doi:10.1002/smll.201000326.

    Article  CAS  PubMed  Google Scholar 

  40. 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. 2012;101(3):1021–7. doi:10.1002/jps.23019.

    Article  CAS  PubMed  Google Scholar 

  41. Matsuo K, Hirobe S, Yokota Y, Ayabe Y, Seto M, Quan YS, et al. Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza. J Control Release Off J Control Release Soc. 2012;160(3):495–501. doi:10.1016/j.jconrel.2012.04.001.

    Article  CAS  Google Scholar 

  42. Sharma M, Brahmne H, Bafna P. Potency testing of novel DTP group of vaccines. Int J Compr Pharmacol. 2011;11(2):1–9.

    Google Scholar 

  43. 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. 2011. doi:10.1002/jps.23019.

    PubMed  Google Scholar 

  44. WHO/CDS/CSR/NCS. WHO manual of animal influenza diagnosis and surveillance. Department of Communicable Disease Surveillance and Response. 2002.

  45. Skountzou I, Quan FS, Gangadhara S, Ye L, Vzorov A, Selvaraj P, et al. Incorporation of glycosylphosphatidylinositol-anchored granulocyte- macrophage colony-stimulating factor or CD40 ligand enhances immunogenicity of chimeric simian immunodeficiency virus-like particles. J Virol. 2007;81(3):1083–94. doi:10.1128/JVI.01692-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. Am J Hyg. 1938;27:493–7.

    Google Scholar 

  47. Sha Z, Compans RW. Induction of CD4(+) T-cell-independent immunoglobulin responses by inactivated influenza virus. J Virol. 2000;74(11):4999–5005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kommareddy S, Bonificio A, Gallorini S, Baudner B, Singh M, O’Hagan D. Preparation of highly concentrated influenza vaccine for use in novel delivery approaches. J Pharm Sci. 2013;102(3):866–75. doi:10.1002/jps.23444.

    Article  CAS  PubMed  Google Scholar 

  49. Gill HS, Prausnitz MR. Coated microneedles for transdermal delivery. J Control Release Off J Control Release Soc. 2007;117(2):227–37. doi:10.1016/j.jconrel.2006.10.017.

    Article  CAS  Google Scholar 

  50. Koutsonanos DG, del Pilar MM, Zarnitsyn VG, Sullivan SP, Compans RW, Prausnitz MR, et al. Transdermal influenza immunization with vaccine-coated microneedle arrays. PLoS ONE. 2009;4(3), e4773. doi:10.1371/journal.pone.0004773.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fischer K. Neues verfahren zur maßanalytischen bestimmung des wassergehaltes von flüssigkeiten und festen körpern. Angew Chem. 1935;48(26):394–6. doi:10.1002/ange.19350482605.

    Article  CAS  Google Scholar 

  52. Wood JM, Schild GC, Newman RW, Seagroatt V. An improved single-radial-immunodiffusion technique for the assay of influenza haemagglutinin antigen: application for potency determinations of inactivated whole virus and subunit vaccines. J Biol Stand. 1977;5(3):237–47.

    Article  CAS  PubMed  Google Scholar 

  53. Williams MS. Single-radial-immunodiffusion as an in vitro potency assay for human inactivated viral vaccines. Vet Microbiol. 1993;37(3–4):253–62.

    Article  CAS  PubMed  Google Scholar 

  54. Sullivan SP, Koutsonanos DG, Del Pilar Martin M, Lee JW, Zarnitsyn V, Choi SO, et al. Dissolving polymer microneedle patches for influenza vaccination. Nat Med. 2010;16(8):915–20. doi:10.1038/nm.2182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Prevention CfDCa. Epidemiology and prevention of vaccine-preventable diseases the pink book: course textbook. In: Atkinson WWS, Hamborsky J, editors. 12th edition, second printing. Washington DC: Public Health Foundation; 2012.

  56. Zhou H, Thompson WW, Viboud CG, Ringholz CM, Cheng PY, Steiner C, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993–2008. Clin Infect Dis Off publ Infect Dise Soc Am. 2012;54(10):1427–36. doi:10.1093/cid/cis211.

    Article  Google Scholar 

  57. Gruber WC, Taber LH, Glezen WP, Clover RD, Abell TD, Demmler RW, et al. Live attenuated and inactivated influenza vaccine in school-age children. Am J Dis Child. 1990;144(5):595–600.

    CAS  PubMed  Google Scholar 

  58. Kishida N, Fujisaki S, Yokoyama M, Sato H, Saito R, Ikematsu H, et al. Evaluation of influenza virus A/H3N2 and B vaccines on the basis of cross-reactivity of postvaccination human serum antibodies against influenza viruses A/H3N2 and B isolated in MDCK cells and embryonated hen eggs. Clin Vaccine Immunol CVI. 2012;19(6):897–908. doi:10.1128/CVI.05726-11.

    Article  CAS  PubMed  Google Scholar 

  59. Neuzil KM, Jackson LA, Nelson J, Klimov A, Cox N, Bridges CB, et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5–8-year-old children. J Infect Dis. 2006;194(8):1032–9. doi:10.1086/507309.

    Article  CAS  PubMed  Google Scholar 

  60. Kim YC, Quan FS, Compans RW, Kang SM, Prausnitz MR. Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity. J Control Release Off J Control Release Soc. 2010;142(2):187–95. doi:10.1016/j.jconrel.2009.10.013.

    Article  CAS  Google Scholar 

  61. Kostova D, Reed C, Finelli L, Cheng PY, Gargiullo PM, Shay DK, et al. Influenza illness and hospitalizations averted by influenza vaccination in the United States, 2005–2011. PLoS ONE. 2013;8(6):e66312. doi:10.1371/journal.pone.0066312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Skountzou I, Koutsonanos DG, Kim JH, Powers R, Satyabhama L, Masseoud F, et al. Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus. J Immunol. 2010;185(3):1642–9. doi:10.4049/jimmunol.1000091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Dahnide Taylor-Williams for her valuable technical support. We thank Derek O’Hagan, Sushma Kommareddy, and their colleagues at Novartis Vaccines and Diagnostics for providing influenza vaccine monobulks. The work was supported by US National Institutes of Health grant EB012495.

Conflict of interest

Mark Prausnitz is an inventor of patents that have been licensed to companies developing microneedle-based products, is a paid advisor to companies developing microneedle-based products, and is a founder/shareholder of companies developing microneedle-based products. Devin McAllister is an inventor of patents that have been or may be licensed to companies developing microneedle-based products and a founder/shareholder of a company developing microneedle-based products. The terms of this arrangement have been reviewed and approved by Georgia Tech and Emory University in accordance with their conflict of interest policies. Elena Vassilieva, Haripriya Kalluri, Misha Taherbhai, E. Stein Esser, Winston Pewin, Joanna Pulit-Penaloza, Richard Compans, and Ioanna Skountzou declare that they have no conflict of interest.

Animal study statement

All institutional and national guidelines for the care and use of laboratory animals were followed.

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Authors and Affiliations

  1. Department of Microbiology & Immunology and Emory Vaccine Center, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA, 30322, USA

    Elena V. Vassilieva, Misha T. Taherbhai, E. Stein Esser, Joanna A. Pulit-Penaloza, Richard W. Compans & Ioanna Skountzou

  2. School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive, Atlanta, GA, 30332-0100, USA

    Haripriya Kalluri, Devin McAllister, Winston P. Pewin & Mark R. Prausnitz

  3. Influenza Division, Centers for Disease Control, Atlanta, GA, 30322, USA

    Joanna A. Pulit-Penaloza

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  1. Elena V. Vassilieva
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Correspondence to Ioanna Skountzou.

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Vassilieva, E.V., Kalluri, H., McAllister, D. et al. Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature. Drug Deliv. and Transl. Res. 5, 360–371 (2015). https://doi.org/10.1007/s13346-015-0228-0

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