Diphtheria toxoid and N-trimethyl chitosan layer-by-layer coated pH-sensitive microneedles induce potent immune responses upon dermal vaccination in mice

P. Schipper, K. van der Maaden, V. Groeneveld, M.J.R. Ruigrok, S. Romeijn, S. Uleman, C.W.J. Oomens, G. Kersten, W. Jiskoot, J.A. Bouwstra

Research output: Contribution to journalArticleAcademicpeer-review

33 Citations (Scopus)
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Abstract

Dermal immunization using antigen-coated microneedle arrays is a promising vaccination strategy. However, reduction of microneedle sharpness and the available surface area for antigen coating is a limiting factor. To overcome these obstacles, a layer-by-layer coating approach can be applied onto pH-sensitive microneedles. Following this approach, pH-sensitive microneedle arrays (positively charged at coating pH 5.8 and nearly uncharged at pH 7.4) were alternatingly coated with negatively charged diphtheria toxoid (DT) and N-trimethyl chitosan (TMC), a cationic adjuvant. First, the optimal DT dose for intradermal immunization was determined in a dose-response study, which revealed that low-dose intradermal immunization was more efficient than subcutaneous immunization and that the EC50 dose of DT upon intradermal immunization is 3-fold lower, as compared to subcutaneous immunization. In a subsequent immunization study, microneedle arrays coated with an increasing number (2, 5, and 10) of DT/TMC bilayers resulted in step-wise increasing DT-specific immune responses. Dermal immunization with microneedle arrays coated with 10 bilayers of DT/TMC (corresponding with ± 0.6 μg DT delivered intradermally) resulted in similar DT-specific immune responses as subcutaneous immunization with 5 μg of DT adjuvanted with aluminum phosphate (8-fold dose reduction). Summarizing, the layer-by-layer coating approach onto pH-sensitive microneedles is a versatile method to precisely control the amount of coated and dermally-delivered antigen that is highly suitable for dermal immunization.

Original languageEnglish
Pages (from-to)28-36
Number of pages9
JournalJournal of Controlled Release
Volume262
DOIs
Publication statusPublished - 28 Sep 2017

Keywords

  • Coated microneedles
  • Diphtheria toxoid
  • Intradermal immunization
  • Layer-by-layer (self) assembly
  • Microneedles
  • pH-sensitive coating
  • Immunoglobulin G/blood
  • Skin/metabolism
  • Dose-Response Relationship, Immunologic
  • Microinjections
  • Humans
  • Chitosan/administration & dosage
  • Diphtheria Toxoid/administration & dosage
  • Animals
  • Vaccination/instrumentation
  • Injections, Subcutaneous
  • Drug Liberation
  • Female
  • Needles
  • Mice, Inbred BALB C
  • Hydrogen-Ion Concentration

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