MicroneedleBased Transcutaneous Immunisation in M

Authors: Suzanne M Bal Zhi Ding Gideon F A Kersten Wim Jiskoot Joke A Bouwstra

Publish Date: 2010/06/18

Volume: 27, Issue: 9, Pages: 1837-1847

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Abstract

Mice were vaccinated with DTloaded TMC nanoparticles a solution of TMC and DT TMC/DT or DT alone The formulations were applied onto the skin before or after microneedle treatment with two different 300µmlong microneedle arrays and also injected intradermally ID As a positive control alumadjuvanted DT DTalum was injected subcutaneously SC Ex vivo confocal microscopy studies were performed with rhodaminelabelled TMCIndependent of the microneedle array used and the sequence of microneedle treatment and vaccine application transcutaneous immunisation with the TMC/DT mixture elicited 8fold higher IgG titres compared to the TMC nanoparticles or DT solution The toxinneutralising antibody titres from this group were similar to those elicited by SC DTalum After ID immunisation both TMCcontaining formulations induced enhanced titres compared to a DT solution Confocal microscopy studies revealed that transport of the TMC nanoparticles across the microneedle conduits was limited compared to a TMC solutionTranscutaneous immunisation ie immunisation through vaccine application onto the skin has the potential to be an excellent noninvasive vaccination route 1 This is desirable as injection of a vaccine with a needle and a syringe is not only painful 2 but it also bears a risk of transmission of infection with eg hepatitis B or C or human immunodeficiency virus 3 Furthermore the skin is densely populated with antigen presenting cells APCs 4 In the epidermis the Langerhans cells LCs are present and in the dermis the dermal dendritic cells DCs 56 The main function of these professional APCs is to sample their environment process antigens and present specific epitopes to T cells Studies using intradermal ID immunisation ie injection of the antigen into the dermis have shown that this delivery route can result in similar or even enhanced immune responses compared to intramuscular immunisation 78During recent years particlebased immunisation has gained more emphasis 9 The advantage of nanoparticles is that they can function as a depot 10 and are more efficiently taken up by DCs than plain antigens 11 Therefore nanoparticles may function as an adjuvant Nanoparticles can be prepared from polymers such as poly DLlacticcoglycolic acid PLGA or Ntrimethyl chitosan TMC TMC is a derivate of chitosan that bears a permanent positive charge and is therefore water soluble over a wide pH range TMC nanoparticles have mainly been used in mucosal immunisation 12 13 14 but recently we showed that TMC can also function as an immune potentiator in ID immunisation 15 Interestingly we observed that the adjuvant effect could be ascribed primarily to the TMC polymer itself rather than to its formulation in nanoparticles After ID injection of diphtheria toxoid DTloaded TMC nanoparticles or a solution of TMC and DT TMC/DT mixture mice developed 4fold higher IgG titres compared to those induced by plain DT These results indicate that in ID vaccination antigenloaded TMC nanoparticles are not superior to soluble TMC/antigen mixtures in contrast with eg intranasal vaccination 1617 This might be attributed to the fact that with ID injection antigen and adjuvant are immediately delivered to an APCrich environment thereby making nanoparticles unnecessaryTranscutaneous vaccination differs from ID vaccination in that the antigen first has to be transported into the skin Only then can it be taken up by skin resident APCs and induce APC maturation The natural function of the skin is to protect the body from the environment 18 This function is exerted by the upper part of the epidermis the stratum corneum Even though this part is only 15 µm thick in human skin it proves to be an excellent barrier One way to breach this barrier is by using microneedles The idea of using microneedles for transdermal drug delivery dates back to 1971 19 but only in the 1990s the first microneedles were developed 20 Since then their usage has increased and many different microneedles have become available Some devices are currently being tested in clinical trials 21 and several others are in preclinical development 22 23 24 The use of microneedles for vaccine delivery can be based on different principles hollow microneedles can be used for injection of liquids solid microneedles can either be coated with the antigen of interest or used for perforation of the skin prior to vaccine application The main advantage of microneedles is that they are long enough to penetrate the stratum corneum but short enough to avoid pain and major discomfort 2526 During the past few years we have been studying solid microneedle arrays to pretreat the skin followed by vaccine application In previous studies our group showed that microneedle pretreatment significantly increased antibody titres in transcutaneous vaccination studies with DT 2728

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