As a simpler, albeit probably less efficient, method, microneedles can be used to pierce the skin to make it more permeable and thereby enable entry of topically applied vaccines. This method is attractive because the micro-scale pores made by microneedle insertion are generally too small for penetration of microorganisms (Donnelly et al. 2009 ), yet large enough for delivery of sub-unit and possibly viral vaccines. After insertion and removal of the microneedles, vaccine can be applied using a patch or other topical formulation for slow delivery by diffusion through long-lived pores (Kalluri and Banga 2011) . This approach was investigated for transcutaneous vaccination using diphtheria toxoid and influenza vaccine (Ding et al. 2009a; Ding et al. 2009b) . When diphtheria toxoid was applied to microneedle-pretreated skin in combination with cholera toxin adjuvant, a similar immune response was induced compared to SC injection. However, microneedle pretreatment did not enhance immune response for influenza vaccine. This vaccination approach has also been studied in an ex vivo human skin model to investigate skin immune cell responses (Ng et al. 2009 ). Using a related approach, blunt-tipped microneedles were used to scrape the skin, thereby making microtroughs in the skin through which a DNA vaccine encoding HBsAg was administered (Mikszta et al. 2002) . This approach generated stronger humoral and cellular immune responses than IM or ID injection.