We describe methods of modulating skin lipid conformation especially through hydration, to enhance penetration of vaccine antigens. Hydration of porcine skin tissue for a period of 4-8 hours causes a 3-4-fold expansion in the stratum corneum. Significant structural alterations are observed, such as swollen corneocytes, separation of lipid bilayers in the stratum corneum intercellular space, formation of spindle-shaped dilations, and the disruption of lipid membranes. Clear conformational changes of intercellular lipids from lamellar bilayers to rolled-up structures resembling multilamellar vesicles are observed in high clarity. Confocal microscopy studies show distinct enhancement in penetration of a large biomacromolecule, fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) through the skin when hydrated for 4 hours or greater. The fluorescent protein permeates the dermis region of highly hydrated skin, whereas in native skin, it mainly accumulates at the surface of the skin. When the highly hydrated skin is exposed to the environment for an hour, the skin is restored to its former compact structure. The results point towards the development of novel patch technologies for vaccine delivery.