Abstract
The skin is an attractive tissue for vaccination in a clinical setting due to the accessibility of the target, the ease of monitoring and most importantly the immune competent nature of the dermal tissue. While skin electroporation offers an exciting and novel future methodology for the delivery of DNA vaccines in the clinic, little is known about the actual mechanism of the approach and the elucidation of the resulting immune responses. To further understand the mechanism of this platform, the expression kinetics and localization of a reporter plasmid delivered via a surface dermal electroporation (SEP) device as well as the effect that this treatment would have on the resident immune cells in that tissue was investigated. Initially a time course (day 0 to day 21) of enhanced gene delivery with electroporation (EP) was performed to observe the localization of green fluorescent protein (GFP) expression and the kinetics of its appearance as well as clearance. Using gross imaging, GFP expression was not detected on the surface of the skin until 8 h post treatment. However, histological analysis by fluorescent microscopy revealed GFP positive cells as early as 1 h after plasmid delivery and electroporation. Peak GFP expression was observed at 24 h and the expression was maintained in skin for up to seven days. Using an antibody specific for a keratinocyte cell surface marker, reporter gene positive keratinocytes in the epidermis were identified. H&E staining of treated skin sections demonstrated an influx of monocytes and granulocytes at the EP site starting at 4 h and persisting up to day 14 post treatment. Immunological staining revealed a significant migration of lymphocytic cells to the EP site, congregating around cells expressing the delivered antigen. In conclusion, this study provides insights into the expression kinetics following EP enhanced DNA delivery targeting the dermal space. These findings may have implications in the future to design efficient DNA vaccination strategies for the clinic.
Highlights
Delivery of vaccines directly to the skin is an attractive immunization strategy in a clinical setting due to a number of dermal-specific features
To assess the expression kinetics resulting from gene delivery with a dermal EP device, a plasmid expressing green fluorescent protein (GFP) was injected into guinea pig skin at defined time points
Intradermal electroporation is a platform technology which offers a solution to the tolerable delivery of DNA vaccines in the clinic for prophylactic immunization
Summary
Delivery of vaccines directly to the skin (intradermal, ID) is an attractive immunization strategy in a clinical setting due to a number of dermal-specific features. The device consists of three-needle (3 mm in length) electrodes forming a triangle microarray to cover the DNA injection site This depth of penetration treats the entire skin thickness and as such targets the dermal cells in the epidermis, dermis and subdermis. This device has entered the clinic in two studies (ClinTrials identifier—NCT01403155, NCT01405885) sponsored by Inovio Pharmaceuticals (Blue Bell, PA, USA) addressing the delivery of a multi-strain influenza DNA vaccine. These findings may have future implications when designing efficient ID DNA vaccination strategies for the clinic allowing for peak antigen expression to drive the immunization schedule
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