Electroporation delivery of DNA vaccines: prospects for success

Abstract

A number of noteworthy technology advances in DNA vaccines research and development over the past few years have led to the resurgence of this field as a viable vaccine modality. Notably, these include--optimization of DNA constructs; development of new DNA manufacturing processes and formulations; augmentation of immune responses with novel encoded molecular adjuvants; and the improvement in new in vivo delivery strategies including electroporation (EP). Of these, EP mediated delivery has generated considerable enthusiasm and appears to have had a great impact in vaccine immunogenicity and efficacy by increasing antigen delivery upto a 1000 fold over naked DNA delivery alone. This increased delivery has resulted in an improved in vivo immune response magnitude as well as response rates relative to DNA delivery by direct injection alone. Indeed the immune responses and protection from pathogen challenge observed following DNA administration via EP in many cases are comparable or superior to other well studied vaccine platforms including viral vectors and live/attenuated/inactivated virus vaccines. Significantly, the early promise of EP delivery shown in numerous pre-clinical animal models of many different infectious diseases and cancer are now translating into equally enhanced immune responses in human clinical trials making the prospects for this vaccine approach to impact diverse disease targets tangible.

Figure 1

(a) Schematic depicting the EP process. (b) Enhancement of gene expression following DNA delivery with EP. GFP plasmid was delivered to rabbit muscle via IM injection without EP (top panels) or IM injection with EP (bottom panels). The injected muscle was harvested and then sectioned into 1 mm thick sections to visualize GFP expression either under white light (Muscle + GFP) or under a UV lamp (GFP). The highly fluorescent GFP expression is observed only when the DNA is delivered via EP – representing a 100–1000 fold enhancement in gene delivery to the target tissue (Unpublished GFP images courtesy of Inovio Pharmaceuticals).

Figure 2

Electroporation devices developed to target the different depths of the skin/muscle. IM devices include Cellectra^®-5P, ELGEN™, Medpulser. The minimally invasive devices (MID) target the dermis/sub-cutaneous layers (MID-I)[53] or the epidermis/stratum corneum (MID-II)[54]. Also shown is a non-contact device where EP is facilitated by piezoelectric discharge (PID)[58].

Figure 3

(a, top) Comparison of cellular immune responses elicited by an optimized SIV DNA vaccine delivered via EP versus an optimized Ad5 SIV vaccine. The DNA EP vaccine yielded stronger and continuously boostable ELISpot responses relative to the Ad5 vaccine. The DNA EP vaccine also led to better proliferative capacity of both CD4+ and CD8+ T-cells and improved polyfunctionality (Figure adapted from [39]). (b, right) Comparison of NAb responses induced by a DNA EP smallpox vaccine to those induced by the licensed Dryvax^® live attenuated vaccine in a NHP model (Figure adapted from [7]).