DNA Vaccine Delivery - Development of the ideal DNA vaccine requires the optimization of delivery strategies and plasmid vectors. - BioPharm International


DNA Vaccine Delivery
Development of the ideal DNA vaccine requires the optimization of delivery strategies and plasmid vectors.

BioPharm International Supplements
Volume 24, Issue 10, pp. s12-s18


Transdermal DNA immunization involves the use of arrays of microneedles, each a few hundred microns long, to pierce the barrier of the stratum corneum (i.e., the skin's outer layer, typically 10–20 m thick) and deliver the vaccine (7). The skin has a high concentration of APCs called Langerhans cells, which makes it an attractive target. The advantages of microneedles are that they are easy to administer and cause less pain at the injection site than does a conventional needle. There are various strategies to achieve vaccination using microneedles. The simplest involves arrays of microneedles that are used to pierce or scarify the stratum corneum, thus increasing permeability to a topically applied DNA solution. This approach is suitable for preclinical studies, but is not scalable. Alternatively, the microneedles can be coated with the dried vaccine which dissolves following administration. Hollow microneedles can be used to inject solutions containing the vaccine. These can be submillimeter arrays or scaled-down needles in the range of 1–2 mm. An interesting alternative to fixed, disposable microneedles is a solid, soluble microneedle array that is either formulated or coated with the vaccine. This array is inserted into the skin, where the microneedles dissolve or degrade, leaving only the backing to be disposed of and thus eliminating contaminated sharps.

Smallpox DNA vaccination of mice was demonstrated using the Easy Vax device supplied by Cellectis therapeutics (Paris), and was the first example of microneedle-mediated electroporation (8). The gun-shaped Easy Vax combines the electroporation and microneedle approaches, with cutaneous Langerhans cells as the targeted APCs. The plasmid DNA was dried onto the tips of the eighty-microneedle array and inserted into the skin to enable the DNA to dissolve, followed by the delivery of six electric pulses.

While the microneedle approach is gaining interest for delivery of therapeutic and antigenic recombinant proteins, only a few studies in mice have shown immune protection against microneedle-administered DNA vaccines. An additional problem when translating animal results to humans relates to the amount of DNA that can be loaded onto a microneedle array. A typical human clinical trial injected dose of 2–4 mg DNA is already relatively small compared with the murine equivalent from which it is extrapolated, yet this would be prohibitively high to expect to dissolve intradermally from a dried formulation on a microneedle array, which leaves liquid DNA solution injection as the only viable strategy.

Cellectis therapeutics also supplies the DermaVax electroporator (see Figure 1c), which requires a DNA solution to be injected sub-dermally using a hypodermic syringe, followed by electroporation through a series of pulses from 2 mm needle electrodes attached to the bench-top DermaVax apparatus. The DermaVax system induces a 100- to 1000-fold greater increase in gene expression over injection alone and is being used for the delivery of DNA vaccines against HIV-1, as well as vaccines against prostate and colorectal cancers in human clinical trials (9).

Inovio Pharmaceuticals has developed a transdermal electroporation device called CELLECTRA-3P. In pilot studies in nonhuman primates, Inovio demonstrated that intradermal administration of a smallpox vaccine or an H5N1 vaccine successfully protected animals from a lethal challenge of monkeypox or an H5N1 infection, respectively (10, 11). The device is now in Phase I clinical trials for a universal influenza vaccine. Inovio has also developed a prototype minimally invasive electroporation device that has been demonstrated for influenza DNA vaccine delivery.


Gene guns have been used since the advent of DNA vaccination for high-pressure transdermal delivery of microbeads coated with DNA (biolistics). PowderMed (Oxford, UK, acquired by Pfizer) developed a handheld particle-mediated epidermal delivery (PMED) device that uses a high-pressure helium minicylinder to fire DNA-coated gold microbeads into the epidermis. Because the gold beads enter the cell cytoplasm and target more APCs than does needle injection, greater CTL responses can be generated for the same amount of DNA (11). In one example, PMED was used to deliver 2 g of two plasmids to rhesus macaques: one with an H1N1 hemagglutinin gene, the other expressing the adjuvant GM–CSF. This method generated good antibody and CTL responses (12). However, limitation to the microbead approach is the amount of DNA that can be coated onto beads, which could restrict its ability to be scaled up for human applications.

Merial (Duluth, GA) developed the pioneering canine melanoma DNA vaccine Oncept, which was fully approved in 2010. It contains the human tyrosinase gene, delivered (following surgical tumor removal) in four doses at two-week intervals, followed by a single dose every six months. Oncept is administered using a needle-free Canine Transdermal Device developed by Bioject Medical Technologies (Portland, OR) (13). Bioject specializes in the development of needle-free injection systems that use high-pressure injection to fire a stream of the DNA vaccine solution through the epidermis. Their latest device, ZetaJet, is small and spring-activated for ease of use in the field, and fires up to 0.5 mL into skin or muscle tissue.

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