A Review of Transdermal Vaccine Delivery


The transdermal vaccine route offers an opportunity to improve vaccine administration.

According to the World Health Organization, vaccine development and mass immunization strategies remain critical initiatives, especially because of the continued threat of pandemics of diseases such as H1N1 swine influenza, as well as emerging diseases such as Ebola virus disease.

In a recent review article in Biomedicine and Pharmacotherapy, Kevin Ita, PhD, from Touro University, Mare Island-Vallejo, California, discusses some techniques used for enhancing vaccine delivery, highlighting the progress made in their development, as well as some challenges that these techniques continue to pose to scientists.

Although many vaccines are administered as injections, this delivery route is associated with disadvantages such as pain, needle stick injuries, needle-phobia, and poor patient compliance.

The transdermal route therefore offers an opportunity to improve vaccine administration. And, because it targets the skin’s potent immune cell populations, it may lead to a strong immune response at much lower doses than would be needed using an injectable vaccine.

“Two layers of the human skin—epidermis and dermis—are populated by dendritic cells (DCs), which are potent antigen-presenting cells (APCs),” the author writes. “Transcutaneous immunization has therefore become an attractive and alternative route for vaccination.”

Techniques such as sonophoresis, microneedle-assisted delivery, iontophoresis, and elastic liposomes are among those being used and developed for transdermal vaccine delivery.


Sonophoresis is a technique that uses ultrasound to permeabilize the stratum corneum layer of the skin. When ultrasound travels through a coupling fluid, it produces cavitation bubbles. These bubbles oscillate and increase in size over many cycles of the pressure wave. The main mechanism for sonophoresis-enhanced permeability of the skin is particular inertial cavitation, whereby cavitation bubbles can implode when they are close to a liquid—solid interface, generating an intense local shockwave. This produces a jet of liquid that can penetrate the stratum corneum. And, because the cavitation effect inversely correlates with ultrasound frequency, this technique is efficient for permeabilization of the skin.

Sonophoresis has been described for administration of tetanus toxoid in mice and hepatitis B surface antigen in pigs, generating an effective immune response in both cases.

However, this technique may cause burning of the skin in some cases, and epidermal necrosis may occur at high intensities.

Microneedle-assisted delivery

According to the author, “[m]icroneedles (MN) are needles with lengths in the micrometer range (typically less than 1000 micrometers) which create pores in the skin and enable medications or vaccines to be delivered locally or transdermally into systemic circulation”.

MNs can be categorized as hollow, solid, coated, dissolving, or hydrogel-forming. They are advantageous because their use does not require professional training. The technique is also painless, minimally invasive, minimally traumatic, bloodless, and avoids contaminating the bloodstream with pathogens.

The use of MNs has been applied to DNA vaccines to help resolve the problem of their poor immunogenicity. MN delivery is considered to enhance the immunogenicity of DNA vaccine-encoded antigens to the skin, and animal studies using this technique have shown that an effective immune response can be generated to hepatitis B virus and influenza virus. The technique has also been used in animals to deliver immunotherapeutic peptides to vaccinate against ovarian cancer.

Transdermal delivery using MNs has also been used to administer polio vaccine to volunteers. It has also been used to investigate delivery of the bacillus Calmette-Guérin (BCG) vaccine and the tetanus toxoid in animal models.

However, it can be challenging to deliver high doses of medications using MNs, the author says. In addition, matrix retention of some polymeric MNs in the skin can also lead to low patient compliance.


Iontophoresis involves application of a small electric current to permeabilize the skin. It is a noninvasive and efficient technology for transdermal vaccine delivery, and is particularly helpful because, when using transdermal vaccine delivery, it can be challenging to accumulate enough antigen in the epidermis for effective exposure to the skin’s DCs.

In various animal studies, this technique has been shown to effectively deliver and generate an immune response to tumor antigens and hepatitis B vaccines.

Elastic liposomes

There is also mounting interest in using lipid-based vesicles for transdermal vaccine delivery. According to the author, elastic liposomes are interesting in this regard because, unlike conventional liposomes and niosomes, they have fluid bilayers. “These vesicles are made from hydrophobic and hydrophilic moieties and therefore can accommodate drug molecules with a wide range of solubility,” writes Dr Ita.

However, despite their widespread use in transdermal vaccine delivery studies, the ability of elastic liposomes to cross the skin’s stratum corneum layer is controversial. Nevertheless, in one recent study they were used to

enhance the immunogenicity of the asexual blood stage antigen of Plasmodium falciparum, and resulted in a more intense and longer-lasting immune response to this antigen.

“There is optimism in the research community that eventually some of these vaccines will find clinical applications and assist in preventing the spread of infections and/or cancer,” Dr Ita concludes.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.

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