Transcutaneous Methods Get Under the Skin

Pediatric vaccinations make children's skin resemble pincushions. Transcutaneous immunization methods in development aim to make their skin function like sponges. Harnessing the adjuvant activity of cholera toxin (CT) could make this immunization method feasible, predicts Gregory M. Glenn, scientific director of IOMAI Inc., a biotech company in Washington, D.C. Glenn and colleagues are developing a technique that mixes the toxin with antigens to boost immune responses. In one set of experimen

Aug 17, 1998
Stephen Hoffert

Pediatric vaccinations make children's skin resemble pincushions. Transcutaneous immunization methods in development aim to make their skin function like sponges.

Harnessing the adjuvant activity of cholera toxin (CT) could make this immunization method feasible, predicts Gregory M. Glenn, scientific director of IOMAI Inc., a biotech company in Washington, D.C. Glenn and colleagues are developing a technique that mixes the toxin with antigens to boost immune responses. In one set of experiments, the researchers shaved mice, anesthetized them to prevent them from licking their skin, then swabbed on solutions of antigens coupled with CT. Antibodies produced against CT and bovine serum albumin, CT and diphtheria toxoid, and CT and tetanus toxoid were drastically higher than antibodies produced by each of the substances without CT (G.M. Glenn et al., Nature, 391:851, Feb. 26, 1998). The applications produced immunoglobulin G (IgG) responses--the same blood serum antibody response injected vaccines produce. Glenn notes that the transcutaneous CT also produces a mucosal response--a finding that will be detailed in an upcoming paper in the Journal of Immunology.


TINY HYBRID: A microneedle array designed by scientists at the Georgia Institute of Technology combines the painlessness of a patch with the penetration of needles.
In April, IOMAI began human Phase I trials using CT as an adjuvant. Glenn acknowledges that he's not certain which mechanisms result in antibody production. Scientists also don't know why CT boosts the immune response to other antigens--just that it does. These uncertainties are not necessarily unusual in vaccinology, though, he notes: "Vaccines are mostly black boxes,"

Despite the uncertainties, Glenn hypothesizes that the CT-laden solutions somehow interact with Langerhans cells, antigen-presenting cells found in uninflamed skin. More basic research will be necessary to determine the mechanisms by which the transcutaneuous methods work. Glenn predicts that transcutaneous methods will be popular with parents, if the technology pans out the way he hopes. Ideally, a doctor or nurse could administer all the childhood vaccinations in one dose--in the form of a patch, a gel, a cream, or a solution.

ALZA Inc. of Palo Alto, Calif., is taking a similar approach--developing a transdermal device that uses CT as an adjuvant. Peter Daddona, ALZA vice president of biological sciences, declined to characterize the device as a patch or a microneedle array. Over the past 30 years, the company has focused on skin-based delivery, including a popular nicotine patch. "We know a lot about the skin, and we think that future applications of our delivery technology should now focus, in addition to drug delivery, on opportunities for vaccine delivery."

Daddona notes that, like mucosal linings, the skin is designed to offer protection from harmful elements. "Skin is a highly immunogenic site for antigen presentation and could lead to better vaccine response and maybe even allow a group of immune responses to be based on the antigen formulation," Daddona explains. "It's probably one of the most immunogenic sites that you can deliver an antigen to. If you can do that in a controlled way, you could really optimize [immune responses]." ALZA's technology under development seeks to boost both blood serum responses and cytotoxic T cell responses. Unlike the IOMAI approach, ALZA's methods do not produce a mucosal response, according to Daddona.

The possibility of triggering multiple immune responses through the skin shows promise, Daddona notes. "It's very interesting because you can really play with the biology and direct the antigen to give you the right kind of immune response, depending upon [how] you introduce it." Daddona notes that others have attempted transcutaneous vaccine administration through injections between layers of skin. But that procedure is inefficient. "You can probably get a good response, but it's very difficult to administer intradermal injections. It takes a very skilled person to place the needle in the right place and deliver all the volume you want in that specified region." However, their device under development could mimic that method and make it routine. "Preclinical studies look extremely promising," Daddona concludes.

Patches of needles thinner than a human hair at their base, tapering to microns at their tip, might also be able to penetrate the initial layers of skin and release vaccines or other medication between, while avoiding hitting pain-inducing nerves, according to Mark R. Prausnitz, engineering professor at the Georgia Institute of Technology. Prausnitz and colleagues presented data on their device in development in June at the 25th International Symposium on Controlled Release of Bioactive Materials.

In addition to reaching a receptive layer of skin, the device has the potential advantage of controlling the rate of delivery and frequency of doses. Prausnitz envisions the microneedles being coupled with computer chips and electricial current to push the drugs through the needle. The microneedle patches require more refinement before they can be marketable. For example, the needles are now solid. A hollow prototype in development could make the arrays better at drug delivery.

Still, the method has some potential advantages, including better access into the capillaries than conventional transdermal patches provide. "Transdermal patches only work for small lipids or oil-soluble stuff that are effective at low doses," Prausnitz comments. Few compounds--one notable exception is nicotine--fit that bill. Needles, on the other hand, can deliver many compounds, but pharmaceutical companies are looking for ways to deliver drugs to avoid the pain associated with needles, as well as the risks of transmitting blood-born pathogens. The microneedle strategy represents a hybrid between those two approaches.

Prausnitz says that the device's first goal--eliminating pain--has been reached. "We've done very limited tests on humans--when you push the needles in, you're [only] aware of the pushing." Prausnitz, who has stuck the device to his own skin, describes the sensation as akin to a piece of tape or a first-aid bandage on the skin. The next test, Prausnitz reports, is to use the patchlike arrays of needles to deliver medicine in animals.