In animal studies, we have demonstrated that the dose of an injected H5N1 vaccine candidate can be significantly reduced by using a skin patch containing E. coli heat-labile enterotoxin (LT) applied over the injection site. LT-activated epidermal Langerhans cells migrate to the nearby draining lymph node and enhance the immune response to the injected antigen. A dry patch formulation has been optimized as a dose sparing strategy for pandemic flu and other vaccines. Iomai Corporation has developed a proprietary stabilizing formulation for the patch that allows use and storage at ambient temperature. The patch withstands temperature extremes during shipment, and is suitable for stockpiling.
To improve the efficiency of LT delivery to the Langerhans cells in the epidermis, mild disruption of the stratum corneum (SC), the outermost layer of the human skin, is needed prior to the application of the skin patch. For this skin pretreatment, Iomai has developed a disposable skin preparation system (SPS) device to gently abrade the SC to enhance delivery of LT.14 The SPS consists of a strip-pull device with an abrasive surface that is placed on the skin. As the strip is pulled, the SC is gently disrupted. Strip-pulling is simple, painless, and effective for delivery of vaccine, LT, or both into the skin.
Our preclinical studies using LT-IS patches applied over pretreated skin have demonstrated up to 100-fold dose sparing in animals vaccinated with a bird flu recombinant protein vaccine candidate.5
In addition, the LT-IS patch was found capable of augmenting immune responses to different commercial seasonal flu vaccines in preclinical studies. More importantly, the LT-IS patch has been tested in a Phase 1 trial involving a commercial influenza vaccine.15 In this clinical trial, the LT-IS patch was applied to subjects over 60 years of age receiving their annual influenza vaccine. The clinical data demonstrated that an LT-IS patch can enhance immune responses to influenza vaccination in the elderly. Taken together, the results of the preclinical and clinical studies reinforce the idea of a potential universal dose sparing strategy by using an immunostimulant patch containing E. coli LT.
In the preclinical and clinical studies just described, LT was used in a wet patch format to demonstrate proof-of-concept principles. The wet patch format involves pipetting a liquid LT solution onto a gauze pad placed over the injection site, and subsequently covering the wet gauze with a protective adhesive overlay. When compared to a wet patch format, a dry patch format is more appealing in terms of ease of use in a clinical setting and commercial viability. Also, a dry patch product is expected to demonstrate a better stability profile due to the significant reduction of water-mediated degradation processes.
Recently, we have developed a stabilizing formulation matrix to present biological products in such a dry patch format. Using this formulation platform technology, we have applied LT in a dry formulated patch, and have conducted a clinical trial to compare the effect of a dry versus wet LT patch with respect to skin delivery. The clinical results presented in this paper show that the dry LT patch is equal to or better than the wet patch in terms of vaccine delivery.