BCG vaccine powder-laden and dissolvable microneedle arrays for lesion-free vaccination

Abstract

Live attenuated Bacille Calmette-Guerin (BCG) bacillusis the only licensed vaccine for tuberculosis prevention worldwide to date. It must be delivered intradeemally to be effective, which causes severe skin inflammation and sometimes, permanent scars. To minimize the side effects, we developed a novel microneedle array (MNA) that could deliver live attenuated freeze-dried BCG powder into the epidermis in a painless, lesion-free, and self-applicable fashion. The MNA was fabricated with biocompatible and dissolvable hyaluronic acid with a deep cave formed in the basal portion of each microneedle, into which BCG powder could be packaged directly. Viability of BCG vaccine packaged in the caves and the mechanical strength of the powder-laden MNA did not alter significantly before and after more than two months of storage at room temperature. Following insertion of the MNA into the skin, the individual microneedle shafts melted away by interstitial fluid from the epidermis and upper dermis, exposing the powder to epidermal tissues. The powder sucked interstitial fluid, dissolved slowly, and diffused into the epidermis in a day against the interstitial fluid influx. Vaccination with BCG-MNA caused no overt skin irritation, in marked contrast to intradermal vaccination that provoked severe inflammation and bruise.While causing little skin irritation, vaccination efficacy of BCG-MNAs was comparable to that of intradermal immunization whether it was evaluated by humoral or cellular immunity. This powder-laden and dissolvable MNA represents a novel technology to sufficiently deliver live attenuated vaccine powders into the skin.

Delivery of allergen powder for safe and effective epicutaneous immunotherapy

“…8 We used an ablative fractional laser to generate an array of self-renewable microchannels in the skin onto which a patch decorated with an identical pattern of antigen powder dots was aligned, resulting in approximately 80% powder delivery in approximately 1 hour in mouse, human, and pig skin concurrent with little skin irritation. 17,[24][25][26] The powder was retained within the epidermis for an extended period of time, constantly stimulating the immune system for days. [25][26][27] In addition, we identified CpG, an agonist of Toll-like receptor 9 for T H 1 immune responses, and 1,25-dihydroxyvitamin D3 (VD3), an immunosuppressant, to be a potent tolerogenic adjuvant when combined.…”

“…17,[24][25][26] The powder was retained within the epidermis for an extended period of time, constantly stimulating the immune system for days. [25][26][27] In addition, we identified CpG, an agonist of Toll-like receptor 9 for T H 1 immune responses, and 1,25-dihydroxyvitamin D3 (VD3), an immunosuppressant, to be a potent tolerogenic adjuvant when combined. 17 To tailor this powder delivery technology for clinical uses, we recently engineered powder-laden, dissolvable microneedle arrays (PLD-MNAs) that could be directly applied onto intact skin to deliver powdered antigens into the epidermis 26 without the need for a laser to perforate the skin.…”

Recent Approaches for Solid Dose Vaccine Delivery

“…For instance, in one study, the administration of rabies DNA vaccine in dogs using dissolving microneedle patches was reported to be well tolerated in the skin, with mild erythema, minimal wheal formation and a complete resolution of skin reactions within 7 days, without generating any systemic adverse effects [109]. In another study, it was reported that the BCG (Bacille Calmette-Guerin) vaccine powder-laden and dissolvable microneedle arrays displayed similar vaccination efficacy compared to the intradermal (ID) route without incurring significant skin inflammation, whereas the ID vaccination of BCG is known to cause severe inflammation for weeks at the site of inoculation [111].…”

Polymeric Nanoparticles Engineered as a Vaccine Adjuvant-Delivery System

“…They demonstrated that the delivery of Trp 2/CpG ODN to DCs by mLCPbased VADS elicited a potent systemic immune response to tumors in mice but generated, to later stage B16F10 melanoma, a marginal efficacy, which however, was remarkably boosted through silencing the immune-suppressive cytokine TGF-β in tumor cells with siRNA-loaded LPHa NPs to engender increased tumor infiltrating CD8+ T cells and decreased regulatory T cells within tumor microenvironment. Wu's group fabricated a microneedle array (MA) with HA with a deep cave formed in the basal portion of each microneedle, into which BCG (Bacille Calmette-Guerin bacillus) powder could be packaged directly, thus producing a painless VADS of MA-BCG, which after vaccination by patching on skin of mice caused no overt skin irritation, but elicited strong humoral and cellular immunity comparable to that of intradermal immunization [71]. Notably, other researchers showed in a clinical trial that HA-constructed MA containing trivalent influenza hemagglutinins (A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008, 15 μg each) induced immune responses against A/H1N1 and A/H3N2 strains equal to that by subcutaneous injection groups without stirring severe local or systemic adverse reactions and engendered the efficacy against the B strain much stronger than that by the injection group, proving HA-MA a promising practical use as an easy and effective method to replace conventional injection systems [72].…”