A new anthrax vaccine under clinical investigation is based on recombinant Bacillus anthracis protective antigen (rPA). Here, we investigated microneedle-based cutaneous and nasal mucosal delivery of rPA in mice and rabbits. In mice, intradermal (id) delivery achieved up to 90% seroconversion after a single dose, compared with 20% after intramuscular (im) injection. Intranasal (inl) delivery of a liquid formulation required 3 doses to achieve responses that were comparable with those achieved via the id or im routes. In rabbits, id delivery provided complete protection against aerosol challenge with anthrax spores; in addition, novel powder formulations administered inl provided complete protection, whereas a liquid formulation provided only partial protection. These results demonstrate, for the first time, that cutaneous or nasal mucosal administration of rPA provides complete protection against inhalational anthrax in rabbits. The novel vaccine/device combinations described here have the potential to improve the efficacy of rPA and other biodefense vaccines.

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The recombinant protective antigen (rPA) of Bacillus anthracis is a promising anthrax vaccine. We compared serum immunoglobulin G levels and toxin-neutralizing antibody titers in rabbits following delivery of various doses of vaccine by microneedle-based intradermal (i.d.) delivery or intramuscular (i.m.) injection using conventional needles. Intradermal delivery required less antigen to induce levels of antibody similar to those produced via i.m. injection during the first 2 weeks following primary and booster inoculation. This dosesparing effect was less evident at the later stages of the immune response. Rabbits immunized i.d. with 10 g of rPA displayed 100% protection from aerosol spore challenge, while i.m. injection of the same dose provided slightly lower protection (71%). Groups immunized with lower antigen doses were partially protected (13 to 29%) regardless of the mode of administration. Overall, our results suggest rPA formulated with aluminum adjuvant and administered to the skin by a microneedle-based device is as efficacious as i.m. vaccination.In the autumn of 2001, anthrax spores were intentionally released through the U.S. mail. This bioterror attack resulted in 11 cases of cutaneous anthrax and 11 cases of inhalational anthrax, 5 of which were fatal (7, 9). There has been an unprecedented level of public and private support for the development of new means of preventing and treating anthrax during the years following these attacks. Although antibiotics are nearly 100% effective in treating the cutaneous form of the disease, the case fatality rate for inhalational anthrax was estimated to be 75% or higher, even in the presence of supportive care and postexposure antibiotic treatment (information found at the CDC website [http://www.bt.cdc.gov/agent/anthrax /faq/signs.asp]). A recombinant form of the Bacillus anthracis protective antigen (rPA) is a candidate for replacement of Anthrax Vaccine Adsorbed (BioThrax), the currently licensed anthrax vaccine. Proposed applications of the rPA vaccine include prophylactic vaccination as well as therapeutic postexposure use in combination with antibiotics (5). Numerous preclinical studies have demonstrated that the rPA vaccine can provide complete protection against lethal inhalational anthrax (4, 8,11,13,14,18,23). Results of phase I clinical trials suggest that the vaccine is safe and immunogenic following intramuscular (i.m.) injection in humans (6).Most licensed and new vaccines under clinical development, including rPA, are administered by i.m. or subcutaneous injection using conventional needles and syringes. However, recent studies demonstrate that vaccine delivery to the skin can increase the magnitude of the immune response and, in some cases, do so using less vaccine than required with i.m. injection (1,2,10,12,(18)(19)(20)22). For example, clinical studies evaluating intradermal (i.d.) delivery of influenza vaccine have suggested that dose sparing relative to i.m. administration can be achieved (1, 10). Although conventional needles can be used...

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