Vaccines that provide lasting immunity with a single administration of the antigen can reduce the cost of routine immunization programs while increasing their efficacy by lessening the need for patient compliance. The authors have been developing methods for using biodegradable polymer microspheres to encapsulate vaccines. These microcapsules are designed to provide timed release of the antigen on a schedule that mimics conventional booster shots. The microspheres are made from poly-DL-lactide-co-glycolide. The rate of biodegradation of this polymer is controllable by varying the molar ratio of the monomers. High performance liquid chromatography was used to measure release kinetics in vitro, and a process was developed for the encapsulation of water soluble protein antigens. This process then was used to prepare a microencapsulated vaccine for type A botulism made using a recombinant C fragment antigen. A series of 27 adult C57BL/6J mice were used to study the efficacy of this vaccine. Six mice injected with saline filled microspheres served as a control group. Plasma samples were taken weekly to measure antibody levels using enzyme linked immunosorbent assay. At 14 weeks, 21 immunized mice and six control subjects were used for an aerosol challenge test with botulinum toxin. All control subjects died within 72 hrs. Fifteen (71%) of the immunized mice survived.