Biodegradable polymeric devices intended to provide a viable route for single-dose vaccination were developed using controlled-release technology. One of the main challenges in the development of these devices was to overcome several water-mediated inactivation processes that occur in conventional polymeric systems. Our strategy was focused on the prevention of antigen exposure to environmental conditions. For this purpose a microencapsulation process was designed and optimized to provide an inert and insulated environment for the bioactive material inside controlled-release systems. Tetanus toxoid (TT) was used as a model antigen. The systems consist of core-wall microcapsule structures in which the antigenic protein is entrapped into oil-based cores of TT surrounded by outer polymer shells made of poly(D,L-lactide-co-glycolide), thus potentially protecting the bioactive material against deleterious conditions. Furthermore, using these microcapsules, pulses of immunochemically detected TT were programmed to release at two different times (3 and 7 weeks), as corroborated by in vitro release studies. The engineering of these specific antigen release properties was possible by careful selection of the copolymer composition and molecular weight. The final formulations were characterized with respect to morphology, structure, size distribution, and amount of immunochemically detected TT encapsulated. The new systems offer the potential to control the manner and timing of delivery. Over 92% of the TT released over a 63 day period from these microcapsules was immunochemically detected.