In this study, we describe the construction of poliovirus genomes or 'replicons' which contain the C fragment gene of tetanus toxin substituted for the poliovirus P1 capsid. Upon transfection of replicon RNA into cells, we immunoprecipitated a protein corresponding to the C-fragment of tetanus toxin using tetanus-specific antibodies. Using a recombinant vaccinia virus expressing poliovirus P1 capsid protein (VV-P1) to provide P1 protein, the replicon RNA was encapsidated; stocks of the replicons were generated by passage with VV-P1. The immunogenicity of the replicons was determined by immunization of transgenic mice which are susceptible to poliovirus. A serum antibody response to poliovirus and tetanus toxoid was detected in all of the immunized mice. Protection against a lethal dose of tetanus toxin generally correlated with the levels of serum anti-tetanus antibodies. To address whether pre-existing antibodies to poliovirus limit the effectiveness of the replicon as a vaccine vector, mice were first immunized with the inactivated poliovirus vaccine followed by immunization with the replicons expressing C-fragment protein. Anti-tetanus antibodies were detected in these mice after a single administration of the replicon; these antibodies conferred protection upon challenge with tetanus toxin. These results demonstrate the potential use of poliovirus replicons encoding foreign proteins to induce a protective antibody response, even in the presence of pre-existing antibodies to poliovirus.