Recombinant strains of Salmonella typhimurium have been studied as antigen delivery systems to determine their effectiveness as multivalent vaccines. Here we compare the efficacy of two strains of S. typhimurium, (χ)4072(pYA2905) and (χ)3987(pYA2905), expressing SpaA of Streptococcus sobrinus 6715 as oral vaccines for dental caries. Both strains are attenuated ΔcyaΔcrpΔasd mutants with their Asd- phenotypes complemented by the Asd+ plasmid pYA2905, which also encodes a peptide fragment of SpaA. S. typhimurium (χ)3987(pYA2905), unlike S. typhimurium (χ)4072(pYA2905), contains the 100 kb S. typhimurium virulence plasmid. Fischer rats were orally immunized with ~ 109 S. typhimurium (χ)3987(pYA2905) or (χ)4072(pYA2905) and then challenged with cariogenic S. sobrinus 6715. Rats orally immunized with either strain of recombinant Salmonella developed salivary IgA anti-SpaA responses and had lower levels of S. sobrinus-induced dental caries than nonimmunized, infected animals. In a second series of experiments, the kinetics and isotype of the serum and salivary antibody responses were determined in rats orally immunized with S. typhimurium (χ)3987(pYA2905) or (χ)4072(pYA2905) on weeks 0 and 8. IgG and IgM serum antibody responses to SpaA and S. typhimurium were detected afer the primary and secondary immunizations, and the secondary immunization boosted serum IgG anti-Salmonella activity. In general, animals immunized with (χ)3987(pYA2905) had higher serum anti-SpaA, as well as serum and salivary anti-Salmonella, responses than animals immunized with (χ)4072(pYA2905). This study demonstrates the effective use of two recombinant S. typhimurium strains as oral vaccines for inducing protective and sustained immune responses against a mucosal pathogen and suggests that the recombinant Salmonella vaccine strain carrying the virulence plasmid induced similar or higher protective immune responses than the strain lacking the virulence plasmid.