Mucosal immunity plays a major role in the prevention of infectious diseases. Genetically engineered lactic acid bacteria (LAB) have been tested in the last 10 years as safe mucosal delivery vectors. We previously showed that intranasal co-administration of recombinant lactococci displaying human papillomavirus type 16 (HPV-16) E7 antigen at its surface (LL-E7) and secreting biologically active interleukine-12 (LL-IL-12) has therapeutic effects on HPV-16-induced tumors in mice. In this work, to optimize the immunization protocol, a comparison between intragastric and intranasal routes of administration was performed and two different LAB strains (Lactococcus lactis and Lactobacillus plantarum) were tested as delivery vector. E7-specific systemic and mucosal responses as well as potent anti-tumor effects were higher after intranasal immunization with LL-E7 and LL-IL-12 strains than intragastric administration. Comparisons of the immune responses induced by intranasal administration of either LL-E7 or Lb. plantarum anchoring E7 antigen (LP-E7) revealed highest systemic responses with recombinant Lactobacillus. Furthermore, although only a modest mucosal immune response was observed with LP-E7, this strain was able to induce a significant regression of HPV-induced tumors in contrast to LL-E7. Taken together, our results demonstrate the advantage of intranasal over intragastric route of immunization to induce an antigen-specific immune response and suggest that intrinsic immunomodulatory properties of Lb. plantarum play an important role in the immunogenicity of the expressed antigen.