The hemagglutinin/adhesin HArep domain is present in the gingipains HRgpA and Kgp and in the hemagglutinin HagA of Porphyromonas gingivalis and is felt to be important in the virulence of this bacterium. In the present study, we determined the immunogenicity of recombinant HArep from the gingipain Kgp (termed Kgp-rHArep) and the effectiveness of the B subunit of cholera toxin (CTB), compared to other adjuvants in potentiating a specific response to Kgp-rHArep following intranasal (i.n.) immunization of mice. Furthermore, we determined the effectiveness of anti-Kgp-rHArep antibodies in protection against P. gingivalis invasion of epithelial cells. Evidence is provided that Kgp-rHArep was effective in inducing immune responses following systemic or mucosal immunization. Kgp-rHArep induced both a Th1- and Th2-type response following i.n. immunization. Immunization of mice with Kgp-rHArep and CTB, either admixed or chemically conjugated to the antigen, via the i.n. route, resulted in a significant augmentation of the systemic and mucosal immune response to Kgp-rHArep, which was similar to or higher than the responses seen in mice immunized with antigen and the other adjuvants tested. CTB and the heat-labile toxin of Escherichia coli potentiated a Th1- and Th2-type response to Kgp-rHArep, whereas the adjuvant monophosphoryl lipid A preferentially promoted a Th1-type response to the antigen. Furthermore, anti-Kgp-rHArep antibodies were shown to protect against P. gingivalis invasion of epithelial cells in an in vitro system. These results demonstrate the effectiveness of certain mucosal adjuvants in potentiating and in altering the nature of the immune response to Kgp-rHArep following i.n. immunization, and provide evidence for the potential usefulness of Kgp-rHArep for the development of a vaccine against periodontal disease. © 2005 Elsevier Ltd. All rights reserved.