One of the current goals in vaccine development is the noninvasive administration of protective antigens via mucosal surfaces. In this context, the gut-associated lymphoid tissues have already been extensively explored. Vaccination via the nasal route has only recently been the focus of intensive investigation, and no live vector specifically designed for the respiratory mucosa is yet available. In this study we show that intranasal administration of the recombinant Bordetella pertussis BPGR60, producing the Schistosoma mansoni 28-kDa glutathione S-transferase (Sm28GST) protective antigen fused to filamentous hemagglutinin, induces priming in mice for the production of serum antibodies. In addition to significant levels of anti-Sm28GST immunoglobulin A (IgA) antibodies, high levels of anti-Sm28GST serum antibodies were obtained after intranasal boost with the purified antigen or infection with S. mansoni following intranasal priming with BPGR60. These antibodies were of the IgG1, IgG2a, and IgG2b isotypes, suggesting a mixed immune response. No priming was observed in animals that had received nonrecombinant B. pertussis or purified Sm28GST, indicating specific priming by BPGR60. This priming was also evident in immune protection against S. mansoni challenge. Significant protection against worm burden and egg output was obtained in mice primed with BPGR60 and intranasally boosted with purified Sm28GST. A lower but still significant degree of protection against egg output was also obtained in mice infected with a single dose of BPGR60. These results indicate that intranasal administration of recombinant B. pertussis can prime for serum antibody responses against a foreign antigen and for heterologous protection.