The route of vaccination plays an important role in the generation of protective immunity against pathogens. In one of our previous studies, subcutaneous (SC) immunization with Epivac had been shown to induce a local and systemic Th1-biased response but failed to provide complete protection. In this study, we investigated whether intranasal (IN) immunization with Epivac could protect against Helicobacter pylori infection to a greater extent than SC immunization. Despite the generation of high serum IgG levels via the two routes of vaccination, the protective effect was independent of the humoral response level. At 2-week post-challenge, examination of the IgG subclass response showed that a dominant IgG2a response was generated after IN immunization, which coincided with elevated IFN-γ production in both splenocytes and stomach homogenates, and a significant reduction in the H. pylori load was found. In contrast, a balanced Th1/Th2 response was induced by SC immunization at the same time point and no protective effect was observed. Two weeks later, the immune response in the SC vaccination groups shifted to Th1 and was equivalent in protection to the IN vaccination route. Our results showed that IN vaccination elicited earlier systemic and gastric Th1 response, which may contribute to the earlier protection compared to SC vaccination.