Despite the importance and success of vaccination against bacterial diseases in fish, little is known about the mechanisms of vaccine-induced disease resistance. In this study a known efficacious bacterial vaccine, to Enteric Redmouth Disease (ERM), was used to vaccinate rainbow trout, and sixty days later the fish were challenged with the causative agent of the disease, Yersinia ruckeri. The bacterial burden in the spleen, the spleen index, and the expression profiles of pro- and anti-inflammatory cytokines and marker genes for T helper (Th) cells in the spleen and gills were analyzed, in comparison to the profiles in naïve/challenged fish. As expected, the bacterial burden in the spleen of naïve fish increased over time and was correlated with the spleen index after Y. ruckeri challenge. The gene expression data showed that pro-inflammatory cytokines were upregulated post-infection in the spleen of both naïve and vaccinated fish after Y. ruckeri challenge although the pro-inflammatory cytokine expression was much lower in vaccinated fish compared to the naïve fish. A correlated expression between pro-inflammatory cytokines and anti-inflammatory cytokines was only seen in spleen of ERM vaccinated fish, where a Th1-like response was indicated by the correlated gene expression of IFN-γ, T-bet and IL-2. In contrast, in the gills, the inflammatory gene response was enhanced in vaccinated fish compared to naïve fish, but perhaps more importantly there was a strong upregulation of IL-22 which was negatively correlated with IFN-γ gene expression at this site. Thus, it is possible that different types of adaptive responses are on-going within the vaccinated fish during infection with Y. ruckeri, potentially affected by the site and stage of infection.