This study aimed to improve vaccine performance through understanding molecular host-pathogen interactions in yersiniosis. We investigated effects of different methods of vaccine application. Survival in an experimental challenge was significantly better after double dip and ip vaccination than control unvaccinated fish. Double dip and ip injection vaccination gave better protection than single dip or bath vaccination. The double dip vaccinated group has significantly better survival than the bath vaccinated group but there is no statistical difference between the single dip and bath. The ip vaccinated fish had a very high RPS of 95.5%. While ip vaccination maybe not practical for salmon industry, it provides a positive control for experimental research. The survival 12 weeks post vaccination further confirmed our previous results. There was a relationship between protection and antibody level above a threshold. We used cDNA microarray to characterise the differential response of host genes in the gills of naive unvaccinated and vaccinated Atlantic salmon challenged with Y. ruckeri. Differentially expressed genes were identified using two-way ANOVA and restricted to those with >2.5-fold change at P<0.05. We identified 7 genes in response to infection and 4 genes specifically associated with the protective host response to yersiniosis. These findings provide knowledge of the host-pathogen interaction in response to bacterial infection and immunisation in fish. Significantly, we identified a transcriptional biosignature consisting of predominantly immune-relevant genes (14 up and 3 down-regulated) in the gills of Atlantic salmon after immersion vaccination and before bacterial challenge. This biosignature may be used as a surrogate of protection and therefore as a predictor of vaccine success against yersiniosis.