Updated project metadata. Mandatory potency testing of Leptospira vaccine batches relies partially on in vivo procedures, requiring large numbers of laboratory animals. Cell-based assays could replace in vivo tests if biomarkers indicative of Leptospira vaccine potency are identified. We investigated innate immune responsiveness induced by inactivated L. interrogans serogroups Canicola and Icterohaemorrhagiae, and two bivalent, non-adjuvanted canine Leptospira vaccines containing the same serogroups. First, the transcriptome and proteome analysis of canine 030-D cells stimulated with Leptospira strains, and the corresponding vaccine revealed more than 900 DEGs and 23 DEPs in common to these three stimuli. Second, comparison of responses induced by this Leptospira vaccine and a vaccine from another manufacturer revealed a large overlap in DEGs and DEPs as well, suggesting potential to identify biomarkers of Leptospira vaccine activity. Because not many common DEPs were identified, we selected seven molecules from the identified DEGs, associated with pathways related to innate immunity, of which CXCL-10, IL-1β, SAA, and complement C3 showed increased secretion upon stimulation with both Leptospira vaccines. These molecules could be interesting targets for development of biomarker-based assays in the future. Additionally, this study contributes to the understanding of the mechanisms by which Leptospira vaccines induce innate immune responses in the dog.