Proliferative Kidney disease (PKD) in fish is caused by the parasite T. bryosalmonae and can cause massive economic damage for European aquaculture companies. Combining comparative parasite transcriptomics with functional approaches provides a solid foundation for antigen selection for vaccine studies and identification of other targets for drug intervention. Vaccine candidates for PKD were identified and selected for testing in field trials at a rainbow trout fish farm. The vaccines were initially developed as DNA vaccines, with multiple antigens delivered simultaneously to the fish. Subsequently individual molecules were tested, with codon optimisation for expression in trout a key refinement. The most promising vaccine candidate was also tested as a recombinant protein, in an adjuvanted vaccine. Full protection against PKD was not achieved, however, partial protection was seen using specific antigens, and a combined pool of other antigens. This was evidenced as reduced “higher” pathologies during PKD infection and reduced (kidney) parasite load. These findings are promising and represent a positive step towards the future development of a vaccine for PKD.