In the search for a better vaccine against Ehrlichia ruminantium infection in ruminants, four E. ruminantium open reading frames (ORFs) derived from the Welgevonden isolate were tested using either DNA vaccination or DNA primemodified viral or DNA prime-recombinant protein boost strategies. Both the DNA vaccination and the DNA prime.recombinant protein boost strategy provided complete protection against E. ruminantium Welgevonden needle challenge, while the DNA prime.modified viral boost strategy only provided 90 % protection. The DNA prime.recombinant protein boost strategy also coincided with elevated cellular immunology as was evident from increased IFN-ã production. Furthermore, we could show that the 1H12 DNA vaccine could induce protection against heterologous needle challenge when animals were immunised with the Welgevonden-derived 1H12 ORFs and challenged with selected E. ruminantium stocks. Unfortunately the DNA only and the DNA prime.recombinant protein boost strategy were not protective in the field. Therefore, our results suggest that there is a vast difference between needle challenge and natural tick infestation and that E. ruminantium organisms transmitted by ticks have the ability to evade the protective immunity induced by immunization with the four 1H12 ORFs.