Abstract: Currently, there is no effective vaccination against M. bovis on the market, and treatment options become increasingly limited due to restrictions in the use of, and resistance to antibiotics. This is complicated by results that demonstrate the induction of vaccine-enhanced disease, upon the use of certain M. bovis proteins as a vaccine. Thus, there is an urgent need for an effective and safe M. bovis vaccine. A novel vaccine composition was found that comprises one or more recombinant proteins which (combined) contain one or more epitopes from each of a set of specific M. bovis proteins. Vaccines based on these recombinant proteins were found to be safe, and were effective in protecting ruminants against infection and disease resulting from a severe challenge infection with M. bovis, as was apparent from a strong reduction of lung damage and colonisation of the trachea.