Bovine leukemia virus (BLV) caused the enzootic bovine leucosis (EBL) which is a B-cell lymphoma in cattle. BLV has spread worldwide and caused large amounts of economic damage. This economic damage is due to not only lymphoma but also reduction in milk pro-duction, shortened longevity, high incidence of infectious disease due to immunosuppression, reproductive inefficiency and international trading problem. The rate of BLV infection and in-cidence of EBL in cattle is increasing. However, a vaccine against BLV is currently not available. One of the reasons why vaccine development has not succussed is that immune response against BLV depends on polymorphisms of bovine major histocompatibility complex (MHC) (BoLA). Therefore, we have developed a virus-like particle that is effective even in BLV-susceptible cattle by adapting the main epitope to the BLV-susceptible BoLA using a “novel Reverse Vaccinology”. This virus-like particle (VLP) induced immune response regardless of MHC polymorphism and decreased proviral loads and CD5-positive B cells. In this review, we will outline the relationship between vaccines and MHC, and introduce the current status of BLV vaccine development and the development of BLV-VLP vaccines using “novel Reverse Vaccinology”.