Abstract: Epstein-Barr virus (EBV) infects>90% of human population and was identified as an oncogenic agent associated with a panel of lymphomas and solid tumors. Although EBV infection leads to a high burden of medical care, no vaccine is approved in clinic to serve the prevention. This situation is largely due to the long-standing focus on the induction of neutralizing antibody to target a few structural antigens, which excluded potentially effective antigens and restrained the possibility to eliminate infected cells, the major driven force of lateral oncogenesis. To overcome such limitation, we carried out a new design of EBV vaccine via in silico approaches, in which we ascertain structural and non-structural proteins encoded by representative strains of either Type 1 or 2 were taken into consideration. Candidate epitopes were then screened for both humoral and cellular immunity, in which the ones with conservancy and immunodominance were then highlighted in balance of effectiveness and safety. After assembly of selected epitopes, vaccine candidates were generated and subjected to multiple evaluations. Robust and extensive immune responses were then demonstrated via immune simulation, which suggested the effectiveness of our vaccine candidates in blocking EBV infection and consequent diseases.