Candidate Neisseria meningitidis serogroup B vaccines that are based on outer-membrane vesicles induce protective immunity in adults but provide neither crossprotection for infants nor long-lasting immunity. We suggest that this lack of vaccine efficacy is not solely because the best antigens are yet to be identified but also results from inappropriate programming of the immune response. Natural carriage of N. meningitidis and related bacteria leads to the development of protective immunity both at the mucosal surface and in the circulation. We propose that vaccine strategies that mimic this natural immunization process would better-optimize vaccine-induced protective immunity. Thus, mucosal immunization before a systemic booster vaccination could provide the solution and reduce the necessity for multiple injections to achieve immunity.