M2e is the external domain of the influenza A M2-protein. It is minimally immunogenic during infection and conventional vaccination, which explains in part its striking sequence conservation across all human influenza A strains. Previous research has shown that when M2e is linked to an appropriate carrier such as hepatitis B virus core (HBc) particles, it becomes highly immunogenic, eliciting antibodies that fully protect mice against a potentially lethal virus infection. Different M2e-HBc particles and adjuvants suitable for human use were compared for induction of protective immunity. Strong immunogenicity and full protection were obtained after either intraperitoneal or intranasal administration. The most protective particle contained three consecutive M2e-copies linked to the N-terminus of HBc. Although HBc is highly immunogenic, the optimized M2e-HBc vaccine induced an anti-M2e antibody titer even higher than that of anti-HBc.