Immunization against M2 peptide, also called M2e, from influenza A virus is an innovative vaccine approach for induction of cross-strain protective immunity. Two promising M2 vaccine compositions reported to date are M2 peptide chemically conjugated to carrier proteins or M2 peptide recombinantly expressed on the surface of virus like particles (VLPs) of hepatitis B virus core antigen (HBVc). To conduct a head-to-head comparison of these approaches, we constructed two recombinant HBVc VLPs expressing M2 peptide and prepared two conjugate vaccines with M2 peptide chemically coupled to Neisseria meningitidis outer membrane complex (OMPC) or HBVc VLP, respectively. Here, we showed superior immunogenicity of M2 peptide conjugated to OMPC and M2 peptide expressed on the surface of HBVc antigen based on dose-titration responses in mice. Surprisingly, HBVc expressing M2 peptide was an inferior vaccine in rhesus monkeys, whether as a primary vaccine or as a booster vaccine, when compared with M2-OMPC conjugate vaccine.