The design of a universal influenza vaccine has been the major focus of researchers in the influenza vaccinology field. The external domain of matrix protein 2 (M2e) has been one of the main interests for the generation of a universal AI vaccine. The M2e is encoded by a separate open reading frame of segment 7 of the influenza virus genome, is located in the viral envelope, and projects from the surface of the virus as tetramers [5, 6] . The M2 is composed of 97 amino acids which forms 3 domains: the external domain, the transmembrane domain, and the internal domain. The external domain of M2 (M2e) is recognized by the host's immune system [7] [8] [9] . Initially, vaccination of ferrets with whole M-or M2-expressing recombinant vaccinia virus showed no evidence of protection [10] . However, later vaccine constructs using plasmid and recombinant salmonella expressing M or M2 induced significant protection in terms of reduction in virus growth and mortality in mice and chickens, respectively [11] [12] [13] . A multiple antigenic peptide construct containing M2e (M2e-MAP) induced strong M2especific antibody titers in the serum of mice and resulted in significant protection against influenza virus challenge [13] . Liang et al., 1994 [14] showed the importance of CD4 + T cells for nasal resistance and protection against the virus. It is assumed that M2e-specific memory T h cells also may have an important role in protection against the virus in the nose and trachea of mice [13] . De Filette et al., 2005 [15] used the hepatitis B virus core particle (HBc) as a carrier and fused M2e (conserved region of human influenza A virus) to either the C-terminus of HBc or inserted it in the immune-dominant loop of HBc. Immunization of mice with this M2e-HBc vaccine was 100% protective against lethal challenge [15] [16] [17] .