title: Sublingual immunization with M2-based vaccine induces broad protective immunity against influenza.
abstract: BACKGROUND
  The ectodomain of matrix protein 2 (M2e) of influenza A virus is a rationale target antigen candidate for the development of a universal vaccine against influenza as M2e undergoes little sequence variation amongst human influenza A strains. Vaccine-induced M2e-specific antibodies (Abs) have been shown to display significant cross-protective activity in animal models. M2e-based vaccine constructs have been shown to be more protective when administered by the intranasal (i.n.) route than after parenteral injection. However, i.n. administration of vaccines poses rare but serious safety issues associated with retrograde passage of inhaled antigens and adjuvants through the olfactory epithelium. In this study, we examined whether the sublingual (s.l.) route could serve as a safe and effective alternative mucosal delivery route for administering a prototype M2e-based vaccine. The mechanism whereby s.l. immunization with M2e vaccine candidate induces broad protection against infection with different influenza virus subtypes was explored.
  
  
  RESULTS
  A recombinant M2 protein with three tandem copies of the M2e (3M2eC) was expressed in Escherichia coli. Parenteral immunizations of mice with 3M2eC induced high levels of M2e-specific serum Abs but failed to provide complete protection against lethal challenge with influenza virus. In contrast, s.l. immunization with 3M2eC was superior for inducing protection in mice. In the latter animals, protection was associated with specific Ab responses in the lungs.
  
  
  CONCLUSIONS
  The results demonstrate that s.l. immunization with 3M2eC vaccine induced airway mucosal immune responses along with broad cross-protective immunity to influenza. These findings may contribute to the understanding of the M2-based vaccine approach to control epidemic and pandemic influenza infections.
authors.affiliation: Laboratory Science Division, International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Byoung-Shik
authors.initials: BS
authors.lastname: Shim
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Choi
authors.forename: Cheol-Heui
authors.initials: CH
authors.lastname: Yun
authors.forename: Eu-Gene
authors.initials: EG
authors.lastname: Lee
authors.forename: Yoon Seong
authors.initials: YS
authors.lastname: Jeon
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Park
authors.forename: In Su
authors.initials: IS
authors.lastname: Cheon
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Joo
authors.forename: Chung Hwan
authors.initials: CH
authors.lastname: Cho
authors.forename: Min-Suk
authors.initials: MS
authors.lastname: Song
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Seo
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Byun
authors.forename: Hae-Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Haryoung
authors.initials: H
authors.lastname: Poo
authors.forename: Baik Lin
authors.initials: BL
authors.lastname: Seong
authors.forename: Jae Ouk
authors.initials: JO
authors.lastname: Kim
authors.forename: Huan Huu
authors.initials: HH
authors.lastname: Nguyen
authors.forename: Konrad
authors.initials: K
authors.lastname: Stadler
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Kee-Jong
authors.initials: KJ
authors.lastname: Hong
authors.forename: Cecil
authors.initials: C
authors.lastname: Czerkinsky
authors.forename: Man Ki
authors.initials: MK
authors.lastname: Song
mesh_terms: D000281:Administration, Intranasal; D000286:Administration, Sublingual; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D056738:Cross Protection / Q000276:immunology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007114:Immunization; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D012995:Solubility; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D000086082:Viroporin Proteins
chemical_list: D007252:Influenza Vaccines; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins