Improved design and intranasal delivery of an M2e-based human influenza A vaccine.
M2 is the third integral membrane protein of influenza A. M2e, the extracellular, 23 amino acid residues of M2, has been remarkably conserved in all human influenza A strains. This prompted us to evaluate the use of M2e as a potential broad-spectrum immunogen in a mouse model for influenza infection. Genetic fusion of the M2e and hepatitis B virus core (HBc) coding sequences allowed us to obtain highly immunogenic virus-like particles. This M2e-HBc vaccine induced complete protection in mice against a lethal influenza challenge. Protective immunity was obtained regardless of the position of M2e in the M2e-HBc chimera at the amino-terminus or inserted in the immuno-dominant loop of the HBc protein. Increasing the copy number of M2e inserted at the N-terminus from one to three per monomer (240-720 per particle) significantly enhanced the immune response and reduced the number of vaccinations required for complete protection against a lethal challenge with influenza A virus. A series of M2e-HBc constructs was subsequently combined with CTA1-DD, a recombinant cholera toxin A1 derived mucosal adjuvant, to test its efficacy as an intranasally delivered vaccine. All hybrid VLPs tested with CTA1-DD completely protected mice from a potentially lethal infection and, in addition, significantly reduced morbidity. Overall, increased resistance to influenza challenge in the mice correlated with an enhanced Th1-type M2e-specific antibody response induced by vaccination. These results show that M2e is a valid and versatile vaccine candidate to protect against any strain of human influenza A.
De Filette
Marina
M
Department for Molecular Biomedical Research, VIB-Ghent University, FSVM Building, Technologiepark 927, B-9052 Ghent, Zwijnaarde, Belgium.
Fiers
Walter
W
Martens
Wouter
W
Birkett
Ashley
A
Ramne
Anna
A
Löwenadler
Björn
B
Lycke
Nils
N
Jou
Willy Min
WM
Saelens
Xavier
X
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D006801:Humans; D007114:Immunization; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D000086082:Viroporin Proteins
D000276:Adjuvants, Immunologic; D002772:Cholera Toxin; D007252:Influenza Vaccines; D011993:Recombinant Fusion Proteins; D014763:Viral Matrix Proteins; C440610:CTA1-DD protein, recombinant; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C509609:M2e-HBc influenza vaccine