Enhanced influenza virus-like particle vaccines containing the extracellular domain of matrix protein 2 and a Toll-like receptor ligand.
The extracellular domain of matrix protein 2 (M2e) is conserved among influenza A viruses. The goal of this project is to develop enhanced influenza vaccines with broad protective efficacy using the M2e antigen. We designed a membrane-anchored fusion protein by replacing the hyperimmunogenic region of Salmonella enterica serovar Typhimurium flagellin (FliC) with four repeats of M2e (4.M2e-tFliC) and fusing it to a membrane anchor from influenza virus hemagglutinin (HA). The fusion protein was incorporated into influenza virus M1-based virus-like particles (VLPs). These VLPs retained Toll-like receptor 5 (TLR5) agonist activity comparable to that of soluble FliC. Mice immunized with the VLPs by either intramuscular or intranasal immunization showed high levels of systemic M2-specific antibody responses compared to the responses to soluble 4.M2e protein. High mucosal antibody titers were also induced in intranasally immunized mice. All intranasally immunized mice survived lethal challenges with live virus, while intramuscularly immunized mice showed only partial protection, revealing better protection by the intranasal route. These results indicate that a combination of M2e antigens and TLR ligand adjuvants in VLPs has potential for development of a broadly protective influenza A virus vaccine.
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Bao-Zhong
BZ
Wang
Harvinder S
HS
Gill
Sang-Moo
SM
Kang
Li
L
Wang
Ying-Chun
YC
Wang
Elena V
EV
Vassilieva
Richard W
RW
Compans
D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005408:Flagellin / Q000235:genetics / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D018928:Immunity, Mucosal; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D007273:Injections, Intramuscular; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D051198:Toll-Like Receptor 5 / Q000819:agonists*; D022721:Vaccines, Virosome / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D000086082:Viroporin Proteins
D000914:Antibodies, Viral; D005408:Flagellin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D008024:Ligands; D011993:Recombinant Fusion Proteins; D051198:Toll-Like Receptor 5; D022721:Vaccines, Virosome; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins