title: Comparative efficacy of hemagglutinin, nucleoprotein, and matrix 2 protein gene-based vaccination against H5N1 influenza in mouse and ferret.
abstract: Efforts to develop a broadly protective vaccine against the highly pathogenic avian influenza A (HPAI) H5N1 virus have focused on highly conserved influenza gene products. The viral nucleoprotein (NP) and ion channel matrix protein (M2) are highly conserved among different strains and various influenza A subtypes. Here, we investigate the relative efficacy of NP and M2 compared to HA in protecting against HPAI H5N1 virus. In mice, previous studies have shown that vaccination with NP and M2 in recombinant DNA and/or adenovirus vectors or with adjuvants confers protection against lethal challenge in the absence of HA. However, we find that the protective efficacy of NP and M2 diminishes as the virulence and dose of the challenge virus are increased. To explore this question in a model relevant to human disease, ferrets were immunized with DNA/rAd5 vaccines encoding NP, M2, HA, NP+M2 or HA+NP+M2. Only HA or HA+NP+M2 vaccination conferred protection against a stringent virus challenge. Therefore, while gene-based vaccination with NP and M2 may provide moderate levels of protection against low challenge doses, it is insufficient to confer protective immunity against high challenge doses of H5N1 in ferrets. These immunogens may require combinatorial vaccination with HA, which confers protection even against very high doses of lethal viral challenge.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
authors.forename: Wing-Pui
authors.initials: WP
authors.lastname: Kong
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Wei
authors.forename: Neal
authors.initials: N
authors.lastname: Van Hoeven
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Gorres
authors.forename: Martha
authors.initials: M
authors.lastname: Nason
authors.forename: Hanne
authors.initials: H
authors.lastname: Andersen
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D005260:Female; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000378:metabolism*; D007252:Influenza Vaccines / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009698:Nucleoproteins / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry*; D000086082:Viroporin Proteins
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D009698:Nucleoproteins; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins