title: Oligomeric recombinant H5 HA1 vaccine produced in bacteria protects ferrets from homologous and heterologous wild-type H5N1 influenza challenge and controls viral loads better than subunit H5N1 vaccine by eliciting high-affinity antibodies.
abstract: Recombinant hemagglutinin from influenza viruses with pandemic potential can be produced rapidly in various cell substrates. In this study, we compared the functionality and immunogenicity of bacterially produced oligomeric or monomeric HA1 proteins from H5N1 (A/Vietnam/1203/04) with those of the egg-based licensed subunit H5N1 (SU-H5N1) vaccine in ferrets challenged with homologous or heterologous H5N1 highly pathogenic influenza strains. Ferrets were vaccinated twice with the oligomeric or monomeric rHA1 or with SU-H5N1 (Sanofi Pasteur) emulsified with Titermax adjuvant and were challenged with wild-type homologous (A/Vietnam/1203/04; clade 1) or heterologous (A/Whooperswan/Mongolia/244/2005; clade 2.2) virus. Only the oligomeric rHA1 (not the monomeric rHA1) immunogen and the SU-H5N1 vaccine provided protection against the lethality and morbidity of homologous and heterologous highly pathogenic H5N1. Oligomeric rHA1 generated more cross-neutralizing antibodies and higher levels of serum antibody binding to HA1, with stronger avidity and a better IgG/IgM ratio, than monomeric HA1 and SU-H5N1 vaccines, as determined by surface plasmon resonance (SPR). Importantly, viral loads after heterologous H5N1 challenge were more efficiently controlled in ferrets vaccinated with the oligomeric rHA1 immunogen than in SU-H5N1-vaccinated ferrets. The reduction of viral loads in the nasal washes correlated strongly with higher-avidity antibodies to oligomeric rHA1 derived from H5N1 clade 1 and clade 2.2 viruses, as measured by SPR. This is the first study to show the role of antibody avidity for the HA1 globular head domain in reduction of viral loads in the upper respiratory tract, which could significantly reduce viral transmission.
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Verma
authors.forename: Milena
authors.initials: M
authors.lastname: Dimitrova
authors.forename: Ashok
authors.initials: A
authors.lastname: Munjal
authors.forename: Juan
authors.initials: J
authors.lastname: Fontana
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Crevar
authors.forename: Donald M
authors.initials: DM
authors.lastname: Carter
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
authors.forename: Surender
authors.initials: S
authors.lastname: Khurana
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry; D002850:Chromatography, Gel; D018076:DNA, Complementary / Q000378:metabolism; D004912:Erythrocytes / Q000821:virology; D004926:Escherichia coli / Q000378:metabolism; D005289:Ferrets; D006384:Hemagglutination; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007075:Immunoglobulin M / Q000737:chemistry; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics*; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000821:virology*; D009500:Neutralization Tests; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry*; D012137:Respiratory System / Q000821:virology; D020349:Surface Plasmon Resonance; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D018076:DNA, Complementary; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007252:Influenza Vaccines; D011994:Recombinant Proteins