title: Single- and multiple-clade influenza A H5N1 vaccines induce cross protection in ferrets.
abstract: The rapid evolution, genetic diversity, broad host range, and increasing human infection with avian influenza A (H5N1) viruses highlight the need for an efficacious cross-clade vaccine. Using the ferret model, we compared induction of cross-reactive immunity and protective efficacy of three single-clade H5N1 vaccines and a novel multiple-clade H5N1 vaccine, with and without MF59 adjuvant. Reverse genetics (rg) was used to generate vaccine viruses containing the hemagglutinin (HA) and neuraminidase genes of wild-type H5N1 viruses. Ferrets received two doses of inactivated whole-virus vaccine separated by 3 weeks. Single-clade vaccines (7.5 microg HA per dose) included rg-A/Vietnam/1203/04 (clade 1), rg-A/Hong Kong/213/03 (clade 1), and rg-A/Japanese White Eye/Hong Kong/1038/06 (clade 2.3). The multiple-clade vaccine contained 3.75 microg HA per dose of each single-clade vaccine and of rg-A/Whooper Swan/Mongolia/244/05 (clade 2.2). Two doses of vaccine were required to substantially increase anti-HA and virus neutralizing antibody titers to H5N1 viruses. MF59 adjuvant enhanced induction of clade-specific and cross-clade serum antibody responses, reduced frequency of infection (as determined by upper respiratory tract virus shedding and seroconversion data), and eliminated disease signs. The rg-A/Hong Kong/213/03 vaccine induced the highest antibody titers to homologous and heterologous H5N1 viruses, while rg-A/Japanese White Eye/Hong Kong/1038/06 vaccine induced the lowest. The multiple-clade vaccine was broadly immunogenic against clade 1 and 2 viruses. The rg-A/Vietnam/1203/04 vaccine (the currently stockpiled H5N1 vaccine) most effectively reduced upper respiratory tract virus shedding after challenge with clade 1 and 2 viruses. Importantly, all vaccines protected against lethal challenge with A/Vietnam/1203/04 virus and provided cross-clade protection.
authors.affiliation: Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Forrest
authors.forename: Alexey M
authors.initials: AM
authors.lastname: Khalenkov
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Kim
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Del Giudice
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D003429:Cross Reactions; D005260:Female; D005289:Ferrets; D006801:Humans; D007117:Immunization, Secondary; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D008297:Male; D009500:Neutralization Tests; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011136:Polysorbates / Q000008:administration & dosage / Q000494:pharmacology; D013185:Squalene / Q000008:administration & dosage / Q000494:pharmacology; D015164:Vaccines, Inactivated / Q000235:genetics / Q000276:immunology; D017201:Virus Shedding / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D011136:Polysorbates; D015164:Vaccines, Inactivated; D013185:Squalene