title: Antibody titer has positive predictive value for vaccine protection against challenge with natural antigenic-drift variants of H5N1 high-pathogenicity avian influenza viruses from Indonesia.
abstract: Vaccines are used in integrated control strategies to protect poultry against H5N1 high-pathogenicity avian influenza (HPAI). H5N1 HPAI was first reported in Indonesia in 2003, and vaccination was initiated in 2004, but reports of vaccine failures began to emerge in mid-2005. This study investigated the role of Indonesian licensed vaccines, specific vaccine seed strains, and emerging variant field viruses as causes of vaccine failures. Eleven of 14 licensed vaccines contained the manufacturer's listed vaccine seed strains, but 3 vaccines contained a seed strain different from that listed on the label. Vaccines containing A/turkey/Wisconsin/1968 (WI/68), A/chicken/Mexico/28159-232/1994 (Mex/94), and A/turkey/England/N28/1973 seed strains had high serological potency in chickens (geometric mean hemagglutination inhibition [HI] titers, ≥ 1:169), but vaccines containing strain A/chicken/Guangdong/1/1996 generated by reverse genetics (rg; rgGD/96), A/chicken/Legok/2003 (Legok/03), A/chicken/Vietnam/C57/2004 generated by rg (rgVN/04), or A/chicken/Legok/2003 generated by rg (rgLegok/03) had lower serological potency (geometric mean HI titers, ≤ 1:95). In challenge studies, chickens immunized with any of the H5 avian influenza vaccines were protected against A/chicken/West Java/SMI-HAMD/2006 (SMI-HAMD/06) and were partially protected against A/chicken/Papua/TA5/2006 (Papua/06) but were not protected against A/chicken/West Java/PWT-WIJ/2006 (PWT/06). Experimental inactivated vaccines made with PWT/06 HPAI virus or rg-generated PWT/06 low-pathogenicity avian influenza (LPAI) virus seed strains protected chickens from lethal challenge, as did a combination of a commercially available live fowl poxvirus vaccine expressing the H5 influenza virus gene and inactivated Legok/03 vaccine. These studies indicate that antigenic variants did emerge in Indonesia following widespread H5 avian influenza vaccine usage, and efficacious inactivated vaccines can be developed using antigenic variant wild-type viruses or rg-generated LPAI virus seed strains containing the hemagglutinin and neuraminidase genes of wild-type viruses.
  
  
  OBJECTIVE
  H5N1 high-pathogenicity avian influenza (HPAI) virus has become endemic in Indonesian poultry, and such poultry are the source of virus for birds and mammals, including humans. Vaccination has become a part of the poultry control strategy, but vaccine failures have occurred in the field. This study identified possible causes of vaccine failure, which included the use of an unlicensed virus seed strain and induction of low levels of protective antibody because of an insufficient quantity of vaccine antigen. However, the most important cause of vaccine failure was the appearance of drift variant field viruses that partially or completely overcame commercial vaccine-induced immunity. Furthermore, experimental vaccines using inactivated wild-type virus or reverse genetics-generated vaccines containing the hemagglutinin and neuraminidase genes of wild-type drift variant field viruses were protective. These studies indicate the need for surveillance to identify drift variant viruses in the field and update licensed vaccines when such variants appear.
authors.affiliation: Exotic and Emerging Avian Viral Diseases Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia, USA David.Swayne@ars.usda.gov.
authors.forename: David E
authors.initials: DE
authors.lastname: Swayne
authors.affiliation: Exotic and Emerging Avian Viral Diseases Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Suarez
authors.affiliation: Exotic and Emerging Avian Viral Diseases Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Spackman
authors.affiliation: Exotic and Emerging Avian Viral Diseases Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia, USA.
authors.forename: Samadhan
authors.initials: S
authors.lastname: Jadhao
authors.affiliation: Food and Agriculture Organization of the United Nations, Emergency Preventions System for Animal Health (EMPRES-AH), Rome, Italy.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Dauphin
authors.affiliation: Food and Agriculture Organization of the United Nations, Emergency Preventions System for Animal Health (EMPRES-AH), Rome, Italy.
authors.forename: Mia
authors.initials: M
authors.lastname: Kim-Torchetti
authors.affiliation: Food and Agriculture Organization of the United Nations, Emergency Centre for Transboundary Animal Diseases (ECTAD), Jakarta, Indonesia.
authors.forename: James
authors.initials: J
authors.lastname: McGrane
authors.affiliation: Food and Agriculture Organization of the United Nations, Emergency Centre for Transboundary Animal Diseases (ECTAD), Jakarta, Indonesia.
authors.forename: John
authors.initials: J
authors.lastname: Weaver
authors.affiliation: Australian Animal Health Laboratory, Geelong, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Daniels
authors.affiliation: Australian Animal Health Laboratory, Geelong, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Wong
authors.affiliation: Australian Animal Health Laboratory, Geelong, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Selleck
authors.affiliation: Indonesian Research Center for Veterinary Science (IRCVS), Bogor, Indonesia.
authors.forename: Agus
authors.initials: A
authors.lastname: Wiyono
authors.affiliation: Indonesian Research Center for Veterinary Science (IRCVS), Bogor, Indonesia.
authors.forename: Risa
authors.initials: R
authors.lastname: Indriani
authors.affiliation: National Veterinary Drug Assay Laboratory, Bogor, Indonesia.
authors.forename: Yuni
authors.initials: Y
authors.lastname: Yupiana
authors.affiliation: Directorate General of Livestock Services and Animal Health, Ministry of Agriculture, Jakarta, Indonesia.
authors.forename: Elly
authors.initials: E
authors.lastname: Sawitri Siregar
authors.affiliation: Japfa Comfeed Indonesia, Jakarta, Indonesia.
authors.forename: Teguh
authors.initials: T
authors.lastname: Prajitno
authors.affiliation: Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Derek
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Fouchier
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D000940:Antigenic Variation; D002645:Chickens; D056738:Cross Protection; D040961:Genetic Drift; D007214:Indonesia; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000302:isolation & purification; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D005585:Influenza in Birds / Q000276:immunology / Q000517:prevention & control*; D016019:Survival Analysis; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated