title: Development of a dual-protective live attenuated vaccine against H5N1 and H9N2 avian influenza viruses by modifying the NS1 gene.
abstract: An increasing number of outbreaks of avian influenza H5N1 and H9N2 viruses in poultry have caused serious economic losses and raised concerns for human health due to the risk of zoonotic transmission. However, licensed H5N1 and H9N2 vaccines for animals and humans have not been developed. Thus, to develop a dual H5N1 and H9N2 live-attenuated influenza vaccine (LAIV), the HA and NA genes from a virulent mouse-adapted avian H5N2 (A/WB/Korea/ma81/06) virus and a recently isolated chicken H9N2 (A/CK/Korea/116/06) virus, respectively, were introduced into the A/Puerto Rico/8/34 backbone expressing truncated NS1 proteins (NS1-73, NS1-86, NS1-101, NS1-122) but still possessing a full-length NS gene. Two H5N2/NS1-LAIV viruses (H5N2/NS1-86 and H5N2/NS1-101) were highly attenuated compared with the full-length and remaining H5N2/NS-LAIV viruses in a mouse model. Furthermore, viruses containing NS1 modifications were found to induce more IFN-β activation than viruses with full-length NS1 proteins and were correspondingly attenuated in mice. Intranasal vaccination with a single dose (10(4.0) PFU/ml) of these viruses completely protected mice from a lethal challenge with the homologous A/WB/Korea/ma81/06 (H5N2), heterologous highly pathogenic A/EM/Korea/W149/06 (H5N1), and heterosubtypic highly virulent mouse-adapted H9N2 viruses. This study clearly demonstrates that the modified H5N2/NS1-LAIV viruses attenuated through the introduction of mutations in the NS1 coding region display characteristics that are desirable for live attenuated vaccines and hold potential as vaccine candidates for mammalian hosts.
authors.affiliation: Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, 12 Gaeshin-Dong Heungduk-Ku, Cheongju, 361-763, Republic of Korea.
authors.forename: Eun-hye
authors.initials: EH
authors.lastname: Choi
authors.forename: Min-Suk
authors.initials: MS
authors.lastname: Song
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Philippe Noriel Q
authors.initials: PN
authors.lastname: Pascua
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Baek
authors.forename: Hyeok-il
authors.initials: HI
authors.lastname: Kwon
authors.forename: Eun-Ha
authors.initials: EH
authors.lastname: Kim
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
authors.forename: Hyung-Kwan
authors.initials: HK
authors.lastname: Jang
authors.forename: Haryoung
authors.initials: H
authors.lastname: Poo
authors.forename: Chul-Joong
authors.initials: CJ
authors.lastname: Kim
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Choi
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002645:Chickens; D005260:Female; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology*; D053127:Influenza A Virus, H9N2 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D005585:Influenza in Birds / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007251:Influenza, Human / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011201:Poultry Diseases / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; C085820:INS1 protein, influenza virus; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins