title: Enhancement of the safety of live influenza vaccine by attenuating mutations from cold-adapted hemagglutinin.
abstract: In our previous study, X-31ca-based H5N1 LAIVs, in particular, became more virulent in mice than the X-31ca MDV, possibly by the introduction of the surface antigens of highly pathogenic H5N1 influenza virus, implying that additional attenuation is needed in this cases to increase the safety level of the vaccine. In this report we suggest an approach to further increase the safety of LAIV through additional cold-adapted mutations in the hemagglutinin. The cold-adaptation of X-31 virus resulted in four amino acid mutations in the HA. We generated a panel of 7:1 reassortant viruses each carrying the hemagglutinins with individual single amino acid mutations. We examined their phenotypes and found a major attenuating mutation, N81K. This attenuation marker conferred additional temperature-sensitive and attenuation phenotype to the LAIV. Our data indicate that the cold-adapted mutation in the HA confers additional attenuation to the LAIV strain, without compromising its productivity and immune response.
authors.affiliation: Graduate Program in Biomaterials Science and Engineering, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Vaccine Translational Research Center, Yonsei University, Seoul, South Korea.
authors.forename: Yoon Jae
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Yo Han
authors.initials: YH
authors.lastname: Jang
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Vaccine Translational Research Center, Yonsei University, Seoul, South Korea.
authors.forename: Paul
authors.initials: P
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Vaccine Translational Research Center, Yonsei University, Seoul, South Korea.
authors.forename: Yun Ha
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Vaccine Translational Research Center, Yonsei University, Seoul, South Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Byun
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Kyusik
authors.initials: K
authors.lastname: Kim
authors.affiliation: Graduate Program in Biomaterials Science and Engineering, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Vaccine Translational Research Center, Yonsei University, Seoul, South Korea. Electronic address: blseong@yonsei.ac.kr.
authors.forename: Baik Lin
authors.initials: BL
authors.lastname: Seong
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D003080:Cold Temperature; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D014765:Viral Vaccines
keywords: Cold adaptation; Hemagglutinin; Influenza virus; Live attenuated vaccine; Safety