title: Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets.
abstract: New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Lulan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Su-Yang
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Hsiang-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Chapon
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Unit of Anti-Viral Immunity and Genetic Therapy, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yao E
authors.initials: YE
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Quanquin
authors.affiliation: Unit of Anti-Viral Immunity and Genetic Therapy, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Guiqin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Tian
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650106, China.
authors.forename: Zhanlong
authors.initials: Z
authors.lastname: He
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650106, China.
authors.forename: Longding
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650106, China.
authors.forename: Wenhai
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: David Jesse
authors.initials: DJ
authors.lastname: Sanchez
authors.affiliation: 295K Animal Science/Veterinary Medicine, University of Minnesota, 1988 Fitch Avenue, St. Paul, MN 55108, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
authors.forename: Taijiao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Modlin
authors.affiliation: Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Bloom
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650106, China.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Deng
authors.affiliation: Unit of Anti-Viral Immunity and Genetic Therapy, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Paul
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China. Electronic address: fqin1@foxmail.com.
authors.forename: F Xiao-Feng
authors.initials: FX
authors.lastname: Qin
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: gcheng@mednet.ucla.edu.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D056738:Cross Protection; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D005289:Ferrets; D005820:Genetic Testing; D064789:Immunity, Heterologous; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000302:isolation & purification*; D051379:Mice; D016254:Mutagenesis, Insertional; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology / Q000302:isolation & purification
chemical_list: D004251:DNA Transposable Elements; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated
keywords: flu vaccine; genome-wide mutagenesis; influenza vaccine; matrix protein