title: A live attenuated H1N1 M1 mutant provides broad cross-protection against influenza A viruses, including highly pathogenic A/Vietnam/1203/2004, in mice.
abstract: The emergence of novel influenza A H1N1 and highly pathogenic avian influenza (HPAI) H5N1 viruses underscores the urgency of developing efficient vaccines against an imminent pandemic. M(NLS-88R) (H1N1), an A/WSN/33 mutant with modifications in the multibasic motif 101RKLKR105 of the matrix (M1) protein and its adjacent region, was generated by reverse genetics. The M(NLS-88R) mutant had in vitro growth characteristics similar to those of wild-type A/WSN/33 (wt-WSN), but it was attenuated in mice. Vaccination with M(NLS-88R) not only fully protected mice from lethal homologous challenges but also prevented mortality caused by antigenically distinct H3N2 and H5N1 viruses. M(NLS-88R)-induced homologous protection was mainly antibody dependent, but cellular immunity was also beneficial in protecting against sublethal wt-WSN infection. Adoptive transfer studies indicated that both humoral and cellular immune responses were crucial for M(NLS-88R)-induced heterologous protection. Our study suggests an alternative approach to attenuate wt influenza viruses for the development of a pandemic vaccine with broad cross-protection.
authors.affiliation: Laboratory of Respiratory Viral Diseases, Division of Viral Products, Office of Vaccine Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, USA. Zhiping.Ye@fda.hhs.gov
authors.forename: Hang
authors.initials: H
authors.lastname: Xie
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Liu
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Lu
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Wu
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Belser
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Katz
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Ye
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001835:Body Weight; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D019562:Viral Load; D014763:Viral Matrix Proteins / Q000235:genetics*
chemical_list: D000914:Antibodies, Viral; D007252:Influenza Vaccines; C488936:M1 protein, Influenza A virus; D014613:Vaccines, Attenuated; D014763:Viral Matrix Proteins