Tweet
Published ahead of print 19 June 2013, doi: 10.1128/JVI.01203-13 JVI.01203-13
Molecular Basis for Broad Neuraminidase Immunity: Conserved Epitopes in Seasonal and Pandemic H1N1 as well as H5N1 Influenza Viruses
Hongquan Wana,
Jin Gaoa,
Kemin Xub,
Hongjun Chenb,
Laura K. Couzensa,
Katie H. Riversa,
Judy D. Easterbrookc,
Kevin Yanga,
Lei Zhongd,
Mohsen Rajabia,
Jianqiang Yee,
Ishrat Sultanaa,
Xiu-Feng Wane,
Xiufan Liud,
Daniel R. Perezb,
Jeffery K. Taubenbergerc and
Maryna C. Eichelbergera*
+ Author Affiliations
aDivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
bDepartment of Veterinary Medicine, University of Maryland College Park and Virginia-Maryland Regional College of Veterinary Medicine, MD 20742, USA
cViral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
dAnimal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
eDepartment of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
ABSTRACT
Influenza A viruses, including H1N1 and H5N1 subtypes, pose a serious threat to public health. Neuraminidase (NA)-related immunity contributes to protection against influenza. Antibodies to N1 subtype provide protection against homologous and heterologous H1N1 as well as H5N1 virus challenge. Since neither the strain-specific nor conserved epitopes of N1 have been identified, we generated a panel of mouse monoclonal antibodies (mAbs), which exhibit different reactivity spectra with H1N1 and H5N1 viruses, and used these mAbs to map N1 antigenic domains. We identified 12 amino acids essential for mAb binding to the NA of a recent seasonal H1N1 virus, A/Brisbane/59/2007. Of these, residues 248, 249, 250, 341 and 343 are recognized by strain-specific group A mAbs, while residues 273, 338 and 339 are within conserved epitope(s), which allows cross-reactive group B mAbs to bind the NA of seasonal H1N1, the 1918 and 2009 pandemic (09pdm) H1N1 as well as H5N1 viruses. A single dose of group B mAbs administered prophylactically fully protected mice against lethal challenge with seasonal and 09pdm H1N1, and resulted in significant protection against the highly pathogenic wild-type H5N1 virus. Another 3 N1 residues (at positions 396, 397 and 456) are essential for binding of cross-reactive group E mAbs, which differ from group B mAbs in that they do not bind 09pdm H1N1 viruses. The identification of conserved N1 epitopes reveals the molecular basis for NA-mediated immunity between H1N1 and H5N1 viruses, and demonstrates the potential for developing broadly-protective NA-specific antibody treatments for influenza.
Molecular Basis for Broad Neuraminidase Immunity: Conserved Epitopes in Seasonal and Pandemic H1N1 as well as H5N1 Influenza Viruses
Hongquan Wana,
Jin Gaoa,
Kemin Xub,
Hongjun Chenb,
Laura K. Couzensa,
Katie H. Riversa,
Judy D. Easterbrookc,
Kevin Yanga,
Lei Zhongd,
Mohsen Rajabia,
Jianqiang Yee,
Ishrat Sultanaa,
Xiu-Feng Wane,
Xiufan Liud,
Daniel R. Perezb,
Jeffery K. Taubenbergerc and
Maryna C. Eichelbergera*
+ Author Affiliations
aDivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
bDepartment of Veterinary Medicine, University of Maryland College Park and Virginia-Maryland Regional College of Veterinary Medicine, MD 20742, USA
cViral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
dAnimal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
eDepartment of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
ABSTRACT
Influenza A viruses, including H1N1 and H5N1 subtypes, pose a serious threat to public health. Neuraminidase (NA)-related immunity contributes to protection against influenza. Antibodies to N1 subtype provide protection against homologous and heterologous H1N1 as well as H5N1 virus challenge. Since neither the strain-specific nor conserved epitopes of N1 have been identified, we generated a panel of mouse monoclonal antibodies (mAbs), which exhibit different reactivity spectra with H1N1 and H5N1 viruses, and used these mAbs to map N1 antigenic domains. We identified 12 amino acids essential for mAb binding to the NA of a recent seasonal H1N1 virus, A/Brisbane/59/2007. Of these, residues 248, 249, 250, 341 and 343 are recognized by strain-specific group A mAbs, while residues 273, 338 and 339 are within conserved epitope(s), which allows cross-reactive group B mAbs to bind the NA of seasonal H1N1, the 1918 and 2009 pandemic (09pdm) H1N1 as well as H5N1 viruses. A single dose of group B mAbs administered prophylactically fully protected mice against lethal challenge with seasonal and 09pdm H1N1, and resulted in significant protection against the highly pathogenic wild-type H5N1 virus. Another 3 N1 residues (at positions 396, 397 and 456) are essential for binding of cross-reactive group E mAbs, which differ from group B mAbs in that they do not bind 09pdm H1N1 viruses. The identification of conserved N1 epitopes reveals the molecular basis for NA-mediated immunity between H1N1 and H5N1 viruses, and demonstrates the potential for developing broadly-protective NA-specific antibody treatments for influenza.
