Broad cross-protection against H5N1 avian influenza virus infection by means of monoclonal antibodies that map to conserved viral epitopes.

BACKGROUND Passive immunization with human H5 antisera or H5-specific monoclonal antibodies (MAbs) has potential as an effective treatment for acute H5N1 influenza virus infection, but its efficacy against antigenically diverse H5N1 viruses is unconfirmed. METHODS Cross-protection against antigenically diverse H5N1 strains with H5-specific MAbs, generated by successive immunization of antigenically distinct strains, was evaluated in mice. RESULTS A panel of 52 broadly cross-reactive H5 specific MAbs were generated and characterized. One of these MAbs, 13D4, has been demonstrated to protect mice against lethal challenge by 4 H5N1 strains representing the current major genetic populations, clades 1, 2.1, 2.2, and 2.3, even at a stage of infection when H5N1 virus has disseminated beyond the pulmonary system. Complete neutralization of virus in lung tissue of infected animals was observed 24 h after treatment with 13D4. Mapping of this MAb with escape mutants showed it to bind to 2 conserved, possibly critical, sites of H5N1 hemagglutinin, 152 and 182. CONCLUSION Generation of broadly cross-protective MAbs against H5N1 influenza virus may be optimized by selecting MAbs that target conserved sites in hemagglutinin. H5 MAbs such as 13D4 may prove to have therapeutic value in controlling infection due to current and future H5N1 variants.

[1]  Wang Guansong,et al.  Update on avian influenza A (H5N1) virus infection in humans , 2009 .

[2]  Oie,et al.  Toward a Unified Nomenclature System for Highly Pathogenic Avian Influenza Virus (H5N1) , 2008, Emerging infectious diseases.

[3]  Jian Wang,et al.  H5N1 avian influenza re-emergence of Lake Qinghai: phylogenetic and antigenic analyses of the newly isolated viruses and roles of migratory birds in virus circulation , 2008, The Journal of general virology.

[4]  A. Parkinson.  The International Polar Year, 2007–2008, An Opportunity to Focus on Infectious Diseases in Arctic Regions , 2008, Emerging infectious diseases.

[5]  Gavin J. D. Smith,et al.  Antigenic Profile of Avian H5N1 Viruses in Asia from 2002 to 2007 , 2007, Journal of Virology.

[6]  W. Marasco,et al.  The growth and potential of human antiviral monoclonal antibody therapeutics , 2007, Nature Biotechnology.

[7]  Y. Guan,et al.  Treatment with convalescent plasma for influenza A (H5N1) infection. , 2007, The New England journal of medicine.

[8]  Jiang Gu,et al.  H5N1 infection of the respiratory tract and beyond: a molecular pathology study , 2007, The Lancet.

[9]  R. Webster,et al.  Epitope Mapping of the Hemagglutinin Molecule of a Highly Pathogenic H5N1 Influenza Virus by Using Monoclonal Antibodies , 2007, Journal of Virology.

[10]  T. Uyeki,et al.  Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005-June 2006. , 2007, The Journal of infectious diseases.

[11]  J. Farrar,et al.  Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza , 2007, PLoS medicine.

[12]  R. Webster,et al.  Influenza (H5N1) Viruses in Poultry, Russian Federation, 2005–2006 , 2007, Emerging infectious diseases.

[13]  Yong Poovorawan,et al.  New Strain of Influenza A Virus (H5N1), Thailand , 2007, Emerging infectious diseases.

[14]  M. Kiso,et al.  Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A infection in children. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Keiji Fukuda,et al.  WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus , 2006, The Lancet Infectious Diseases.

[16]  David J. Stevens,et al.  Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors , 2006, Nature.

[17]  Gavin J. D. Smith,et al.  Emergence and predominance of an H5N1 influenza variant in China , 2006, Proceedings of the National Academy of Sciences.

[18]  S. Hoffman,et al.  Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment? , 2006, Annals of Internal Medicine.

[19]  R. Webby,et al.  Passive immunoprophylaxis and therapy with humanized monoclonal antibody specific for influenza A H5 hemagglutinin in mice , 2006, Respiratory research.

[20]  Gavin J. D. Smith,et al.  H5N1 Influenza Viruses in Lao People’s Democratic Republic , 2006, Emerging infectious diseases.

[21]  M. Saad,et al.  Qinghai-like H5N1 from Domestic Cats, Northern Iraq , 2006, Emerging infectious diseases.

[22]  A. Osterhaus,et al.  Avian Flu: Multiple introductions of H5N1 in Nigeria , 2006, Nature.

[23]  Gavin J. D. Smith,et al.  Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam. , 2006, Virology.

[24]  Gavin J. D. Smith,et al.  Distribution of amantadine-resistant H5N1 avian influenza variants in Asia. , 2006, The Journal of infectious diseases.

[25]  Zhong-min Guo,et al.  Passive immunotherapy for influenza A H5N1 virus infection with equine hyperimmune globulin F(ab')2 in mice , 2006, Respiratory research.

[26]  Y. Guan,et al.  Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Y. Guan,et al.  H5N1 Outbreaks and Enzootic Influenza , 2006, Emerging infectious diseases.

[28]  Y. Guan,et al.  Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia , 2004, Nature.

[29]  R. Webster,et al.  Structure of antigenic sites on the haemagglutinin molecule of H5 avian influenza virus and phenotypic variation of escape mutants. , 2002, The Journal of general virology.

[30]  Y. Guan,et al.  Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Uenza Manu.  WHO Manual on Animal Influenza Diagnosis and Surveillance , 2002 .

[32]  Larisa V. Gubareva,et al.  Comparison of the Activities of Zanamivir, Oseltamivir, and RWJ-270201 against Clinical Isolates of Influenza Virus and Neuraminidase Inhibitor-Resistant Variants , 2001, Antimicrobial Agents and Chemotherapy.

[33]  R. Webster,et al.  The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. , 2000, Antiviral research.

[34]  N. Cox,et al.  Genetic characterization of the pathogenic influenza A/Goose/Guangdong/1/96 (H5N1) virus: similarity of its hemagglutinin gene to those of H5N1 viruses from the 1997 outbreaks in Hong Kong. , 1999, Virology.

[35]  H. Goto,et al.  Biological Heterogeneity, Including Systemic Replication in Mice, of H5N1 Influenza A Virus Isolates from Humans in Hong Kong , 1999, Journal of Virology.

[36]  Keiji Fukuda,et al.  Detection of Antibody to Avian Influenza A (H5N1) Virus in Human Serum by Using a Combination of Serologic Assays , 1999, Journal of Clinical Microbiology.

[37]  F. Kostolanský,et al.  Preparation of monoclonal antibodies for the diagnosis of influenza A infection using different immunization protocols. , 1995, Journal of immunological methods.

[38]  V. Hinshaw,et al.  Hemagglutinin mutations related to attenuation and altered cell tropism of a virulent avian influenza A virus , 1990, Journal of virology.

[39]  V. Hinshaw,et al.  Neutralizing epitopes of the H5 hemagglutinin from a virulent avian influenza virus and their relationship to pathogenicity , 1989, Journal of virology.

[40]  R. Webster,et al.  Determination of the number of nonoverlapping antigenic areas on Hong Kong (H3N2) influenza virus hemagglutinin with monoclonal antibodies and the selection of variants with potential epidemiological significance. , 1980, Virology.