Subclade 2.2.1-Specific Human Monoclonal Antibodies That Recognize an Epitope in Antigenic Site A of Influenza A(H5) Virus HA Detected between 2015 and 2018

Highly pathogenic avian H5 influenza viruses persist among poultry and wild birds throughout the world. They sometimes cause interspecies transmission between avian and mammalian hosts. H5 viruses possessing the HA of subclade 2.3.4.4, 2.3.2.1, 2.2.1, or 7.2 were detected between 2015 and 2018. To understand the neutralizing epitopes of H5-HA, we characterized 15 human monoclonal antibodies (mAbs) against the HA of H5 viruses, which were obtained from volunteers who received the H5N1 vaccine that contains a subclade 2.2.1 or 2.1.3.2 virus as an antigen. Twelve mAbs were specific for the HA of subclade 2.2.1, two mAbs were specific for the HA of subclade 2.1.3.2, and one mAb was specific for the HA of both. Of the 15 mAbs analyzed, nine, which were specific for the HA of subclade 2.2.1, and shared the VH and VL genes, possessed hemagglutination inhibition and neutralizing activities, whereas the others did not. A single amino acid substitution or insertion at positions 144–147 in antigenic site A conferred resistance against these nine mAbs to the subclade 2.2.1 viruses. The amino acids at positions 144–147 are highly conserved among subclade 2.2.1, but differ from those of other subclades. These results show that the neutralizing epitope including amino acids at positions 144–147 is targeted by human antibodies, and plays a role in the antigenic difference between subclade 2.2.1 and other subclades.

[1]  Y. Kawaoka,et al.  Differences in the ease with which mutant viruses escape from human monoclonal antibodies against the HA stem of influenza A virus. , 2018, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[2]  R. Gao,et al.  Genetic characterization of the first detected human case of avian influenza A (H5N6) in Anhui Province, East China , 2018, Scientific Reports.

[3]  Kozue Hotta,et al.  Multiple polymerase gene mutations for human adaptation occurring in Asian H5N1 influenza virus clinical isolates , 2018, Scientific Reports.

[4]  J. Peiris,et al.  Human Clade 2.3.4.4 A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers and Does Not Transmit via the Airborne Route between Ferrets , 2018, mSphere.

[5]  Y. Kawaoka,et al.  Human protective monoclonal antibodies against the HA stem of group 2 HAs derived from an H3N2 virus-infected human. , 2017, The Journal of infection.

[6]  T. Harder,et al.  Isolation and genetic characterization of a novel 2.2.1.2a H5N1 virus from a vaccinated meat-turkeys flock in Egypt , 2017, Virology Journal.

[7]  M. Kiso,et al.  A Broadly Reactive Human Anti-hemagglutinin Stem Monoclonal Antibody That Inhibits Influenza A Virus Particle Release , 2017, EBioMedicine.

[8]  C. Macken,et al.  Risk assessment of recent Egyptian H5N1 influenza viruses , 2016, Scientific Reports.

[9]  Hualan Chen,et al.  Characterization of Clade 7.2 H5 Avian Influenza Viruses That Continue To Circulate in Chickens in China , 2016, Journal of Virology.

[10]  Zhiwei Chen,et al.  Cross-protection of newly emerging HPAI H5 viruses by neutralizing human monoclonal antibodies: A viable alternative to oseltamivir , 2016, mAbs.

[11]  Boping Zhou,et al.  Comprehensive analysis of antibody recognition in convalescent humans from highly pathogenic avian influenza H5N1 infection , 2015, Nature Communications.

[12]  Tiago J. S. Lopes,et al.  Development of high-yield influenza A virus vaccine viruses , 2015, Nature Communications.

[13]  J. Crowe,et al.  Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites , 2015, Proceedings of the National Academy of Sciences.

[14]  P. Collins,et al.  Structures of complexes formed by H5 influenza hemagglutinin with a potent broadly neutralizing human monoclonal antibody , 2015, Proceedings of the National Academy of Sciences.

[15]  Jens Meiler,et al.  Human antibodies that neutralize respiratory droplet transmissible H5N1 influenza viruses. , 2013, The Journal of clinical investigation.

[16]  Linqi Zhang,et al.  Unraveling of a Neutralization Mechanism by Two Human Antibodies against Conserved Epitopes in the Globular Head of H5 Hemagglutinin , 2012, Journal of Virology.

[17]  E. H. Chowdhury,et al.  New introduction of clade 2.3.2.1 avian influenza virus (H5N1) into Bangladesh. , 2012, Transboundary and emerging diseases.

[18]  Yuxian He,et al.  The Epitope and Neutralization Mechanism of AVFluIgG01, a Broad-Reactive Human Monoclonal Antibody against H5N1 Influenza Virus , 2012, PloS one.

[19]  Boping Zhou,et al.  A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses , 2012, Journal of Virology.

[20]  J. Kwang,et al.  Prophylactic and therapeutic efficacy of a chimeric monoclonal antibody specific for H5 haemagglutinin against lethal H5N1 influenza , 2009, Antiviral therapy.

[21]  K. Ikuta,et al.  Broad neutralizing human monoclonal antibodies against influenza virus from vaccinated healthy donors , 2009, Biochemical and Biophysical Research Communications.

[22]  K. Subbarao,et al.  Antigenic Fingerprinting of H5N1 Avian Influenza Using Convalescent Sera and Monoclonal Antibodies Reveals Potential Vaccine and Diagnostic Targets , 2009, PLoS medicine.

[23]  Gavin J. D. Smith,et al.  The development and genetic diversity of H5N1 influenza virus in China, 1996-2006. , 2008, Virology.

[24]  Tokiko Watanabe,et al.  Generation of influenza A viruses entirely from cloned cDNAs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Virus.  Update: isolation of avian influenza A(H5N1) viruses from humans--Hong Kong, 1997-1998. , 1998, MMWR. Morbidity and mortality weekly report.