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Author Notes:

E-mail: chwanchuen@gmail.com

Conceived and designed the experiments: CLK CCK.

Performed the experiments: CLK CHT KYC SFC.

Analyzed the data: CLK TCC CCL ZRTL KWW.

Contributed reagents/materials/analysis tools: CLK LYC YHS LMH PIL.

Wrote the paper: CLK.

Coordinated the study: CCK.

Revised the manuscript: CCK CLK.

Provided critical review: CLY RC BTR CCK.

Responsible for this paper: CCK.

The authors would like to express our sincere gratitude to Dr. Rafi Ahmed from Emory University for his scientific discussion, advice and critical English editing.

We also would like to thank Dr. Chuan-Hsiung Chang from National Yang-Ming University for help with global sequence data analyses, Miss Hui-Ying Ko for her help with the structure analysis of HA, Deputy Director, Tanya J. Cassingham at the Emory- UGA (University of Georgia at Athens) Influenza Pathogenesis and Immunology Research Center (IPIRC) and Dr. Abdul M Jabbar at the Emory Vaccine Center for their administration assistance, and Mr. Johnathan Kao at University of California-Berkeley for his English editing.

We also sincerely thank Centers for Disease Control and Prevention (CDC), USA for providing the laboratory protocols and WHO influenza reagent kit.

In addition, the sincere assistance of health-care workers' collecting specimens from patients at National Taiwan University Hospital and Yuan's General Hospital is highly appreciated.

The authors have declared that no competing interests exist.


Research Funding:

This research was supported by three grants: NSC #98-2321-B-002-016 from Taiwan's National Science Council, and financial support from the National Institutes of Health in the United States (NIH grant #2U19AI05726606 and NIH grant #HHSN266200700006C).


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • A(H1N1)

Emerged HA and NA Mutants of the Pandemic Influenza H1N1 Viruses with Increasing Epidemiological Significance in Taipei and Kaohsiung, Taiwan, 2009-10

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Journal Title:



Volume 7, Number 2


, Pages e31162-e31162

Type of Work:

Article | Final Publisher PDF


The 2009 influenza pandemic provided an opportunity to observe dynamic changes of the hemagglutinin (HA) and neuraminidase (NA) of pH1N1 strains that spread in two metropolitan areas -Taipei and Kaohsiung. We observed cumulative increases of amino acid substitutions of both HA and NA that were higher in the post-peak than in the pre-peak period of the epidemic. About 14.94% and 3.44% of 174 isolates had one and two amino acids changes, respective, in the four antigenic sites. One unique adaptive mutation of HA2 (E374K) was first detected three weeks before the epidemic peak. This mutation evolved through the epidemic, and finally emerged as the major circulated strain, with significantly higher frequency in the post-peak period than in the pre-peak (64.65% vs 9.28%, p < 0.0001). E374K persisted until ten months post-nationwide vaccination without further antigenic changes (e.g. prior to the highest selective pressure). In public health measures, the epidemic peaked at seven weeks after oseltamivir treatment was initiated. The emerging E374K mutants spread before the first peak of school class suspension, extended their survival in high-density population areas before vaccination, dominated in the second wave of class suspension, and were fixed as herd immunity developed. The tempo-spatial spreading of E374K mutants was more concentrated during the post-peak (p = 0.000004) in seven districts with higher spatial clusters (p < 0.001). This is the first study examining viral changes during the naïve phase of a pandemic of influenza through integrated virological/serological/clinical surveillance, tempo-spatial analysis, and intervention policies. The vaccination increased the percentage of E374K mutants (22.86% vs 72.34%, p < 0.001) and significantly elevated the frequency of mutations in Sa antigenic site (2.36% vs 23.40%, p < 0.001). Future pre-vaccination public health efforts should monitor amino acids of HA and NA of pandemic influenza viruses isolated at exponential and peak phases in areas with high cluster cases.

Copyright information:

© 2012 Kao et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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