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

Chuan-Liang Kao,Kuan-Ying Chu,Zheng-Rong Tiger Li,Luan-Yin Chang,Chinglai Yang,Chwan-Chuen King,Ko-Wen Wu,Shu-Fang Chuang,Yea-Huei Shen,Richard Compans,Chang-Chun Lee,Chu-Han Tsai,Ping-Ing Lee,Barry T Rouse,Li-Min Huang,Ta-Chien Chan,Jianming Tang

doi:10.1371/journal.pone.0031162

Abstract

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.

Highlights

Emerged triple reassortant 2009 pandemic influenza A (HIN1) viruses were detected in patients with respiratory illness in Mexico and the United States in early April, 2009 [1,2,3]
The specific aims of this study were: (1) to examine the variations in nucleotide and amino acid sequences and comutations of HA and NA of the pH1N1 viruses isolated in the post-peak period versus in the pre-peak period of the epidemic in Taipei and Kaohsiung from June 2009 through October 2010, (2) to compare viral mutation rates and qualitative amino acid changes at receptor-binding sites (RBS), antigenic sites and Nglycosylation sites before and after the implementation of three public health interventions, including anti-viral program, school class suspension and vaccination, and (3) to analyze the epidemiologically tempo-spatial conditions in Taipei City that are associated with the spread of the unique mutant of HA of pH1N1
Patients with influenza like illness (ILI) or ILI with severe complications involving any one of the following clinical manifestations within four weeks requiring hospitalizations were recruited for the study: pulmonary complications, neurological complications, myocarditis or pericariditis, invasive bacterial infection or intensive care unit admission from the National Taiwan University Hospital (NTUH) in Taipei and Yuan’s General Hospital (YGH) in Kaohsiung from June 1, 2009 through October 31, 2010

Summary

Introduction

Emerged triple reassortant 2009 pandemic influenza A (HIN1) (pH1N1) viruses were detected in patients with respiratory illness in Mexico and the United States in early April, 2009 [1,2,3]. These novel viruses rapidly spread worldwide through human-to-human transmission. How these novel influenza viruses underwent spontaneous evolution [4,5] and dynamic changes over different time periods and various places within different epidemiological entities and intervention strategies is an important public health issue. The impact of amino acids changes of HA and NA of these pH1N1 viruses related to epidemiological characteristics, clinical severity, and after public health interventions has remained unclear

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Conclusion