Antigenic Drift of the Pandemic 2009 A(H1N1) Influenza Virus in a Ferret Model

PLoS Pathogens

Raphael T. C. Lee¹  Stephen Petrie¹  Louise A. Carolan²  Emma Job³  Ian G. Barr⁴  Patrick C. Reading⁵  James M. McCaw⁶  Aeron C. Hurt⁶  Karen L. Laurie⁷  Jennifer Mosse⁷  Anne Kelso⁷  Jodie McVernon⁸  Teagan Guarnaccia⁸  Sebastian Maurer-Stroh⁸ 

[1] Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore;Monash University, School of Applied Sciences, Churchill, Victoria, Australia;National Public Health Laboratory, Communicable Diseases Division Ministry of Health, Singapore;Royal Children's Hospital, Murdoch Childrens Research Institute, Vaccine and Immunisation Research Group, Melbourne, Victoria, Australia;School of Biological Sciences (SBS), Nanyang Technological University (NTU), Singapore;The University of Melbourne, Department Microbiology & Immunology, Melbourne, Victoria, Australia;The University of Melbourne, Melbourne School of Population Health, Melbourne, Victoria, Australia;WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia

关键词: Ferrets;    Microbial mutation;    Influenza viruses;    Influenza;    Cell cultures;    Mutation detection;    Reverse transcriptase-polymerase chain reaction;    Antibodies;   

DOI  :  10.1371/journal.ppat.1003354

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Surveillance data indicate that most circulating A(H1N1)pdm09 influenza viruses have remained antigenically similar since they emerged in humans in 2009. However, antigenic drift is likely to occur in the future in response to increasing population immunity induced by infection or vaccination. In this study, sequential passaging of A(H1N1)pdm09 virus by contact transmission through two independent series of suboptimally vaccinated ferrets resulted in selection of variant viruses with an amino acid substitution (N156K, H1 numbering without signal peptide; N159K, H3 numbering without signal peptide; N173K, H1 numbering from first methionine) in a known antigenic site of the viral HA. The N156K HA variant replicated and transmitted efficiently between naïve ferrets and outgrew wildtype virus in vivo in ferrets in the presence and absence of immune pressure. In vitro, in a range of cell culture systems, the N156K variant rapidly adapted, acquiring additional mutations in the viral HA that also potentially affected antigenic properties. The N156K escape mutant was antigenically distinct from wildtype virus as shown by binding of HA-specific antibodies. Glycan binding assays demonstrated the N156K escape mutant had altered receptor binding preferences compared to wildtype virus, which was supported by computational modeling predictions. The N156K substitution, and culture adaptations, have been detected in human A(H1N1)pdm09 viruses with N156K preferentially reported in sequences from original clinical samples rather than cultured isolates. This study demonstrates the ability of the A(H1N1)pdm09 virus to undergo rapid antigenic change to evade a low level vaccine response, while remaining fit in a ferret transmission model of immunization and infection. Furthermore, the potential changes in receptor binding properties that accompany antigenic changes highlight the importance of routine characterization of clinical samples in human A(H1N1)pdm09 influenza surveillance.

【 授权许可】

CC BY