Antigenic Drift of the Influenza A(H1N1)pdm09 Virus Neuraminidase Results in Reduced Effectiveness of A/California/7/2009 (H1N1pdm09)-Specific Antibodies

• Type of Material: Article
• Authors: Jin Gao, Food and Drug Administration; Laura Couzens, Food and Drug Administration; David F. Burke, University of Cambridge; Hongquan Wan, Food and Drug Administration; Patrick Wilson, University of Chicago; Matthew J. Memoli, National Institutes of Health; Xiyan Xu, Centers for Disease Control and Prevention; Ruth Harvey, Medicines and Healthcare products Regulatory Agency; Jens Wrammert, Emory University; Rafi Ahmed, Emory University; Jeffery K. Taubenberger, National Institutes of Health; Derek J. Smith, University of Cambridge; Ron A. M. Fouchier, Erasmus Medical Center; Maryna C. Eichelberger, Food and Drug Administration
• Language: English
• Date: 2019-03-01
• Publisher: American Society for Microbiology: Open Access Journals
• Publication Version: Final Published Version
• Copyright Statement: This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.00307-19
• Title of Journal or Parent Work: mBio
• ISSN: 2150-7511
• Volume: 10
• Issue: 2
• Start Page: 00307
• End Page: 00319
• Grant/Funding Information: This research was also partly supported by NIAID/NIH contract HHSN272201400008C and the intramural research programs of the National Institute of Allergy and Infectious Diseases (J.K.T.) and the Center for Biologics Evaluation and Research (M.C.E.).; This project was funded in part with federal funds from the U.S. Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract HHSO100201500033C.
• Keywords: neuraminidase; influenza; antigenic drift; IMMUNITY; ASSAY; Microbiology; SERUM; EPITOPES; Life Sciences & Biomedicine; RESISTANCE; HUMANS; vaccines; Science & Technology; VACCINE; MONOCLONAL-ANTIBODIES; PANDEMIC H1N1; monoclonal antibodies; INFECTION
• Research Categories: Health Sciences, Immunology; Biology, Zoology; Biology, Microbiology

Abstract

The effectiveness of influenza vaccines against circulating A(H1N1)pdm09 viruses was modest for several seasons despite the absence of antigenic drift of hemagglutinin (HA), the primary vaccine component. Since antibodies against HA and neuraminidase (NA) contribute independently to protection against disease, antigenic changes in NA may allow A(H1N1)pdm09 viruses to escape from vaccine-induced immunity. In this study, analysis of the specificities of human NA-specific monoclonal antibodies identified antigenic sites that have changed over time. The impact of these differences on in vitro inhibition of enzyme activity was not evident for polyclonal antisera until viruses emerged in 2013 without a predicted glycosylation site at amino acid 386 in NA. Phylogenetic and antigenic cartography demonstrated significant antigenic changes that in most cases aligned with genetic differences. Typical of NA drift, the antigenic difference is observed in one direction, with antibodies against conserved antigenic domains in A/California/7/2009 (CA/09) continuing to inhibit NA of recent A(H1N1)pdm09 viruses reasonably well. However, ferret CA/09-specific antiserum that inhibited the NA of A/Michigan/45/2015 (MI/15) very well in vitro, protected mice against lethal MI/15 infection poorly. These data show that antiserum against the homologous antigen is most effective and suggest the antigenic properties of NA should not be overlooked when selecting viruses for vaccine production.IMPORTANCE The effectiveness of seasonal influenza vaccines against circulating A(H1N1)pdm09 viruses has been modest in recent years, despite the absence of antigenic drift of HA, the primary vaccine component. Human monoclonal antibodies identified antigenic sites in NA that changed early after the new pandemic virus emerged. The reactivity of ferret antisera demonstrated antigenic drift of A(H1N1)pdm09 NA from 2013 onward. Passive transfer of serum raised against A/California/7/2009 was less effective than ferret serum against the homologous virus in protecting mice against a virus with the NA of more recent virus, A/Michigan/45/2015. Given the long-standing observation that NA-inhibiting antibodies are associated with resistance against disease in humans, these data demonstrate the importance of evaluating NA drift and suggest that vaccine effectiveness might be improved by selecting viruses for vaccine production that have NAs antigenically similar to those of circulating influenza viruses.