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Neuraminidase Sequence Analysis and Susceptibilities of Influenza Virus Clinical Isolates to Zanamivir and Oseltamivir

Division of Health Sciences and Nutrition, Commonwealth Scientific and Industrial Research Organisation, Parkville,¹ World Health Organization Collaborating Centre for Reference & Research on Influenza, Melbourne, Australia,³ GlaxoSmithKline Research and Development, Greenford,² World Health Organization Collaborating Center for Reference & Research on Influenza, London,⁴ Public Health Laboratory Service, London, United Kingdom,⁸ World Health Organization Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Atlanta, Georgia,⁵ World Health Organization Collaborating Center for Reference & Research on Influenza, Tokyo, Japan,⁶ University of Virginia Health Science Center, Charlottesville, Virginia⁷

Received 16 December 2002/ Returned for modification 20 February 2003/ Accepted 31 March 2003

The influenza virus neuraminidase (NA) inhibitors zanamivir and oseltamivir were introduced into clinical practice in various parts of the world between 1999 and 2002. In order to monitor the potential development of resistance, the Neuraminidase Inhibitor Susceptibility Network was established to coordinate testing of clinical isolates collected through the World Health Organization influenza surveillance network from different regions of the world (M. Zambon and F. G. Hayden, Antivir. Res. 49:147-156, 2001). The present study establishes the baseline susceptibilities prior to and shortly after the introduction of the NA inhibitors. Over 1,000 clinical influenza isolates recovered from 1996 to 1999 were tested. Susceptibilities were determined by enzyme inhibition assays with chemiluminescent or fluorescent substrates with known NA inhibitor-resistant viruses as controls. The 50% inhibitory concentrations (IC₅₀s) depended upon the assay method, the drug tested, and the influenza virus subtype. By both assays, the mean zanamivir IC₅₀s were 0.76, 1.82, and 2.28 nM for the subtype H1N1 (N1), H3N2 (N2), and B NAs, respectively, and the oseltamivir IC₅₀s were 1.2, 0.5, and 8.8 nM for the N1, N2, and B NAs, respectively. The drug susceptibilities of known zanamivir- and oseltamivir-resistant viruses with the NA mutations E119V, R292K, H274Y, and R152K fell well outside the 95% confidence limits of the IC₅₀s for all natural isolates. Sequence analysis of the NAs of viruses for which the IC₅₀s were above the 95% confidence limits and several control isolates for which the IC₅₀s were in the normal range revealed variations in some previously conserved residues, including D151, A203, T225, and E375 (N2 numbering). Known resistance mutations are both influenza virus subtype and drug specific, but there was no evidence of naturally occurring resistance to either drug in any of the isolates.

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