Characteristics of a Widespread Community Cluster of H275Y Oseltamivir-Resistant A(H1N1)pdm09 Influenza in Australia

Hurt, Aeron C.; Hardie, Kate; Wilson, Noelene; Deng, Yi‐Mo; Osbourn, Maggi; Leang, Sook-Kwan; Lee, R. T. C.; Iannello, Pina; Gehrig, Nicole; Shaw, Robert; Wark, Peter; Caldwell, Natalie; Givney, Rodney; Xue, Lumin; Maurer‐Stroh, Sebastian; Dwyer, Dominic E.; Wang, B.; Smith, David W.; Levy, Avram; Booy, Robert; Dixit, Rashmi; Merritt, Tony; Kelso, Anne; Dalton, Craig; Dürrheim, David N; Barr, Ian G.

doi:10.1093/infdis/jis337

Cited by 152 publications

(177 citation statements)

References 36 publications

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“…Despite the low incidence of oseltamivir resistance observed during the 2011 Southern Hemisphere season, the spread of oseltamivir‐resistant A(H1N1)pdm09 viruses is still a concern and may develop as a result of selective pressure or spontaneous mutation, such as the cluster of oseltamivir‐resistant H275Y variants detected in the Hunter New England region of New South Wales, Australia 18, 19. Therefore, it remains prudent to continue conducting NAI sensitivity testing of viruses to monitor emergence of H275Y and other NAI‐resistant virus variants, particularly if the use of NAIs increases in the community.…”

Section: Discussionmentioning

confidence: 99%

“…In the subsequent 2010–2011 season, the United States reported approximately 1·0% oseltamivir resistance among the A(H1N1)pdm09 viruses,17 with evidence suggesting a low level of community transmission of these H275Y variants. In September 2011, a cluster of 29 cases infected with oseltamivir‐resistant influenza A(H1N1)pdm09 viruses was reported in Australia 18, 19. These oseltamivir‐resistant H275Y viruses were in circulation between May, 2011, and August, 2011, a period corresponding to the peak of the SH 2011 influenza season 20.…”

Section: Introductionmentioning

confidence: 99%

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Neuraminidase inhibitor susceptibility surveillance of influenza viruses circulating worldwide during the 2011 Southern Hemisphere season

Okomo-Adhiambo

Sleeman

Lysen

et al. 2013

Influenza Resp Viruses

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BackgroundNeuraminidase (NA) inhibitors (NAIs) are currently the only antivirals effective against influenza infections due to widespread resistance to M2 inhibitors.MethodsInfluenza A and B viruses (n = 1079) collected worldwide between April 01, 2011, and September 30, 2011, were assessed for susceptibility to FDA‐approved NAIs, oseltamivir and zanamivir, and investigational peramivir, using the fluorescent‐based NA‐Fluor™ Influenza Neuraminidase Assay Kit. A subset of viruses (n = 98) were tested for susceptibility to the investigational NAI, laninamivir.ResultsInfluenza A(H1N1)pdm09 viruses (n = 326) were sensitive to all NAIs, except for two (0·6%) with H275Y (N1 numbering; H274Y in N2 numbering) substitution, which exhibited elevated IC 50s for oseltamivir and peramivir, and a third with previously unreported N325K substitution, exhibiting reduced susceptibility to oseltamivir. Influenza A(H3N2) viruses (n = 407) were sensitive to all NAIs. Influenza B viruses (n = 346) were sensitive to all NAIs, except two (0·6%) with H273Y (N1 numbering; H274Y in N2 numbering) substitution, exhibiting reduced susceptibility to oseltamivir and peramivir, and one with previously unreported G140R and N144K substitutions, exhibiting reduced susceptibility to oseltamivir, zanamivir, and peramivir. All influenza A and B viruses were sensitive to laninamivir. It is unknown whether substitutions N325K, G140R, and N144K were present in the virus prior to culturing because clinical specimens were unavailable for testing.ConclusionsThis study summarizes NAI susceptibility of influenza viruses circulating worldwide during the 2011 Southern Hemisphere (SH) season, assessed using the NA‐Fluor™ Kit. Despite low resistance to NAIs among tested influenza viruses, constant surveillance of influenza virus susceptibility to NAIs should be emphasized.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuraminidase inhibitor susceptibility surveillance of influenza viruses circulating worldwide during the 2011 Southern Hemisphere season

Okomo-Adhiambo

Sleeman

Lysen

et al. 2013

Influenza Resp Viruses

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“…The licensure of NA inhibitors, e.g., oseltamivir and zanamivir, provides evidence that inhibition of NA activity impacts the duration of infection and clinical disease. Resistance to oseltamivir has possibly occurred as a result of selection during treatment with this antiviral, but it has also occurred in the absence of antiviral treatment (6)(7)(8). This has limited the options available for the control of influenza, and consequently, researchers are examining the prospect of new prophylactic and therapeutic approaches against influenza, including antibody therapy.…”

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confidence: 99%

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

Jiang

Fantoni

Couzens

et al. 2016

J Virol

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Antibodies against the neuraminidase (NA) of influenza virus correlate with resistance against disease, but the effectiveness of antibodies against different NA epitopes has not been compared. In the present study, we evaluated the in vitro and in vivo efficacies of four monoclonal antibodies (MAbs): HF5 and CD6, which are specific to two different epitopes in the NA of 2009 pandemic H1N1 (pH1N1) virus, and 4E9 and 1H5, which are specific to a conserved epitope in the NA of both H1N1 and H5N1 viruses. In the in vitro assays, HF5 and CD6 inhibited virus spread and growth more effectively than 4E9 and 1H5, with HF5 being the most effective inhibitor. When administered prophylactically at 5 mg/kg of body weight, HF5 and CD6 protected ϳ90 to 100% of DBA/2 mice against lethal wild-type pH1N1 virus challenge; however, at a lower dose (1 mg/kg), HF5 protected ϳ90% of mice, whereas CD6 protected only 25% of mice. 4E9 and 1H5 were less effective than HF5 and CD6, as indicated by the partial protection achieved even at doses as high as 15 mg/kg. When administered therapeutically, HF5 protected a greater proportion of mice against lethal pH1N1 challenge than CD6. However, HF5 quickly selected pH1N1 virus escape mutants in both prophylactic and therapeutic treatments, while CD6 did not. Our findings confirm the important role of NA-specific antibodies in immunity to influenza virus and provide insight into the properties of NA antibodies that may serve as good candidates for therapeutics against influenza. IMPORTANCENeuraminidase (NA) is one of the major surface proteins of influenza virus, serving as an important target for antivirals and therapeutic antibodies. The impact of NA-specific antibodies on NA activity and virus replication is likely to depend on where the antibody binds. Using in vitro assays and the mouse model, we compared the inhibitory/protective efficacy of four mouse monoclonal antibodies (MAbs) that bind to different sites within the 2009 pandemic H1N1 (pH1N1) virus NA. The ability of each MAb to protect mice against lethal pH1N1 infection corresponded to its ability to inhibit NA activity in vitro; however, the MAb that was the most effective inhibitor of NA activity selected pH1N1 escape variants in vivo. One of the tested MAbs, which binds to a conserved region in the NA of pH1N1 virus, inhibited NA activity but did not result in escape variants, highlighting its suitability for development as a therapeutic agent.

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“…In the United States, the fraction of cases of resistance not associated with oseltamivir exposure increased significantly from 11% in the 2009-2010 season to 75% in the 2010-2011 season (47). A few small clusters of oseltamivir resistance cases not associated with treatment and likely involving transmission of H1N1pdm09 mutant (MUT) strains have been reported in Europe (20,32), Australia (25,27), and Vietnam (34). The pandemic strain completely displaced the prior seasonal H1N1 strain (A/Brisbane/59/2007), which, in the 2008-2009 season, was nearly 100% resistant to oseltamivir (11,18).…”

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confidence: 99%

The H275Y Neuraminidase Mutation of the Pandemic A/H1N1 Influenza Virus Lengthens the Eclipse Phase and Reduces Viral Output of Infected Cells, Potentially Compromising Fitness in Ferrets

Pinilla

Holder

Abed

et al. 2012

J Virol

111

225

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The H275Y amino acid substitution of the neuraminidase gene is the most common mutation conferring oseltamivir resistance in the N1 subtype of the influenza virus. Using a mathematical model to analyze a set of in vitro experiments that allow for the full characterization of the viral replication cycle, we show that the primary effects of the H275Y substitution on the pandemic H1N1 (H1N1pdm09) strain are to lengthen the mean eclipse phase of infected cells (from 6.6 to 9.1 h) and decrease (by 7-fold) the viral burst size, i.e., the total number of virions produced per cell. We also find, however, that the infectious-unit-to-particle ratio of the H275Y mutant strain is 12-fold higher than that of the oseltamivir-susceptible strain (0.19 versus 0.016 per RNA copy). A parallel analysis of the H275Y mutation in the prior seasonal A/Brisbane/59/2007 background shows similar changes in the infection kinetic parameters, but in this background, the H275Y mutation also allows the mutant to infect cells five times more rapidly. Competitive mixed-strain infections in vitro, where the susceptible and resistant H1N1pdm09 strains must compete for cells, are characterized by higher viral production by the susceptible strain but suggest equivalent fractions of infected cells in the culture. In ferrets, however, the mutant strain appears to suffer a delay in its infection of the respiratory tract that allows the susceptible strain to dominate mixed-strain infections. In 2009, the World Health Organization (WHO) declared the first influenza pandemic of this century and described the virus (H1N1pdm09) as naturally resistant to adamantanes but susceptible to the neuraminidase (NA) inhibitors oseltamivir and zanamivir (10, 29). In the past 3 years, isolated cases of oseltamivir resistance in H1N1pdm09 strains have been reported-almost always associated with the H275Y mutation within the NA genebut the overall level of resistance has remained relatively low (42) at ϳ1% in the United States (47), Ͻ1% in Canada (40), ϳ2.5% in Europe (14, 26), and Ͻ1.6% worldwide (26). In the United States, the fraction of cases of resistance not associated with oseltamivir exposure increased significantly from 11% in (11,18). That dominance of an oseltamivir-resistant H275Y MUT strain was surprising at the time because it had been shown that the mutation usually compromised strain fitness (30). A return to widespread oseltamivir resistance, with a mutated H1N1pdm09 virus, could have significant public health consequences (19).Laboratory experiments have often been used to assess a particular influenza virus strain's phenotype in cell culture and animal models, particularly in relation to oseltamivir resistance. Prior to 2007, experiments demonstrated strongly attenuated growth of H275Y MUT strains of H1N1 in vitro (1, 21), a higher viral titer inoculum required for the infection of ferrets (21, 30), and generally less-pathogenic infections in ferrets, quantified by reduced fevers and smaller inflammatory cell counts in nasal washes (30). This mirrored...

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Characteristics of a Widespread Community Cluster of H275Y Oseltamivir-Resistant A(H1N1)pdm09 Influenza in Australia

Cited by 152 publications

References 36 publications

Neuraminidase inhibitor susceptibility surveillance of influenza viruses circulating worldwide during the 2011 Southern Hemisphere season

Neuraminidase inhibitor susceptibility surveillance of influenza viruses circulating worldwide during the 2011 Southern Hemisphere season

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

The H275Y Neuraminidase Mutation of the Pandemic A/H1N1 Influenza Virus Lengthens the Eclipse Phase and Reduces Viral Output of Infected Cells, Potentially Compromising Fitness in Ferrets

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