A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013

Takashita, Emi; Ejima, Miho; Itoh, Roichi; Miura, Miwa; Ohnishi, Asami; Nishimura, Hidekazu; Odagiri, Takato; Tashiro, Masato

doi:10.2807/1560-7917.es2014.19.1.20666

Cited by 70 publications

(61 citation statements)

References 13 publications

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“…However, it rapidly selected escape mutants of CA/09 virus in vivo, which diminishes its potential to serve as a therapeutic agent against pH1N1 virus infection. In fact, the N397K mutation, detected in the NA of escape mutants from the HF5-treated mice, has occurred in the current circulating pH1N1 viruses (37,38). In addition, the N369K mutation, which abolishes the binding of HF5 to CA/09 NA, was selected soon after the introduction of pH1N1 virus into the human population and by 2011 was present in Ն99% of the circulating strains (8).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In November and December 2013, all six A(H1N1)pdm09 viruses isolated in Sapporo were resistant to oseltamivir and peramivir and possessed the H275Y substitution (15). We subsequently increased nationwide monitoring for NA inhibitor-resistant viruses and observed a further spread of this resistant virus to other areas of Hokkaido in January and February 2014.…”

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confidence: 99%

“…Recently, we reported a community cluster of A(H1N1)pdm09 viruses exhibiting cross-resistance to oseltamivir and peramivir in Sapporo, the capital of Hokkaido, Japan (15). In November and December 2013, all six A(H1N1)pdm09 viruses isolated in Sapporo were resistant to oseltamivir and peramivir and possessed the H275Y substitution (15).…”

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confidence: 99%

Characterization of a Large Cluster of Influenza A(H1N1)pdm09 Viruses Cross-Resistant to Oseltamivir and Peramivir during the 2013-2014 Influenza Season in Japan

Takashita

Kiso

Fujisaki

et al. 2015

Antimicrob Agents Chemother

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, 2,482 influenza 2009 pandemic A(H1N1) [A(H1N1)pdm09] viruses were screened in Japan for the H275Y substitution in their neuraminidase (NA) protein, which confers cross-resistance to oseltamivir and peramivir. We found that a large cluster of the H275Y mutant virus was present prior to the main influenza season in Sapporo/ Hokkaido, with the detection rate for this mutant virus reaching 29% in this area. Phylogenetic analysis suggested the clonal expansion of a single mutant virus in Sapporo/Hokkaido. To understand the reason for this large cluster, we examined the in vitro and in vivo properties of the mutant virus. We found that it grew well in cell culture, with growth comparable to that of the wildtype virus. The cluster virus also replicated well in the upper respiratory tract of ferrets and was transmitted efficiently between ferrets by way of respiratory droplets. Almost all recently circulating A(H1N1)pdm09 viruses, including the cluster virus, possessed two substitutions in NA, V241I and N369K, which are known to increase replication and transmission fitness. A structural analysis of NA predicted that a third substitution (N386K) in the NA of the cluster virus destabilized the mutant NA structure in the presence of the V241I and N369K substitutions. Our results suggest that the cluster virus retained viral fitness to spread among humans and, accordingly, caused the large cluster in Sapporo/Hokkaido. However, the mutant NA structure was less stable than that of the wild-type virus. Therefore, once the wild-type virus began to circulate in the community, the mutant virus could not compete and faded out. The neuraminidase (NA) inhibitors oseltamivir and zanamivir are recommended by the World Health Organization (WHO) for the treatment of influenza patients, as well as for chemoprophylaxis (1). In Japan, four NA inhibitors, oseltamivir, zanamivir, peramivir, and laninamivir, are approved and prescribed at the highest frequency in the world. Therefore, the surveillance of NA inhibitor-resistant viruses is important for public health authorities and clinicians to control influenza. We have been conducting such surveillance throughout Japan since 1999 (2-6).During the 2006-2007 influenza season, an oseltamivir-resistant former seasonal influenza A(H1N1) virus was first reported in Norway; this virus then spread rapidly and predominated globally until it was replaced by the pandemic A(H1N1) [A(H1N1)pdm09] virus in 2009 (7). The resistant A(H1N1) virus possessed a histidine-to-tyrosine substitution at position 275 (N1 numbering, H275Y) in its NA protein, which was responsible for its drug resistance (7). Four additional NA substitutions, R222Q, V234M, D344N, and D354G, were shown to compensate for the detrimental effect of the H275Y substitution on viral fitness, thereby making the mutant virus more transmissible in the community than the wild-type virus (8-11). However, since the A(H1N1)pdm09 virus began circulating globally in 2009, the H275Y mutant A(H1N1)pdm09 virus has been detected in various regions of t...

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“…However, in December 2013, H1N1 pdm09 with an H275Y substitution in NA (H1N1 pdm09 H275Y) was identified in Japanese patients who had not been exposed to oseltamivir (7). This suggests that this variant will circulate worldwide and all H1N1 pdm09 cases will be resistant to oseltamivir in the near future, according to trends observed for seasonal H1N1 until the 2008-2009 influenza season (8).…”

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confidence: 99%

Influenza Viral Load and Peramivir Kinetics after Single Administration and Proposal of Regimens for Peramivir Administration against Resistant Variants

Sato

Ito

Suzuki

et al. 2015

Antimicrob Agents Chemother

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fWe estimated the efficacy of the current single administration of peramivir on the basis of peramivir pharmacokinetics in the upper respiratory tract (URT) and determined the predictive peramivir concentration-time curve to assess its efficacy against viruses with decreased susceptibility to neuraminidase inhibitors. Serum, nasal swab, or aspiration samples were collected from 28 patients treated with 10 mg/kg body weight peramivir. The sequential influenza viral RNA load and susceptibility after peramivir administration were measured using a quantitative real-time reverse transcription-PCR and neuraminidase inhibition assay. The peramivir concentrations in the serum and URT after a single administration at 10 mg/kg were measured, and the predictive blood and URT peramivir concentration-time curves were determined to assess various administration regimens against resistant variants. The peramivir concentration decreased to <0.1% of the maximum concentration of drug in serum (C max ) at 24 h after administration. Rapid elimination of peramivir from the URT by 48 h after administration may contribute to an increase in the influenza A viral load after day 3 but not to a decrease in the influenza B viral load, despite the absence of a decrease in the susceptibility to peramivir. A longer maintenance of a high level of peramivir in the URT is expected by divided administration rather than once-daily administration. When no clinical improvement is observed in patients with normal susceptibility influenza A and B, peramivir readministration should be considered. In severe cases caused by resistant variants, better inhibitory effectiveness and less frequent adverse events are expected by divided administration rather than once-daily administration with an increased dosage.

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A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013

Cited by 70 publications

References 13 publications

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

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

Characterization of a Large Cluster of Influenza A(H1N1)pdm09 Viruses Cross-Resistant to Oseltamivir and Peramivir during the 2013-2014 Influenza Season in Japan

Influenza Viral Load and Peramivir Kinetics after Single Administration and Proposal of Regimens for Peramivir Administration against Resistant Variants

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