Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates

Itoh, Yasushi; Shichinohe, Shintaro; Nakayama, Misako; Igarashi, Manabu; Ishii, Akihiro; Ishigaki, Hirohito; Ishida, Hideyuki; Kitagawa, Naoko; Sasamura, Takako; Shiohara, Masanori; Doi, Michiko; Tsuchiya, Hideaki; Nakamura, Shinichiro; Okamatsu, Masatoshi; Sakoda, Yoshihiro; Kida, Hiroshi; Ogasawara, Kunio

doi:10.1128/aac.00793-15

Cited by 40 publications

(39 citation statements)

References 56 publications

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“…To mitigate against infection from new circulating viruses, seasonal influenza vaccines are formulated each year and neuraminidase (NA) inhibitors can be used to ameliorate the symptoms and spread of the virus (Moscona, 2005). However, the seasonal vaccines are not always effective, especially in the elderly, and NA-resistant viruses have begun to emerge over recent years (Chen et al, 2009; Hai et al, 2013; Hayden and de Jong, 2011; Itoh et al, 2015; Moscona, 2005; Ujike et al, 2010; Zhou et al, 2011). Thus, there is constant pressure to discover new therapeutics and to design more universal vaccines for broader and longer-term protection against emerging and seasonal influenza viruses.…”

Section: Introductionmentioning

confidence: 99%

Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

et al. 2017

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SUMMARY Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here we describe a new VH1-69 antibody 27F3 that broadly recognizes heterosubtypic HAs from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates 27F3 shares the key features observed in other VH1-69 antibodies to the HA stem. Compared to other VH1-69 antibodies, the 27F3 VH domain interacts with the HA stem in a distinct orientation, which alters its epitope and may have influenced its breadth. The diverse rotations of VH1-69 antibodies on the HA stem epitope highlight the different ways that this antibody family can evolve to broadly neutralize influenza A viruses. These results have important implications for understanding how to elicit broad antibody responses against influenza virus.

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Section: Introductionmentioning

confidence: 99%

Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

et al. 2017

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“…However, NAIs only consistently reduce the severity of disease if taken within 48 h of the onset of clinical symptoms (Dobson et al, 2015). Further, there is evidence that A(H7N9) can gain NAI resistance while maintaining in vivo virulence in animal models (Hai et al, 2013; Itoh et al, 2015). Supporting this, virus with reduced susceptibility to the commonly-used NAI oseltamivir has been isolated from A(H7N9) patients treated with NAI (Hu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody with prophylactic and therapeutic activity in vivo

et al. 2016

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Zoonotic A(H7N9) avian influenza viruses emerged in China in 2013 and continue to be a threat to human public health, having infected over 800 individuals with a mortality rate approaching 40%. Treatment options for people infected with A(H7N9) include the use of neuraminidase (NA) inhibitors. However, like other influenza viruses, A(H7N9) can become resistant to these drugs. The use of monoclonal antibodies is a rapidly developing strategy for controlling influenza virus infection. Here we generated a murine monoclonal antibody (3c10-3) directed against the NA of A(H7N9) and show that prophylactic systemic administration of 3c10-3 fully protected mice from lethal challenge with wild-type A/Anhui/1/2013 (H7N9). Further, post-infection treatment with a single systemic dose of 3c10-3 at either 24, 48 or 72 h post A(H7N9) challenge resulted in both dose- and time-dependent protection of up to 100% of mice, demonstrating therapeutic potential for 3c10-3. Epitope mapping revealed that 3c10-3 binds near the enzyme active site of NA, and functional characterization showed that 3c10-3 inhibits the enzyme activity of NA and restricts the cell-to-cell spread of the virus in cultured cells. Affinity analysis also revealed that 3c10-3 binds equally well to recombinant NA of wild-type A/Anhui/1/2013 and to a variant NA carrying a R289K mutation known to infer NAI resistance. These results suggest that 3c10-3 has the potential to be used as a therapeutic to treat A(H7N9) infections either as an alternative to, or in combination with, current NA antiviral inhibitors.

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“…Amino acid substitutions known to reduce susceptibility to oseltamivir E119V, I222K/R, H274Y, R292K, and R371K (N2 numbering) have been detected in the NA of A(H7N9) viruses isolated from humans . In addition, I222T was detected in an A(H7N9) virus isolated from a non‐human primate after oseltamivir treatment . To determine whether iART is able to identify NA with these changes as resistant to oseltamivir, the respective recombinant N9 (rN9) proteins were generated using the A/Shanghai/2/2013 NA as a backbone, as previously described .…”

Section: Recombinant N9 Proteins With Known Markers Of Ri/hri By Oselmentioning

confidence: 99%

Detection of oseltamivir‐resistant zoonotic and animal influenza A viruses using the rapid influenza antiviral resistance test

Hodges

et al. 2019

Influenza Resp Viruses

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Mutations in the influenza virus neuraminidase (NA) that cause reduced susceptibility to the NA inhibitor (NAI) oseltamivir may occur naturally or following antiviral treatment. Currently, detection uses either a traditional NA inhibition assay or gene sequencing to identify known markers associated with reduced inhibition by oseltamivir. Both methods are laborious and require trained personnel. The influenza antiviral resistance test (iART), a prototype system developed by Becton, Dickinson and Company for research use only, offers a rapid and simple method to identify such viruses. This study investigated application of iART to influenza A viruses isolated from non‐human hosts with a variety of NA subtypes (N1‐N9).

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Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates

Cited by 40 publications

References 56 publications

Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody with prophylactic and therapeutic activity in vivo

Detection of oseltamivir‐resistant zoonotic and animal influenza A viruses using the rapid influenza antiviral resistance test

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