Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance
Djin-Ye Oh, Jeanette Milde, Youngsun Ham, Julia Patricia Ramos Calderón, Marianne Wedde, Ralf Dürrwald, Susanne C Duwe Robert Koch Institute, Department 1: Infectious Diseases, Unit 17: Influenza and Other Respiratory Viruses, National Influenza Center, Berlin, GermanyCorrespondence: Susanne C Duwe,...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2023-02-01
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| Series: | Infection and Drug Resistance |
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| Online Access: | https://www.dovepress.com/preparing-for-the-next-influenza-season-monitoring-the-emergence-and-s-peer-reviewed-fulltext-article-IDR |
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| author | Oh DY Milde J Ham Y Ramos Calderón JP Wedde M Dürrwald R Duwe SC |
| author_facet | Oh DY Milde J Ham Y Ramos Calderón JP Wedde M Dürrwald R Duwe SC |
| author_sort | Oh DY |
| collection | DOAJ |
| description | Djin-Ye Oh, Jeanette Milde, Youngsun Ham, Julia Patricia Ramos Calderón, Marianne Wedde, Ralf Dürrwald, Susanne C Duwe Robert Koch Institute, Department 1: Infectious Diseases, Unit 17: Influenza and Other Respiratory Viruses, National Influenza Center, Berlin, GermanyCorrespondence: Susanne C Duwe, Robert Koch Institute, Department 1: Infectious Diseases, Unit 17: Influenza Viruses and Other Respiratory Viruses | National Influenza Center, Seestr. 10, Berlin, 13353, Germany, Tel +49 30 18754 2283, Fax +49 30 18754 2699, Email DuweS@rki.dePurpose: The relaxation of pandemic restrictions in 2022 has led to a reemergence of respiratory virus circulation worldwide and anticipation of substantial influenza waves for the 2022/2023 Northern Hemisphere winter. Therefore, the antiviral susceptibility profiles of human influenza viruses circulating in Germany were characterized.Methods: Between October 2019 (week 40/2019) and March 2022 (week 12/2022), nasal swabs from untreated patients with acute respiratory symptoms were collected in the national German influenza surveillance system. A total of 598 influenza viruses were isolated and analyzed for susceptibility to oseltamivir, zanamivir and peramivir, using a neuraminidase (NA) inhibition assay. In addition, next-generation sequencing was applied to assess molecular markers of resistance to NA, cap-dependent endonuclease (PA) and M2 ion channel inhibitors (NAI, PAI, M2I) in 367 primary clinical samples. Furthermore, a genotyping assay based on RT-PCR and pyrosequencing to rapidly assess the molecular resistance marker PA-I38X in PA genes was designed and established.Results: While NAI resistance in the strict sense, defined by a ≥ 10-fold (influenza A) or ≥ 5-fold (influenza B) increase of NAI IC50, was not detected, a subtype A(H1N1)pdm09 isolate displayed 2.3- to 7.5-fold IC50 increase for all three NAI. This isolate carried the NA-S247N substitution, which is known to enhance NAI resistance induced by NA-H275Y. All sequenced influenza A viruses carried the M2-S31N substitution, which confers resistance to M2I. Of note, one A(H3N2) virus displayed the PA-I38M substitution, which is associated with reduced susceptibility to the PAI baloxavir marboxil. Pyrosequencing analysis confirmed these findings in the original clinical specimen and in cultured virus isolate, suggesting sufficient replicative fitness of this virus mutant.Conclusion: Over the last three influenza seasons, the vast majority of influenza viruses in this national-level sentinel were susceptible to NAIs and PAIs. These findings support the use of antivirals in the upcoming influenza season.Keywords: influenza viruses, antiviral resistance, phenotypic assay, genotypic assay, surveillance, neuraminidase, cap-dependent endonuclease, baloxavir marboxil, molecular resistance marker |
| first_indexed | 2024-04-10T09:52:38Z |
| format | Article |
| id | doaj.art-f0f1b242b75544f7b039875b1ec295a8 |
| institution | Directory Open Access Journal |
| issn | 1178-6973 |
| language | English |
| last_indexed | 2024-04-10T09:52:38Z |
| publishDate | 2023-02-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Infection and Drug Resistance |
| spelling | doaj.art-f0f1b242b75544f7b039875b1ec295a82023-02-16T18:07:27ZengDove Medical PressInfection and Drug Resistance1178-69732023-02-01Volume 1694995981663Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral ResistanceOh DYMilde JHam YRamos Calderón JPWedde MDürrwald RDuwe SCDjin-Ye Oh, Jeanette Milde, Youngsun Ham, Julia Patricia Ramos Calderón, Marianne Wedde, Ralf Dürrwald, Susanne C Duwe Robert Koch Institute, Department 1: Infectious Diseases, Unit 17: Influenza and Other Respiratory Viruses, National Influenza Center, Berlin, GermanyCorrespondence: Susanne C Duwe, Robert Koch Institute, Department 1: Infectious Diseases, Unit 17: Influenza Viruses and Other Respiratory Viruses | National Influenza Center, Seestr. 10, Berlin, 13353, Germany, Tel +49 30 18754 2283, Fax +49 30 18754 2699, Email DuweS@rki.dePurpose: The relaxation of pandemic restrictions in 2022 has led to a reemergence of respiratory virus circulation worldwide and anticipation of substantial influenza waves for the 2022/2023 Northern Hemisphere winter. Therefore, the antiviral susceptibility profiles of human influenza viruses circulating in Germany were characterized.Methods: Between October 2019 (week 40/2019) and March 2022 (week 12/2022), nasal swabs from untreated patients with acute respiratory symptoms were collected in the national German influenza surveillance system. A total of 598 influenza viruses were isolated and analyzed for susceptibility to oseltamivir, zanamivir and peramivir, using a neuraminidase (NA) inhibition assay. In addition, next-generation sequencing was applied to assess molecular markers of resistance to NA, cap-dependent endonuclease (PA) and M2 ion channel inhibitors (NAI, PAI, M2I) in 367 primary clinical samples. Furthermore, a genotyping assay based on RT-PCR and pyrosequencing to rapidly assess the molecular resistance marker PA-I38X in PA genes was designed and established.Results: While NAI resistance in the strict sense, defined by a ≥ 10-fold (influenza A) or ≥ 5-fold (influenza B) increase of NAI IC50, was not detected, a subtype A(H1N1)pdm09 isolate displayed 2.3- to 7.5-fold IC50 increase for all three NAI. This isolate carried the NA-S247N substitution, which is known to enhance NAI resistance induced by NA-H275Y. All sequenced influenza A viruses carried the M2-S31N substitution, which confers resistance to M2I. Of note, one A(H3N2) virus displayed the PA-I38M substitution, which is associated with reduced susceptibility to the PAI baloxavir marboxil. Pyrosequencing analysis confirmed these findings in the original clinical specimen and in cultured virus isolate, suggesting sufficient replicative fitness of this virus mutant.Conclusion: Over the last three influenza seasons, the vast majority of influenza viruses in this national-level sentinel were susceptible to NAIs and PAIs. These findings support the use of antivirals in the upcoming influenza season.Keywords: influenza viruses, antiviral resistance, phenotypic assay, genotypic assay, surveillance, neuraminidase, cap-dependent endonuclease, baloxavir marboxil, molecular resistance markerhttps://www.dovepress.com/preparing-for-the-next-influenza-season-monitoring-the-emergence-and-s-peer-reviewed-fulltext-article-IDRinfluenza virusesantiviral resistancephenotypic assaygenotypic assaysurveillanceneuraminidasecap-dependent endonucleasebaloxavir marboxilmolecular resistance marker |
| spellingShingle | Oh DY Milde J Ham Y Ramos Calderón JP Wedde M Dürrwald R Duwe SC Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance Infection and Drug Resistance influenza viruses antiviral resistance phenotypic assay genotypic assay surveillance neuraminidase cap-dependent endonuclease baloxavir marboxil molecular resistance marker |
| title | Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance |
| title_full | Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance |
| title_fullStr | Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance |
| title_full_unstemmed | Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance |
| title_short | Preparing for the Next Influenza Season: Monitoring the Emergence and Spread of Antiviral Resistance |
| title_sort | preparing for the next influenza season monitoring the emergence and spread of antiviral resistance |
| topic | influenza viruses antiviral resistance phenotypic assay genotypic assay surveillance neuraminidase cap-dependent endonuclease baloxavir marboxil molecular resistance marker |
| url | https://www.dovepress.com/preparing-for-the-next-influenza-season-monitoring-the-emergence-and-s-peer-reviewed-fulltext-article-IDR |
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