Assessing the fitness of a dual-antiviral drug resistant human influenza virus in the ferret model

Stannard, Harry L.; Mifsud, Edin; Wildum, Steffen; Brown, Sook Kwan; Koszalka, Paulina; Shishido, Toetsu; Kojima, Satoshi; Omoto, Shinya; Baba, Keiko; Kuhlbusch, Klaus; Hurt, Aeron C.; Barr, Ian G.

doi:10.1038/s42003-022-04005-4

Cited by 7 publications

(4 citation statements)

References 66 publications

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“…Beyond individual patient benefit through mitigation of lethal infection and alleviation of viral pneumonia and lung immunopathogenesis, 4’-FlU statistically significant reduced upper respiratory tract virus load and viral shedding when treating 12 hours after infection, resulting in fully suppressed spread to untreated direct-contact sentinels in the highly sensitive ferret transmission model [ 50 ]. Later treatment initiation still reduced transmission efficiency, manifesting in delayed onset of virus replication and reduced upper respiratory tract peak virus load, which serves as a biomarker for risk of progression to severe viral pneumonia [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

et al. 2023

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Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4’-Fluorouridine (4’-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium (HAE) models, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4’-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar to sub-micromolar potency in HAE cells. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4’-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4’-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (pdmCa09) with 4’-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating a broad time window for effective intervention. Therapeutic oral 4’-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pdmCa09. Recoverees were protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4’-FlU and supports 4’-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

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Section: Discussionmentioning

confidence: 99%

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

et al. 2023

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“…Beyond individual patient benefit through mitigation of lethal infection and alleviation of viral pneumonia and lung immunopathogenesis, 4'-FlU statistically significant reduced upper respiratory tract virus load and viral shedding when treating 12 hours after infection, resulting in fully suppressed spread to untreated direct-contact sentinels in the highly sensitive ferret transmission model (49). Later treatment initiation still reduced transmission efficiency, resulting in delayed onset of virus replication and reduced upper respiratory tract peak virus load, which serves as a biomarker for risk of progression to severe viral pneumonia (50).…”

Section: Discussionmentioning

confidence: 99%

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

Lieber

Aggarwal

Yoon

et al. 2022

Preprint

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Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4-Fluorouridine (4-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus, we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium organoids, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar potency in organoids. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented direct-contact transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1) (Ca09) with 2 mg/kg 4-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating an unusually broad window for effective intervention. Therapeutic oral 4-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pandemic Ca09. Recoverees were fully protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4-FlU and supports 4-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

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“…It has also been concluded that resistance is largely due to the spread of a single variant [ 40 ]. Now, more than 10 years after this discovery, knowledge about not only the phenomenon of drug resistance, but also new anti-influenza drugs, vaccinations, or the genetics of the influenza virus itself, has significantly increased through the work of scientists and medical doctors [ 41 , 42 ]. Assessment of the susceptibility of currently circulating influenza viruses to antivirals is an important element of influenza virological surveillance required by the WHO, which the National Influenza Centers are trying to fulfill [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants of Drug Resistance and Mutation Patterns in Influenza Viruses Circulating in Poland Across Multiple Epidemic Seasons: Implications for Vaccination Strategies

Hallmann,

Masny,

Poznańska

et al. 2024

Med Sci Monit

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Background According to the WHO, up to 650 000 people die each year from seasonal flu-related respiratory illnesses. The most effective method of fighting the virus is seasonal vaccination. However, if an infection does occur, antiviral medications should be used as soon as possible. No studies of drug resistance in influenza viruses circulating in Poland have been systematically conducted. Therefore, the aim of the present study was to investigate the drug resistance and genetic diversity of influenza virus strains circulating in Poland by determining the presence of mutations in the neuraminidase gene. Material/Methods A total of 258 clinical specimens were collected during the 2016–2017, 2017–2018, and 2018–2019 epidemic seasons. The samples containing influenza A and B were analyzed by RT-PCR and Sanger sequencing. Results Differences were found between the influenza virus strains detected in different epidemic seasons, demonstrating the occurrence of mutations. Influenza A virus was found to be more genetically variable than influenza B virus ( P <0.001, Kruskal-Wallis test). However, there was no significant difference in the resistance prevalence between the influenza A subtypes A/H1N1/pdm09 (4.8%) and A/H3N2/ (6.1%). In contrast, more mutations of drug-resistance genes were found in the influenza B virus ( P <0.001, chi-square test). In addition, resistance mutations appeared en masse in vaccine strains circulating in unvaccinated populations. Conclusions It seems important to determine whether the influenza virus strains tested for drug resistance as part of global influenza surveillance are equally representative of viruses circulating in populations with high and low vaccination rates, for all countries. Our results suggest that countries with low levels of influenza immunization may constitute reservoirs of drug-resistant influenza viruses.

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Assessing the fitness of a dual-antiviral drug resistant human influenza virus in the ferret model

Cited by 7 publications

References 66 publications

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

Molecular Determinants of Drug Resistance and Mutation Patterns in Influenza Viruses Circulating in Poland Across Multiple Epidemic Seasons: Implications for Vaccination Strategies

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