Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

Govorkova, Elena A.; Takashita, Emi; Daniels, Rod S.; Fujisaki, Seiichiro; Presser, Lance; Patel, Manan S.; Huang, Weijuan; Lackenby, Angie; Nguyen, Ha; Pereyaslov, Dmitriy; Rattigan, Áine; Brown, Sook Kwan; Samaan, Magdi; Subbarao, Kanta; Wong, Sun; Wang, Dayang; Webby, Richard J.; Yen, Hui‐Ling; Zhang, Wenqing; Meijer, Adam; Gubareva, Larisa V.

doi:10.1016/j.antiviral.2022.105281

Cited by 84 publications

(56 citation statements)

References 37 publications

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“…Although both E23G and E23K reduced virus susceptibility to BXA, the EC 50 s with E23K were greater than with E23G, following a trend reported within WHO influenza antiviral technical reports [ 2 , 22 , 29 ]. The opposite was true for in vitro replication, in which E23K viruses were generally more impaired in two separate cell lines, similar to the reported impairment of E23K A/Kanagawa/AC1929/2019 in MDCK cells [ 13 ].…”

Section: Discussionsupporting

confidence: 54%

Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

Zagribelnyy

Pascua

et al. 2022

PLoS Pathog

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Baloxavir marboxil (BXM) is approved for treating uncomplicated influenza. The active metabolite baloxavir acid (BXA) inhibits cap-dependent endonuclease activity of the influenza virus polymerase acidic protein (PA), which is necessary for viral transcription. Treatment-emergent E23G or E23K (E23G/K) PA substitutions have been implicated in reduced BXA susceptibility, but their effect on virus fitness and transmissibility, their synergism with other BXA resistance markers, and the mechanisms of resistance have been insufficiently studied. Accordingly, we generated point mutants of circulating seasonal influenza A(H1N1)pdm09 and A(H3N2) viruses carrying E23G/K substitutions. Both substitutions caused 2- to 13-fold increases in the BXA EC50. EC50s were higher with E23K than with E23G and increased dramatically (138- to 446-fold) when these substitutions were combined with PA I38T, the dominant BXA resistance marker. E23G/K-substituted viruses exhibited slightly impaired replication in MDCK Calu-3 cells, which was more pronounced with E23K. In ferret transmission experiments, all viruses transmitted to direct-contact and airborne-transmission animals, with only E23K+I38T viruses failing to infect 100% of animals by airborne transmission. E23G/K genotypes were predominantly stable during transmission events and through five passages in vitro. Thermostable PA–BXA interactions were weakened by E23G/K substitutions and further weakened when combined with I38T. In silico modeling indicated this was caused by E23G/K altering the placement of functionally important Tyr24 in the endonuclease domain, potentially decreasing BXA binding but at some cost to the virus. These data implicate E23G/K, alone or combined with I38T, as important markers of reduced BXM susceptibility, and such mutants could emerge and/or transmit among humans.

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Section: Discussionsupporting

confidence: 54%

Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

Zagribelnyy

Pascua

et al. 2022

PLoS Pathog

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“…Only two viruses assessed in 2021 were identified as having reduced susceptibility by at least one NAI using phenotypic and/or NA sequence-based methods. One virus had NA-D197N substitution and this substitution was reported previously as a borderline NI/RI phenotype [ 26 ]. One virus showed RI by zanamivir, with the NA-H273Q substitution, which has not been described before.…”

Section: Discussionmentioning

confidence: 95%

Epidemiological and virological surveillance of influenza viruses in China during 2020–2021

et al. 2022

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Background During the coronavirus disease 2019 (COVID-19) pandemic, seasonal influenza activity declined globally and remained below previous seasonal levels, but intensified in China since 2021. Preventive measures to COVID-19 accompanied by different epidemic characteristics of influenza in different regions of the world. To better respond to influenza outbreaks under the COVID-19 pandemic, we analyzed the epidemiology, antigenic and genetic characteristics, and antiviral susceptibility of influenza viruses in the mainland of China during 2020–2021. Methods Respiratory specimens from influenza like illness cases were collected by sentinel hospitals and sent to network laboratories in Chinese National Influenza Surveillance Network. Antigenic mutation analysis of influenza virus isolates was performed by hemagglutination inhibition assay. Next-generation sequencing was used for genetic analyses. We also conducted molecular characterization and phylogenetic analysis of circulating influenza viruses. Viruses were tested for resistance to antiviral medications using phenotypic and/or sequence-based methods. Results In the mainland of China, influenza activity recovered in 2021 compared with that in 2020 and intensified during the traditional influenza winter season, but it did not exceed the peak in previous years. Almost all viruses isolated during the study period were of the B/Victoria lineage and were characterized by genetic diversity, with the subgroup 1A.3a.2 viruses currently predominated. 37.8% viruses tested were antigenically similar to reference viruses representing the components of the vaccine for the 2020–2021 and 2021–2022 Northern Hemisphere influenza seasons. In addition, China has a unique subgroup of 1A.3a.1 viruses. All viruses tested were sensitive to neuraminidase inhibitors and endonuclease inhibitors, except two B/Victoria lineage viruses identified to have reduced sensitivity to neuraminidase inhibitors. Conclusions Influenza activity increased in the mainland of China in 2021, and caused flu season in the winter of 2021–2022. Although the diversity of influenza (sub)type decreases, B/Victoria lineage viruses show increased genetic and antigenic diversity. The world needs to be fully prepared for the co-epidemic of influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus globally.

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“…However, the pandemic strain A(H1N1)pdm09, which did not contain this mutation and was sensitive to OST treatment, emerged, spread, and replaced the previous seasonal A(H1N1) strain. Since then, the frequency of NA:H275Y identification in these viruses has remained low ( 18 ). In addition, we have identified an A(H1N1)pdm09 virus that harbored the NA:S247N marker, which exclusively causes a significant RI effect when it is associated with the NA:H275Y mutation, causing a synergistic effect, increasing the reduction in OST and PER susceptibility ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…The gene encoding the PA protein is highly conserved and the emergence of mutations is a rare event. However, some markers of RI to BXM have already been identified, especially at position PA:I38X (T/F/M/S/L/V), the most frequently found ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

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Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons

Sousa

Martins

Miranda

et al. 2022

Front. Public Health

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The influenza A virus (IAV) is of a major public health concern as it causes annual epidemics and has the potential to cause pandemics. At present, the neuraminidase inhibitors (NAIs) are the most widely used anti-influenza drugs, but, more recently, the drug baloxavir marboxil (BXM), a polymerase inhibitor, has also been licensed in some countries. Mutations in the viral genes that encode the antiviral targets can lead to treatment resistance. Worldwide, a low prevalence of antiviral resistant strains has been reported. Despite that, this situation can change rapidly, and resistant strain surveillance is a priority. Thus, the aim of this was to evaluate Brazilian IAVs antiviral resistance from 2017 to 2019 through the identification of viral mutations associated with reduced inhibition of the drugs and by testing the susceptibility of IAV isolates to oseltamivir (OST), the most widely used NAI drug in the country. Initially, we analyzed 282 influenza A(H1N1)pdm09 and 455 A(H3N2) genetic sequences available on GISAID. The amino acid substitution (AAS) NA:S247N was detected in one A(H1N1)pdm09 strain. We also identified NA:I222V (n = 6) and NA:N329K (n = 1) in A(H3N2) strains. In addition, we performed a molecular screening for NA:H275Y in 437 A(H1N1)pdm09 samples, by pyrosequencing, which revealed a single virus harboring this mutation. Furthermore, the determination of OST IC50 values for 222 A(H1N1)pdm09 and 83 A(H3N2) isolates revealed that all isolates presented a normal susceptibility profile to the drug. Interestingly, we detected one A(H3N2) virus presenting with PA:E119D AAS. Moreover, the majority of the IAV sequences had the M2:S31N adamantanes resistant marker. In conclusion, we show a low prevalence of Brazilian IAV strains with NAI resistance markers, in accordance with what is reported worldwide, indicating that NAIs still remain an option for the treatment of influenza infections in Brazil. However, surveillance of influenza resistance should be strengthened in the country for improving the representativeness of investigated viruses and the robustness of the analysis.

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Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

Cited by 84 publications

References 37 publications

Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

Epidemiological and virological surveillance of influenza viruses in China during 2020–2021

Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons

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