Characterization of Influenza B Virus Variants with Reduced Neuraminidase Inhibitor Susceptibility

Farrukee, Rubaiyea; Zarebski, Alexander E.; McCaw, James M.; Bloom, Jesse D; Reading, Patrick C.; Hurt, Aeron C.

doi:10.1128/aac.01081-18

Cited by 21 publications

(15 citation statements)

References 51 publications

(71 reference statements)

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“…Mutant viruses resistant to FAV are rarely isolated in vitro and in vivo with one exceptional case 3 . Although detection of viruses that exhibit reduced susceptibility to NA inhibitors or baloxavir marboxil in immunocompetent patients has frequently been reported 1,[4][5][6][7][8][9] , such viruses usually do not dominate susceptible viruses with the exception of the worldwide spread of oseltamivir-resistant H1N1 virus in the 2007-2008 season. Recently, broadly protective human monoclonal antibodies (mAbs) against conserved regions of HA, including the receptorbinding site (RBS) and stem region, have been evaluated [10][11][12][13][14][15][16] and studies for their clinical application are being conducted [17][18][19][20] .…”

mentioning

confidence: 99%

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

2020

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Prolonged treatment of immunocompromised influenza patients with viral neuraminidase (NA) inhibitors is required, because the immune system of such patients fails to eradicate the viruses. Here, we attempted to eradicate influenza virus from the respiratory organs of nude mice, which is a model of immunocompromised hosts, by using combination therapy of the viral polymerase inhibitor favipiravir and monoclonal antibodies (mAbs) against the receptorbinding site (RBS) and stem of viral hemagglutinin (HA). Although monotherapy or combination therapy of two antivirals (two mAbs or favipiravir plus a mAb) suppressed virus replication, they failed to eradicate viruses from nude mice. In contrast, the triple combination therapy of favipiravir plus anti-Stem and anti-RBS mAbs completely stopped virus replication in nude mice, resulting in virus clearance. Triple combination approaches should be considered for the treatment of human immunocompromised patients with severe influenza.

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confidence: 99%

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

2020

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“…These two alternative scenarios, beyond competitive exclusion at the single host level, suggest high within-host diversity and low between-host diversity in one case (within-host coexistence at a typical fraction p * ), and low within-host diversity but high between-host diversity in the other (bistability within host yielding “0” and “1” host types at the population level). In a recent study of influenza B transmission fitness differences between strains, even though the classical exponential model was applied, the data contained a signature of possible bistability for MUT-Y273, (Figure 4C of Farrukee et al, 2018 ). Such signature may indeed be missed without an a-priori framework by which it can be detected.…”

Section: Discussionmentioning

confidence: 99%

“…(A) Scenario of competitive exclusion (Equations 2–3 in this paper). Parameters, chosen to represent a realistic influenza infection kinetics (e.g., Farrukee et al, 2018 ; Smith et al, 2018 ):

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(blue: n 1 , red n 2 ). n 1 (0) = pN 0 , with p = 0.5 (50:50 ratio for strains 1:2) and N 0 = 1.…”

Section: Discussionmentioning

confidence: 99%

Modeling Competitive Mixtures With the Lotka-Volterra Framework for More Complex Fitness Assessment Between Strains

Martins

Gjini

2020

Front. Microbiol.

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With increasing resolution of microbial diversity at the genomic level, experimental and modeling frameworks that translate such diversity into phenotypes are highly needed. This is particularly important when comparing drug-resistant with drug-sensitive pathogen strains, when anticipating epidemiological implications of microbial diversity, and when designing control measures. Classical approaches quantify differences between microbial strains using the exponential growth model, and typically report a selection coefficient for the relative fitness differential between two strains. The apparent simplicity of such approaches comes with the costs of limiting the range of biological scenarios that can be captured, and biases strain fitness estimates to polarized extremes of competitive exclusion. Here, we propose a mathematical and statistical framework based on the Lotka-Volterra model, that can capture frequency-dependent competition between microbial strains within-host and upon transmission. As a proof-of-concept, the model is applied to a previously-published dataset from in-vivo competitive mixture experiments with influenza strains in ferrets (McCaw et al., 2011). We show that for the same data, our model predicts a scenario of coexistence between strains, and supports a higher bottleneck size in the range of 35-145 virions transmitted from donor to recipient host. Thanks to its simplicity and generality, such framework could be applied to other ecological scenarios of microbial competition, enabling a more complex and nuanced view of possible outcomes between two strains, beyond competitive exclusion.

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“…Titres of infectious virus in the nasal washes were quantified by a viral infectivity assay and a TCID 50 calculated as described by Reed and Muench [48], with a minimal detection limit of 10 2 TCID 50 /ml. Next generation sequencing was performed on nasal washes from peak shedding day from each ferret, to ensure the genetic stability of the NA gene in viruses post-transmission and following replication in ferrets, as described previously [51]. Briefly, viral RNA was extracted using QIAamp Viral RNA kit (Qiagen, Germany) and influenza genes were amplified utilising previously described primers for influenza B viruses [52] and influenza A viruses [53].…”

Section: Inflammatory Cell and Protein Concentration Virological Andmentioning

confidence: 99%

“…Each time the animals were anaesthetized, body temperature was also measured rectally and the weight recorded. Viral titre in the different samples was quantified by the TCID 50 assay, and next generation sequence analysis was carried out on Day 4 tracheal lavage samples, as previously described [51]. At the completion of the experiment, a necropsy was performed on each animal.…”

Section: Evaluating Ost Efficacy In Macaquesmentioning

confidence: 99%

Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility

Farrukee

Tai

et al. 2020

PLoS Pathog

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The neuraminidase (NA) inhibitor (NAI) oseltamivir (OST) is the most widely used influenza antiviral drug. Several NA amino acid substitutions are reported to reduce viral susceptibility to OST in in vitro assays. However, whether there is a correlation between the level of reduction in susceptibility in vitro and the efficacy of OST against these viruses in vivo is not well understood. In this study, a ferret model was utilised to evaluate OST efficacy against circulating influenza A and B viruses with a range of in vitro generated 50% inhibitory concentrations (IC 50) values for OST. OST efficacy against an A(H1N1)pdm09 and an A(H1N1) pdm09 virus with the H275Y substitution in neuraminidase was also tested in the macaque model. The results from this study showed that OST had a significant impact on virological parameters compared to placebo treatment of ferrets infected with wild-type influenza A viruses with normal IC 50 values (~1 nM). However, this efficacy was lower against wild-type influenza B and other viruses with higher IC 50 values. Differing pathogenicity of the viruses made evaluation of clinical parameters difficult, although some effect of OST in reducing clinical signs was observed with influenza A(H1N1) and A(H1N1)pdm09 (H275Y) viruses. Viral titres in macaques were too low to draw conclusive results. Analysis of the ferret data revealed a correlation between IC 50 and OST efficacy in reducing viral shedding but highlighted that the current WHO guidelines/criteria for defining normal, reduced or highly reduced inhibition in influenza B viruses based on in vitro data are not well aligned with the low in vivo OST efficacy observed for both wild-type influenza B viruses and those with reduced OST susceptibility.

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Characterization of Influenza B Virus Variants with Reduced Neuraminidase Inhibitor Susceptibility

Cited by 21 publications

References 51 publications

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

Modeling Competitive Mixtures With the Lotka-Volterra Framework for More Complex Fitness Assessment Between Strains

Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility

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