isirv Antiviral Group
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Q4 / 2015
Antiviral resistance
Zanamivir-resistant influenza viruses with Q136K or Q136R neuraminidase residue mutations can arise during MDCK cell culture creating challenges for antiviral susceptibility monitoring
Cell culture derived neuraminidase mutation at residue Q136K and Q136R in influenza A(H1N1)pdm09 and A(H3N2) variants confer reduced inhibition to zanamivir. These variants were not present in original clinical specimens but were exclusively selected after passage in MDCK cell line. Results highlight the need for caution when interpreting results from isolates and reaffirms the need to sequence virus from original clinical specimens... read more
Influenza virus surveillance in Argentina during the 2012 season: antigenic characterisation, genetic analysis and antiviral susceptibility
Surveillance of circulating influenza A and B viruses during the 2012 influenza season in Argentina revealed that majority of the A(H1N1)pdm09 viruses were antigenically related to vaccine strain, A/California/07/2009. All influenza A(H3N2) viruses fall into group 3C and majority of the B viruses were of B/Victoria-lineages. All viruses were sensitive to oseltamivir and zanamivir except for one variant (neuraminidase mutation, N295S) conferring highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir... read more
Clinical reports
Phase 1 clinical trials of DAS181, an inhaled sialidase, in healthy adults
Phase 1 clinical trial of DAS181 (Fludase) showed no adverse events in healthy adults participants given 20mg DAS181 up to 3 days. However, administration of 20mg DAS181 for more than 7 days was associated with adverse respiratory events... read more
Investigational antivirals
A broadly neutralising human monoclonal antibody is effective against H7N9
Using a lethal mice model of influenza A(H7N9) infection, human antibody, VIS410, were shown to improves survival of mice (DBA lethal model). In combination with oseltamivir, VIS410 treatment reduced lung viral load and lung cytokines responses in H7N9 infected mice (sub-lethal)... read more
Review articles
The future of antivirals: broad-spectrum inhibitors
A review on different class of antiviral molecules and their potential as the next broad-spectrum inhibitor of viral infection... read more
Commentaries
Controversies in medicine: the rise and fall of the challenge to Tamiflu
An article written by A/Professor Jodie McVernon regarding the controversies surrounding the efficacy of Tamiflu to treat influenza infection... read more
Analysis
Influenza antiviral expenditure and outpatient prescriptions in the United States, 2003-2012
Influenza antiviral expenditure accounted for $3.74 billion to the USA health care system from 2003 to 2012, with one-third of the expenditure occurring in 2009 and prescription were mainly dispensed from community pharmacies... read more
The accuracy and timeliness of neuraminidase inhibitor dispensing data for predicting laboratory-confirmed influenza
Neuraminidase inhibitor dispensing data (NIDD) collected between 2010-2013 in Quebec, Canada, significantly correlate with overall influenza activity and to a lesser extent, influenza-like illness in emergency department (ILI ED). Additionally, NIDD and ILI ED were found to be significant predictors of laboratory-confirmed influenza... read more
Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an IPD meta-analysis
Meta-analysis of individual participant data on influenza-related pneumonia (IRP) revealed that early treatment (<2 days from symptoms onset) with neuraminidase inhibitor (NAI) was able to significantly reduce the likelihood of IRP compared to late treatment cohort. However, NAI treatment was found to increase the likelihood of IRP compared to no treatment... read more
Q3 / 2015
Antiviral resistance
Treatment of resistant influenza virus infection in a hospitalized patient with cystic fibrosis with DAS181, a host-directed antiviral
DAS181 treatment of a patient with persistent oseltamivir-resistant influenza A(H1N1)pdm09 infection successfully resolved infection after 5 days of therapy... read more
Outcomes and susceptibility to neuraminidase inhibitors in individuals infected with different influenza B lineages: The influenza resistance information study
Analysis of influenza B infections (n=914 patients) from the prospective influenza resistance information study (IRIS) revealed no correlation between B virus lineages to either disease outcome or antiviral susceptibility... read more
Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013-2014
98% of circulating viruses (n=10,641) tested during the 2013-2014 period were sensitive to all four neuraminidase inhibitors (oseltamivir, zanamivir, peramivir and laninamivir) with community clusters of A(H1N1)pdm09 viruses with neuraminidase H275Y mutation detected in Japan, China and USA within this period... read more
Structure of influenza A polymerase bound to the viral RNA promotor
Atomic structure of influenza A and B polymerases reveals their unique role in viral replication and the functional relationship of the difference components within the polymerase complex... read more
Clinical reports
Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir (II): a paediatric drug use investigation
The analysis of paediatric treatment with peramivir from 2010 to 2012 (n=1199) demonstrated safety profile of peramivir used in paediatric patients... read more
Investigational antivirals
A potent anti-influenza compound blocks fusion through stabilisation of the prefusion conformation of the hemagglutinin protein
Cell-based high-throughput screening identified a molecule, S20, as a novel antiviral molecule with potent antiviral activity against specific subtype of influenza A viruses [A(H1N1)pdm09 and A(H5N1) but not A(H3N2)]. Mechanisms of action were via the stabilisation of the prefusion conformation of HA preventing the process of viral-host membrane fusion... read more
The Tie2 agonist Vasculotide rescues mice from influenza virus infection
The administration of vasculotide (a synthetic Ang 1 mimetic with vessel stabilising properties) reduced mortality and morbidity in a mouse model of lethal influenza infection. The beneficial effect of vasculotide is specific to improving lung endothelial integrity without affecting the innate immunity response of the host... read more
Co-administration of Hedera helix L. extract enabled mice to overcome insufficient protection against influenza A/PR/8 virus infection under suboptimal treatment with oseltamivir
Administration of Ivy extract fraction containing hedrasaponin F in a mice model of suboptimal oseltamivir treatment induces synergistic antiviral effect in protecting mice from PR8 infection... read more
Mechanistic studies of antivirals
Intravenous peramivir inhibits viral replication, and leads to bacterial clearance and prevention of mortality during murine bacterial co-infection caused by influenza A(H1N1)pdm09 virus and Streptococcus pneumonia
Peramivir has demonstrated a better treatment efficacy to oseltamivir by significantly reducing viral and bacterial titre, and increases the survival rate in a mouse model of bacterial co-infection... read more
Oseltamivir Prophylaxis Reduces Inflammation and Facilitates Establishment of Cross-Strain Protective T Cell Memory to Influenza Viruses
Oseltamivir prophylaxis in mjice reduces CD8+ T cell population without affecting normal recall responses and conferred protection on oseltamivir-treated mice against subsequent heterologous secondary infection... read more
Evaluation of a dry powder delivery system for laninamivir in a ferret model of influenza infection
Powdered influenza antivirals such as laninamivir can be easily administered into a ferret model of influenza infection by using a dry powder insufflator... read more
Targeting importin-α7 as a therapeutic approach against pandemic influenza viruses
Viral resistance generated against cellular host proteins that are essential for viral replication can increase virulence of variants... read more
Arginine-rich histones have strong antiviral activity for influenza A viruses
In vitro viral neutralising assay showed that arginine rich histone, H3 and H4, have a higher antiviral activity against influenza A viruses compared to lysine rich histone, H2A and H2B suggesting a potential role of histone in innate immune response against influenza A viruses... read more
Oseltamivir inhibits influenza virus replication and transmission following ocular-only aerosol inoculation of ferrets
Oral administration of oseltamivir can effectively reduce disease pathogenesis and clinical symptoms in ferrets infected with influenza virus via the ocular route... read more
The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium
The primary culture of human tracheal epithelial cells was used to evaluate the inhibitory effect of neuraminidase inhibitors (NAIs) on influenza A viral replication. In the cell culture system, NAIs (oseltamivir, zanamivir, laninamivir or peramivir) were found to inhibit the replication of influenza A(H1N1)pdm09 in association with lower levels of IL-6 and TNFα in the infected cell supernatant... read more
Review articles
The safety of oseltamivir in pregnancy: an updated review of post-marketing data
A review using the Roche Global Safety Databases revealed that exposure to oseltamivir during pregnancy has minimal effect on pregnancy or foetal outcome... read more
Broad-spectrum antivirals against viral fusion
A review discussing the mechanisms of viral host fusion and how this process can be used as an antiviral target... read more
Q2 / 2015
Antiviral resistance
Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013-2014
98% of circulating viruses(n=10,641)tested during the 2013-2014 period were sensitive to all four neuraminidase inhibitors (oseltamivir, zanamivir, peramivir and laninamivir) with community clusters of A(H1N1)pdm09 viruses with neuraminidase H275Y mutation detected in Japan, China and USA within this period... read more
Molecular surveillance of antiviral drug resistance influenza A/H3N2 virus in Singapore, 2009-2013
No detection of known neuraminidase inhibitor-resistant mutations in the neuraminidase (NA) of 229 influenza A(H3N2). All 241 MP genes contained adamantane resistant genotype, S31N... read more
Profiling and characterization influenza virus N1 strains potentially resistant multiple neuraminidase inhibitors
Recombinant A(H1N1)pdm09 viruses with a single neuraminidase (NA) mutation at E119D or double mutations at E119D-H274Y retain replication fitness and are transmissible in vivo. In contrast, recombinant H5N1 viruses with single NA mutation at E119D or double mutations at positions E119A/D/G-H274Y shows reduced inhibition by NAIs but have impaired replicative fitness... read more
Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses
The application of a ferret model of influenza infection to determine the susceptibility of wild-type and A(H7N9) variants with neuraminidase mutation (R292K or E119V) to oseltamivir treatment... read more
Influenza viruses with B/Yamagata and B/Victoria-like neuraminidases are differentially affected by mutations that alter antiviral susceptibility
Neuraminidase residue mutations at E105K, P139S and G140R in influenza B viruses conferred highly reduced inhibition to neuraminidase inhibitors with mutations in B/Victoria-like neuraminidase having a greater effect than B/Yamagata-like lineages... read more
Competitive fitness of influenza B viruses with neuraminidase inhibitor-resistant substitutions in a coinfection model of the human airway epithelium
The application of normal human bronchial epithelial cell assay to determine replicative fitness of neuraminidase-resistant influenza B viruses revealed E119A or H274Y as the mutations of importance... read more
Application of a seven-target pyrosequencing assay to improve the detection of neuraminidase inhibitor-resistant Influenza A(H3N2) viruses
The application of a 7-target pyrosequencing assay to detect neuraminidase inhibitor-resistant influenza A(H3N2) viruses with mutations at E119V, R292K, N294S, Q136K, I222V, and deletions within residues 245 to 248 and residues 247 to 250... read more
Influenza A viruses of swine circulating in the United States during 2009-2014 are susceptible to neuraminidase inhibitors but show lineage-dependent resistance to adamantanes
Influenza A viruses of swine (n=105) isolated from 2009 to 2011 are susceptible to oseltamivir, zanamivir and peramivir. The frequency of amantadine-resistant markers were high among swine influenza viruses from USA and distribution was M-lineage-dependant... read more
Clinical reports
MediVector completes patient enrolment in two phase 3 studies of Favipiravir for influenza
2021 patients from America, Europe, Australia, New Zealand and South Africa have been successfully enrolled into two phase-3 randomized, double-blind, placebo-controlled trials of Favipiravir (T-705) in adults with uncomplicated influenza... read more
Effects of oseltamivir treatment of index patients with influenza on secondary household illness in an urban setting in Bangladesh: secondary analysis of a randomised, placebo-controlled trial
Further analysis (Fry et al, 2014) on the efficacy of a double-blind oseltamivir efficacy trial to reduce secondary household illness shows modest reduction of secondary influenza in households... read more
Computational modelling
Estimating the United States demands for influenza antivirals and the effect on severe influenza disease during a potential pandemic
Modelling of antiviral demand across different hypothetical pandemic scenarios revealed that the total antiviral stockpile in the USA (at the time of the modelling) will meet treatment needs and will reduce death and hospitalisation... read more
Investigational antivirals
Screening and identification of inhibitors against influenza A Virus from a US drug collection of 1280 drugs
Screening of 1280 compounds for anti-influenza activity revealed 9 novel drug candidates for the treatment of influenza virus infection... read more
Mechanistic studies of antivirals
Visualizing real-time influenza virus infection, transmission and protection in ferrets
Real-time bioluminescent imaging of influenza virus encoding NanoLuc luciferase provides a novel tool to visualise influenza infection in ferrets... read more
A novel video tracking method to evaluate the effect of influenza infection and antiviral treatment on ferret activity
A more sensitive and unbiased method to measure ‘lethargy’ in a ferret model of influenza infection revealed oseltamivir treatment ameliorates the reduction in activity post-influenza infection... read more
Influenza A virus protein PA-X contributes viral growth and suppression of the host antiviral and immune responses
In vitro and in vivo model of influenza infection revealed viral protein, PA-X, in seasonal influenza A virus plays a pathogenic role in dampening host antiviral responses such as the expression of anti-inflammatory proteins (IFNβ) and the production of influenza-specific antibodies... read more
Review articles
Influenza: the rational use of oseltamivir
Commentaries and advice on the rational usage of oseltamivir in light of the meta-analysis study on the efficacy of oseltamivir for the treatment of influenza-like illness and confirmed influenza infection by Joanna Dobson and colleagues... read more
Q1 / 2015
Antiviral resistance
In vitro neuraminidase inhibitory activity of four neuraminidase inhibitors against clinical isolates of influenza virus in the Japanese 2012-2013 season
All clinical isolates (n = 329) remain susceptible to all four NAIs (oseltamivir, zanamivir, laninamivir, peramivir)... read more
Neuraminidase mutations conferring resistance to laninamivir lead to faster drug binding and dissociation
D197E mutation in influenza B and an E119G in an N9 neuraminidase resulted in faster binding and dissociation of the drugs from neuraminidase... read more
Clinical reports
Severe immune thrombocytopenia possibly elicited by the anti-influenza viral again peramivir
An influenza A viral infected patient with pre-existing condition of lower platelet counts developed clinically diagnosed immune thrombocytopenia post treatment with peramivir... read more
Investigational antivirals
Sialic acid-binding protein Sp2CBMTD protects mice against lethal challenge with the emerging A(H7N9) influenza virus
Sp2CBMTD administration protected mice from H7N9 infections in a lethal challenged model. Sp2CBMTD induces pulmonary expression of proinflammatory cytokines and chemokines and recruited neutrophils to the respiratory tract before H7N9 infection resulting in lower pulmonary inflammation and more rapid viral clearance... read more
Preclinical activity of VX-787, a first in class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit
VX-787, novel inhibitor that blocks PB2 cap-snatching activity of the polymerase complex inhibits influenza A viruses replication in vitro and protects mice from infections in a lethal challenge model... read more
Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro
In cell culture based yield-reduction assay, the combination of nitazoxanide and oseltamivir treatment has shown a synergistic effect against influenza A (H1N1) and avian influenza (H5N9). Similar results were obtained with nitazoxanide was administered in combination with zanamivir against influenza A (H1N1)... read more
Inhalable dry powder formulations of siRNA and pH responsive peptides with antiviral activity against H1N1 influenza virus
Complexes of pH responsive peptides formulated into dry powder were highly effective in delivering antiviral siRNA showing significant inhibition of viral replication upon influenza A(H1N1) viral challenge in vitro ... read more
Chimerization and characterization of a monoclonal antibody with potent neutralizing activity across multiple influenza A H5N1 clades
MAb 9F4 with mouse-human chimeric (xi) IgG1 or IgA have high degree of binding and neutralising activity against H5N1 clade 2.3.4... read more
Structure of influenza A polymerase bound the the viral RNA promotor
Atomic structure of influenza A and B polymerases reveals their unique role in viral replication and the functional relationship of the different components within the polymerase complex... read more
Structural insight into cap-snatching and RNA synthesis by influenza polymerase
Atomic structure of influenza A and B polymerases provides mechanistic view on the RNA synthesis process in influenza virus replication... read more
Structure of influenza virus N7: the last piece of the neuraminidase "jigsaw" puzzle
Atomic structure of neuraminidase subtypes, N6 and N7 revealed new structural insights... read more
Influenza virus-host interactome screen as a platform for antiviral drug development
Mapping of influenza virus-host protein interaction network revealed that Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets... read more
Phenyl-substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: inhibitors of influenza A endonuclease
Aza analogues of phenyl substituted 3-hydroxypyridin-2(1H)-one compound were synthesized and evaluated on their ability to inhibit the endonuclease activity of influenza polymerases in vitro... read more
Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of influenza A virus
The evaluation of derivatives of naproxen; naproxen A and C0 as potential antivirals to block NP function... read more
Mechanisitic studies of antivirals
The administration of oseltamivir results in reduced effector and memory CD8+ T cell responses to influenza and affects protective immunity
In mice, oseltamivir treatment significantly decreased effector memory and central memory CD8+T cells which affect the adaptive immune response in heterogenous secondary influenza infection by decreasing CD8+T cell recall responses, increased mobidity and delayed viral clearance... read more
Review articles
Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials
Meta-analysis of individual patients data (n=4328; published and unpublished Roche-sponsored randomised placebo-controlled, double-blind oseltamivir trials in adults) showed that oseltamivir treatment shorten time to symptoms alleviation, lower hospital admission but increases the occurrence of side-effects... read more
Commentaries in NATURE (30th Jan 2015): Analysis of trial data revives flu-drug row... read more
Use of neuraminidase inhibitors for rapid containment of influenza: a systematic review and meta-analysis of individual and household transmission studies
This systematic review utilised the approach of combining data from both pre- and post-exposure prophylaxis studies (including observational studies) and shown that both oseltamivir and zanamivir are effective for prophylaxis of individuals and households irrespective of treatment of index case... read more
Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients
A multicentre cohort study of individual patient data (n=2649) of laboratory-confirmed seasonal and pandemic influenza virus infection from three Asian countries analysed in multivariate models found that NAI treatment best improved survival of hospitalised patients when administered within 2 days of illenss and systemic corticosteroid use affects clinical outcomes... read more
Prepared by: Dr Ding Oh (WHO Collaborating Centre for Influenza, Melbourne)