News
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Q4 / 2016
Antiviral resistance
The I427T neuraminidase (NA) substitution located outside the NA active site of an influenza A(H1N1) pdm09 variant with reduced susceptibility to NA inhibitors alters NA properties and impairs viral fitness
Using recombinant viruses, the I427T mutation in the neuraminidase of influenza A(H1N1)pdm09 was found to confer resistance to oseltamivir, zanamivir, peramivir and laninamivir. However, in vitro and in vivo replication studies of the variant revealed a compromised viral fitness…read more
Biological fitness and natural selection of amantadine resistant variants of avian influenza H5N1 viruses
Using recombinant viruses, amantadine resistance mutation, S31N, of the M2 protein in avian influenza A(H5N1) virus was found to be genetically stable with the S31N variants having a higher replication fitness compared to wild-type viruses in vitro…read more
Investigational antivirals
Antiviral efficacy of Verdinexor in vivo in two animal models of influenza A virus Infection
Verdinexor, an inhibitor blocking the nuclear export of viral ribonucleoprotein complexes, has been shown to exhibit therapeutic effectiveness in inhibiting viral replication and inflammatory immune responses in both mouse and ferret model of influenza infection… read more
Rapid control of pandemic H1N1 influenza by targeting NKT-cells
Targeting the natural killer T cells with agonist compound, α-GalCer in the swine (piglet) model of influenza infection can ameliorated disease symptoms, reduce viral replication in both the upper and lower respiratory tracts and prevent infection associated lung pathology. Improvement in symptoms were only observed when the α-GalCer was administered intranasally …read more
Review articles
Anti-influenza virus effects of catechins: A molecular and clinical review
A review on the antiviral properties of catechins, a class of polyphenolic flavonoids, against influenza infection…read more
The pharmacological management of severe influenza infection - 'existing and emerging therapies'
A review summarising the current and emerging antiviral therapies for the treatment of severe influenza infection…read more
Q3 / 2016
Antiviral resistance
The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models
Recombinant A(H1N1)pdm09 variant viruses with the E119D and E119D+H275Y neuraminidase mutations displayed lower in vitro and in vivo replication fitness compared to wild-type virus, and E119D mutation was genetically unstable… read more
Competitive fitness of influenza B viruses possessing E119A and H274Y neuraminidase inhibitor resistance-associated substitutions in ferrets
Recombinant influenza B viruses with the E119A neuraminidase (NA) mutation showed reduced replication fitness whereas variant viruses with the H274Y NA mutation showed comparable replication fitness to wild-type (WT) recombinant virus. Both E119A and H274Y variants did not display replication advantage over WT recombinant viruses in ferrets… read more
Impact on antiviral resistance of E119V, I222L and R292K substitutions in influenza A viruses bearing a group 2 neuraminidase (N2, N3, N6, N7 and N9)
All group 2 neuraminidase (N2, N3, N6, N7 and N9) with the resistant neuraminidase mutations, E119V, I222L and R292K can confer reduced inhibition by oseltamivir… read more
Antiviral susceptibility of influenza viruses isolated from patients pre- and post-administration of favipiravir
Using a cell based screening assay, it was found that favipiravir treatment in influenza infected patients (n=57) did not result in drug resistance… read more
Clinical reports
Pharmacokinetics of oseltamivir in infants under the age of 1 year
A prospective, uncontrolled, open label study of the pharmacokinetics of oseltamivir in influenza-infected children under 1 year of age (n=4) showed that the dose range of 2.35-3mg/kg/dose are well-tolerated and resulted in a target oseltamivir carboxylate plasma concentration in excess of the proposed 12-hour target exposure in children of this age… read more
Investigational antivirals
Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans
Mycophenolic acid, an immunosuppressant drug, was found to have inhibitory effect on the in vitro replication of different types and subtypes of influenza viruses, such as A(H1N1)pdm09, A(H3N2), A(H7N9) and B viruses… read more
The superiority of IFN-lambda as a therapeutic candidate to control acute influenza viral lung infection
The administration of Interferon-lamda 2/3 protein in a mouse model of influenza infection significantly reduced the replication of influenza A(H1N1) and A(H5N1) in the lungs and induced an up-regulation of interferon-stimulated genes as an innate immune responses towards the infection… read more
IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment
In vitro assessment of the treatment effectiveness of interferon-lamda revealed their ability to exert an inhibitory effect on both influenza virus replication and the stimulation of immune cells, to prevent immune-mediated lung damage caused by immune-stimulating type I interferon, such as interferon-gamma… read more
Human monoclonal antibody 81.39a effectively neutralizes emerging influenza A viruses of group 1 and 2 hemagglutinins
Human IgG1 monoclonal antibody 81.39a exerts broad neutralising activity against influenza A virus of different hemagglutinin subtypes in vitro. In vivo assessment using mice and ferret model of influenza infection showed that the monoclonal antibodies were able to protect and ameliorate disease severity of influenza infection… read more
A novel endonuclease inhibitor exhibits broad-spectrum anti-influenza virus activity in vitro
Putative inhibitor of influenza acid polymerase, RO-7, exhibits low toxicity and broad inhibitory effect on influenza A(H1N1), A(H1N1)pdm09, A(H3N2), B viruses (Yamagata and Victoria-lineages), A(H5N1), A(H7N9) and A(H9N2) in vitro… read more
Computational modelling
Oseltamivir PK/PD modelling and simulation to evaluate treatment strategies against influenza-pneumonia coinfection
Mathematical modelling of influenza-streptococcus pneumonia co-infection with oseltamivir treatment showed that the recommended treatment regimen at 75 mg, twice daily for 5 days in human may yield 47% antiviral efficacy and 9% antibacterial efficacy, and 49% antiviral efficacy and 16% antibacterial efficacy when the dose increases to 150 mg. The model suggests that decreasing oseltamivir intake to once a day or increasing dosing duration to 10 days do not improve both antiviral or antibacterial efficacy… read more
Review articles
Current and novel antiviral strategies for influenza infection
A review summarising the landscape of currently licensed antiviral and promising investigational antiviral compounds for influenza infection… read more
Antiviral therapies on the horizon for influenza
A review on the various investigational antivirals (host cell-directed metabolic inhibitors, broad neutralising antibodies, viral polymerase inhibitors etc.) at different stages of development and/or clinical trial… read more
The influenza virus polymerase complex: an update on its structure, functions, and significance for antiviral drug design
A review on the progress in the understanding of influenza virus polymerase complex and the implication in the design of novel antiviral drugs… read more
Q2 / 2016
Antiviral resistance
Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor
Using direct mutagenesis to introduce point mutations in the endonuclease domains, four mutations (T20A, I79L, F105S, and E119D) conferring resistance to endonuclease inhibitor, L-74200, were identified…read more
Clinical reports
Rising oseltamivir use among hospitalized children in a post pandemic era
A high percentage of paediatrics inpatients (82%) with PCR-confirmed influenza were treated with oseltamivir in Children’s Hospital Colorado, USA from 2010 to 2014…read more
A phase 1 randomized, double-blind, placebo-controlled, crossover trial of DAS181 (Fludase®) in adult subjects with well-controlled asthma
A phase I clinical trial of patients with underlying reactive airway disease reported that the usage of antiviral drug, DAS181 can increase the association of respiratory events (dyspnea, dry cough, chest discomfort etc.) following usage....read more
Host antiviral immunity
Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease
In mice model of influenza infection, it was elucidated that the increased susceptibility to influenza infection in a situation of weakened antiviral immunity is due to an elevated bacterial burden, caspase-1/11 and neutrophils-mediated tissue damage rather than viral load or MyD88-dependent signalling pathway…read more
Investigational antivirals
Direct administration in the respiratory tract improves efficacy of broadly neutralizing anti-influenza virus monoclonal antibodies
Broadly neutralizing anti-hemagglutinin stalk monoclonal antibodies when administered intranasally or via aerosol in a mouse model of influenza infection were more effective in reducing disease associated mortality compared to systemic administration …read more
Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
The neuraminidases (NanA and NanB) of Streptococcus Pneumoniae were able to support influenza viral replication and the activity of this bacterial neuraminidase can be inhibited by selected neuraminidase inhibitors such as oseltamivir, DANA, katsumadain A and artocarpin…read more
Selection of Therapeutic H5N1 Monoclonal Antibodies Following IgVH Repertoire Analysis in Mice
The screening of IgVH repertoires of mice immunized with recombinant H5N1 hemagglutinin by next generation sequencing identified two monoclonal antibodies (from an initial 35 IgVH genes) which have therapeutic and prophylactic activity in a mouse model of influenza infection…read more
Hemagglutinin-targeting Artificial MicroRNAs Expressed by Adenovirus Protect Mice From Different Clades of H5N1 Infection
Artificial microRNA (HA-1405) against hemagglutinin gene of H5N1 virus reduces replication of H5N1 viruses in vitro. The administration of HA-1405 reduces clinical symptoms and viral load in mice challenged with different H5N1 clades….read more
Computational modelling
Impact of the H275Y and I223V Mutations in the Neuraminidase of the 2009 Pandemic Influenza Virus In Vitro and Evaluating Experimental Reproducibility
Mathematical modelling technique were used to compare the replication fitness of influenza A(H1N1)pdm09 with H275Y or I223V NA mutations to their wild-type counterpart. The modelling data suggest I223V mutants has reduced fitness compared to virus with or without H275Y NA mutation…read more
Review articles
The host immune response in respiratory virus infection: balancing virus clearance and immunopathology
A review highlighting the double-edge nature of the host immune system in response to a viral infection …read more
Oseltamivir Treatment for Children with Influenza-Like Illness in China: A Cost-Effectiveness Analysis
A cost effective analysis of the prescription of oseltamivir to children with influenza –like illness (ILI) in China revealed that empiric oseltamivir treatment in children with ILI is the most cost effective compared to treatment after post-rapid influenza diagnostic test or no treatment…read more
Conference report
4th ISIRV antiviral group conference:
Novel antiviral therapies for influenza and other respiratory viruses
A report summarising the 4th International Society for Influenza and other Respiratory Virus Disease (ISIRV) antiviral group conference… read more
Commentaries
Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza
An article written by A/Prof Aeron Hurt and Prof. Heath Kelly on the ongoing debate surrounding the use of oseltamivir for influenza…read more
Q1 / 2016
Antiviral resistance
Clinical reports
Investigational antivirals
Immuno-modulating properties of saliphenylhalamide, SNS-032, obatoclax, and gemcitabine
Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry
Quercetin (flavonoids) inhibit the replication of influenza A virus by interacting with the HA2 subunit…read more
Host antiviral immunity
Review articles
Peramivir: an intravenous neuraminidase inhibitor
A review on the development process and the safety and treatment efficacy of peramivir …read more
Using the ferret as an animal model for investigating influenza antiviral effectiveness
A review discussing the current progress and challenges in using the ferret model to measure antiviral effectiveness…read more
Prepared by: Dr Ding Oh (WHO Collaborating Centre for Influenza, Melbourne)
News
2017 | 2016 | 2015 | 2014 | 2013 | 2012 | 2011 | ||||||||
Q2 & Q3 / 2017
Antiviral resistance
Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015-2016
More than 99% of circulating viruses (n=14,330) tested during the 2015-2016 period were sensitive to all four neuraminidase inhibitors (oseltamivir, zanamivir, peramivir and laninamivir) with 0.8% showing reduced inhibition by at least one neuraminidase inhibitor. The most common neuraminidase amino acid substitution in A(H1N1)pdm09 virus is still H275Y. Four influenza B variants (B/Victoria-lineage) harbouring NA amino acid substitutions at H134N or G104E were found to confer resistance to NAIs. Based on these findings, neuraminidase inhibitors continue to be considered as an appropriate drug option for influenza treatment… read more
Monitoring influenza virus susceptibility to oseltamivir using a new rapid assay, iART
The influenza Antiviral Resistance Test (iART), which utilises enzyme substrate for the measurement of neuraminidase activity for the rapid detection of resistance to oseltamivir, was tested on 149 clinical isolates and the results indicate that it is a valuable tool for resistance surveillance… read more
Clinical reports
Safety and efficacy of MHAA4549A, a broadly neutralizing monoclonal antibody, in a human influenza A challenge model: A Phase 2 randomized trial
In a randomised, double-blind, placebo-controlled human challenge model, the treatment of subjects with a human monoclonal antibody, MHAA4549A, at different concentrations (400, 1200 or 3600 mg) between 24 to 36 hours post-infection with influenza A(H3N2) virus, was well-tolerated and significantly reduced virus shedding compared to placebo-treated arm… read more
Safety and efficacy of anti-influenza drugs, intravenous peramivir against influenza virus infection in elderly patients with underlying disease
A retrospective study (2012 to 2015) on the safety and efficacy of peramivir in elderly patients (≥65 years of age; n=38) hospitalised with influenza showed that 15.8% (7/38) of patients experienced adverse events and median time to fever resolution for all patients was 31.5 hours… read more
Computer modelling
Modelling the emergence of influenza drug resistance: The roles of surface proteins, the immune response and antiviral mechanisms
This study modelled the combined effect of an antiviral mechanism, the immune response and the viral surface proteins on the emergence of drug-resistant influenza variants … read more
Investigational antivirals
Anti-inflammatory effects of rosmarinic acid-4-O-β-D-glucoside in reducing acute lung injury in mice infected with influenza virus
Dicaffeoyl phenolic compound, Rosmarinic acid-4-O-β-D-glucoside (RAG), has been shown to exhibit antiviral properties in a mouse model of influenza A(H1N1) virus infection. Administration of RAG decreased infection-associated mortality, improved clinical signs of illness, such as body weight loss, and downregulated anti-inflammatory cytokines and cellular infiltration into the lungs of infected mice… read more
An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody protects mice from morbidity without interfering with the development of protective immunity to subsequent homologous challenge
Intranasal administration of anti-neuraminidase murine monoclonal antibody (3c10-3) in mice before (24 hours) and after (24, 48 or 72 hours) lethal challenge with influenza A/Anhui/1/2013 (H7N9) viruses reduced disease-associated mortality. Mechanistic studies showed that 3c10-3 binds near the active sites of neuraminidase to inhibit enzymatic activity and restrict the cell-to-cell spread of the virus in cultured cells… read more
Pathogenicity and peramivir efficacy in immunocompromised murine models of influenza B virus infection
An immunocompromised mouse model of influenza B infection was established by infecting genetically-modified immunocompromised mice (SCID) with influenza B/Brisbane/60/2008 (B/Victoria-lineage). Infected mice demonstrated prolonged viral shedding, severe lung pathology and immunological responses to viral infection. In this model, the administration of multiple doses of peramivir (2 and 4 doses) reduced the mortality-associated with infection but had little to no effect on viral clearance… read more
Inhibition of highly pathogenic avian influenza (HPAI) virus by a peptide derived from vFLIP through its direct destabilization of viruses
TAT-Kα2 peptides exhibit antiviral activity against influenza A viruses in vitro and were able to protect mice from lethal challenge with influenza A(H5N1) or A(H1N1) viruses by the proposed mechanism of destabilising viral membranes… read more
The hemagglutinin A stem antibody MEDI8852 prevents and controls disease and limits transmission of pandemic influenza viruses
MEDI8852, a monoclonal antibody against hemagglutinin A stem antibody, ameliorates influenza A(H5N1) and A(H7N9) infection in both mice and ferrets when given either as a prophylactic or therapeutic dose. In particular, MEDI8852 was able to prevent ferrets from becoming infected via airborne transmission of influenza A(H1N1)pdm09 viruses… read more
Discovery of dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, as a broad-spectrum antiviral against both influenza A and B viruses
Dapivirine, an FDA-approved nonnucleosides reverse transcriptase inhibitor for HIV, has been shown to exhibit in vitro antiviral activity against influenza A and B viruses by inhibiting nuclear entry of viral nucleoproteins early in the viral replication cycle. In addition, in vitro serial passaging of viruses in the presence of increasing Dapivirine did not select for resistant variants… read more
Review articles
Influenza A virus nucleoprotein: A highly conserved multi-functional viral protein as a hot antiviral drug target
A review on the development and mechanisms of action of drugs targeting influenza A virus nucleoprotein for viral inhibition… read more
Prepared by: Dr. Ding Oh (Department of Microbiology and Immunology, National University of Singapore)
Q1 / 2017
Antiviral resistance
Selection of multi-drug resistant influenza A and B viruses under zanamivir pressure and their replication fitness in ferrets
The neuraminidase mutations, E119D in influenza A(H1N1)pdm09 and E117D in influenza B viruses which conferred resistance to zanamivir, oseltamivir, peramivir and laninamivir were found to arise under zanamivir pressure. The E119D variants were genetically unstable and the assessment of the replication fitness in the ferret model of influenza infection show that both E119D and E117D variants have reduced viral fitness…read more
The I427T neuraminidase (NA) substitution, located outside the NA active site of an influenza A(H1N1)pdm09 variant with reduced susceptibility to NA inhibitors, alters NA properties and impairs viral fitness
Using reverse genetics, recombinant viruses harbouring the NA mutations, I427T/Q313R were found to be resistant to multiple neuraminidase inhibitors (oseltamivir, zanamivir, peramivir and laninamivir). However, these mutations were associated with a reduction in NA activity and compromised replication fitness in vitro and in vivo…read more
Clinical reports
Pharmacokinetics of oral and intravenous oseltamivir treatment of severe influenza B virus infection requiring organ replacement therapy
Pharmacokinetics analysis of oseltamivir therapy in two patients with severe influenza B infection and multi-organ failure showed that a higher dosage of 100 mg oseltamivir when given intravenously achieved a stable systemic concentration compared to the standard oral dose of 75 mg or 40 mg. Additionally, the higher dosage of oseltamivir (100 mg) decreases viral shedding and improves clinical symptoms of the treated patient…read more
Investigational antivirals
Inhibition of influenza A virus infection by ginsenosides
Using both in vitro and in vivo model of influenza infection, ginseng-derived compound in particular, Rb1 ginsenoside displayed antiviral properties by interfering with viral binding…read more
Review articles
Antiviral therapy for respiratory viral infections in immunocompromised patients
A review on the existing and investigational antivirals used in the treatment of respiratory viral infection in immunocompromised patients…read more
Investigational hemagglutinin-targeted influenza virus inhibitors
A review summarising antivirals which target influenza hemagglutinin protein for the treatment of influenza in the clinics…read more
Prepared by: Dr. Ding Oh (Department of Microbiology and Immunology, National University of Singapore)