isirv

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) 

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