Emerging treatments

Intravenous zanamivir

The European Medicines Agency has approved an intravenous formulation of zanamivir for the treatment of complicated and potentially life-threatening influenza in children ≥6 months of age and adults. The indication is for patients in whom other treatments for influenza, including the inhaled formulation of zanamivir, are unsuitable, and/or the patient’s influenza virus is known or suspected to be resistant to other treatments. In the US, the intravenous formulation is only available through a compassionate use program or enrolment in a clinical trial.

Needle-free technology

Needle-free jet injection for administration of influenza vaccine might avoid the issue of needle phobia and the risk of needle-stick injury.[138]

Combination antiviral therapy

Combining two antivirals that act on different aspects of the viral lifecycle may offer benefits over single agents alone, although options are limited by the small number of antivirals available.[139] Studies in mice demonstrate therapeutic synergism when oseltamivir is combined with amantadine,[140] or with favipiravir.[141] An in vitro study suggests that amantadine and oseltamivir combination therapy may reduce the emergence of drug-resistant influenza A virus.[142] However, caution may be warranted, as a study of combined oseltamivir-zanamivir found it to be less effective than oseltamivir alone.[143]

Recombinant sialidase fusion protein DAS181

Currently under development, this agent targets host respiratory cells rather than the influenza virus itself, specifically the sialic acid receptor used by the influenza virus to attach to the airway epithelium.[139] DAS181 is a sialidase fusion protein consisting of the sialidase catalytic domain of Actinomyces viscosus, fused with a cell surface anchoring sequence. The inhaled fusion protein removes the receptors for influenza attachment on the respiratory epithelium. Studies to date have shown in vitro effectiveness against both influenza A and B,[144] and in vitro and in vivo effectiveness against human parainfluenza viruses.[145]

Cyanovirin-N

Cyanovirin-N is a protein that interacts with the haemagglutinin cell surface protein of both influenza A and influenza B viruses in vitro.[135] It confers antiviral properties by blocking viral entry,[139] but further development has been hindered by problems relating to immunogenicity and cytotoxicity. An initial study with a novel PEGylated cyanovirin-N derivative has; however, yielded positive results.[146]

Short-interfering RNAs

Although currently only studied in mice, short-interfering RNAs specific for conserved regions of the influenza gene reduced viral replication when administered intravenously. More recently, RNA interference has been shown to inhibit influenza virus infection in co-operation with interferon gamma.[147]

Favipiravir

A substituted pyrazine that inhibits virus RNA polymerase.[139] In vitro and in vivo studies have shown inhibition of viral replication and activity against viruses that are resistant to both amantadines and neuraminidase inhibitors. Favipiravir blocks the replication of many strains of influenza virus, including the H7N9 avian virus.[148] In addition, it is active against many arena-, bunya-, flavi-, alpha-, picorna-, and noroviruses.

Viramidine

A prodrug of ribavirin, viramidine targets the cellular enzyme IMP dehydrogenase, which is involved in viral RNA synthesis.[139] It is active against seasonal and H5N1 influenza A viruses,[149] and can be administered intravenously, orally, or by aerosol.

DNA vaccine

A trivalent DNA vaccine has been developed with three plasmids expressing haemagglutinin from different seasonal influenza virus strains. It demonstrated protection against influenza and had a good safety profile.[150] In a phase I clinical trial, adjuvanted-monovalent H5 DNA vaccines were well tolerated and induced haemagglutination inhibition response rates similar to that of inactivated protein-based H5 vaccines.[151] The results suggest that adjuvanted DNA vaccines with rapid vaccine production could be useful for pandemic control.

VIS410

VIS410 is a monoclonal antibody that has been designed to target all known strains of influenza A. It is directed against a specific epitope on haemagglutinin, a surface protein used for cell binding and entry, and is designed to terminate the influenza virus replication cycle. It is is being developed to treat hospitalised patients with influenza A and is currently in phase 2 trials.

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