Influenza infection

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.[147]

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.[148] Studies in mice demonstrate therapeutic synergism when oseltamivir is combined with amantadine or with favipiravir.[149][150] An in vitro study suggests that amantadine and oseltamivir combination therapy may reduce the emergence of drug-resistant influenza A virus.[151] However, caution may be warranted, as a study of combined oseltamivir plus zanamivir found it to be less effective than oseltamivir alone.[152] One study found that combining baloxavir marboxil with a neuraminidase inhibitor in patients hospitalised with severe influenza did not result in superior clinical outcomes compared with a neuraminidase inhibitor alone.[153]

Recombinant sialidase fusion protein DAS181

Currently under development, this agent targets host respiratory cells rather than the seasonal influenza and contributes to 25 influenza virus itself, specifically the sialic acid receptor used by the influenza virus to attach to the airway epithelium.[148] 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 have shown in vitro effectiveness against both influenza A and B, and in vitro and in vivo effectiveness against human parainfluenza viruses.[154][155]

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. It confers antiviral properties by blocking viral entry.[148] However, 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.[156]

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.[157]

Favipiravir

A substituted pyrazine that inhibits virus RNA polymerase.[148] 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.[158] In addition, it is active against many arena-, bunya-, flavi-, alpha-, picorna-, and noroviruses. The World Health Organization (WHO) recommends not administering favipiravir for patients with suspected or confirmed non-severe seasonal influenza virus infection. This is due to a lack of effect on the time to alleviation of symptoms, admission to hospital, or mortality.[138]

Viramidine

A prodrug of ribavirin, viramidine targets the cellular enzyme IMP dehydrogenase, which is involved in viral RNA synthesis.[148] It is active against seasonal and H5N1 influenza A viruses.[159] It 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.[160] In a phase 1 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.[161] The results suggest that adjuvanted DNA vaccines with rapid vaccine production could be useful for pandemic control.

OVX836

OVX836 is a recombinant vaccine containing the nucleoprotein of the influenza A virus A/WSN/1933 (H1N1). In one phase 2a trial, OVX836 showed a preliminary signal of protection against influenza with good safety and tolerability. Therefore, OVX836 is a potential candidate for universal influenza A prevention but further trials are required.[162]

Emerging treatments