Seasonal influenza is currently one of the greatest threats to global health. Flu viruses infect almost one billion people worldwide each year and send millions to hospitals and advanced care.
Limitations of Flu Vaccines
Annual flu vaccines can provide moderate protection, but their benefit is marginal when they are poorly matched with circulating virus strains or when pandemic viral strains emerge. The U.S. Food and Drug Administration currently approves three different antivirals against influenza. However, each of them has a low genetic barrier against viral resistance.
One of these classes is no longer recommended by the Centers for Disease Control and Prevention because of the widespread presence of resistance mutations that circulate in human and animal influenza A virus strains. Aside from this, resistance to the other two classes of antivirals in human viruses has also been observed frequently.
Due to the pre-existing or rapidly emerging resistance of flu viruses to approved antivirals, developing new therapeutics to mitigate seasonal influenza becomes an urgent priority. It can also help in improving preparedness against influenza pandemics in the future.
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New Approach to Impairing Flu Virus
To address this concern, experts from the Center for Translational Antiviral Research at Georgia State University explored the developmental potential of a novel clinical drug candidate for influenza therapy. Their research is discussed in the paper "Influenza A virus resistance to 4'-fluorouridine coincides with viral attenuation in vitro and in vivo".
In this study, the researcher's resistance profiled 4'-fluorouridine (4'-FIU) against influenza viruses and tracked possible routes of viral escapes. Led by Carolin Lieber, the team specifically addressed whether resistance affects viral pathogenicity and transmission ability of flu virus strains.
Previous studies revealed that 4'-FIU demonstrated broad oral efficacy against seasonal, pandemic, and highly pathogenic flu virus strains. This was observed in cell culture, epithelium cells of the human airway, and animal models.
It was found that the variants of resistant influenza A virus are severely weakened in mice. In ferrets, these variants impair their ability to invade the lower respiratory tract and cause viral pneumonia. When it comes to cell culture, six various escape lineages with distinct mutations were discovered.
The mutations were observed in three distinct structural clusters, which are all predicted to affect the active site of the viral RNA polymerase complex. According to the study, this leads to moderately reduced viral sensitivity to the drug.
Moreover, oral 4'-FIU given at the lowest efficacious dose or elevated dose was found to overcome moderate resistance when mice were infected with a fatal amount of influenza virions. The researchers reported that this behavior was demonstrated by reducing virus load and complete survival.
With a standard or five-fold elevated oral dose of 4'-FIU, the research team can fully mitigate lethal infection with the resistance variants and viral spread. This indicates that partial CA09 escape from 4'-FIU can be feasible in principle, although it is unlikely to reach clinical significance or persist in circulation.
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