Influenza B viruses are thought to cause a milder infection than influenza A viruses, however recent studies have established that influenza B can still have a significant disease burden. Neuraminidase inhibitors (NAIs) are sialic acid analogues that block the neuraminidase (NA) glycoprotein on virion surface and are the only available treatment option for influenza B infections. Mutations, often within the active site of the NA, can be associated with resistance to the NAIs. As such, amino acid mutations D197N and H273Y in the influenza B NA have been associated with reduced virus susceptibility to NAIs.
This study characterizes the two NA amino acid mutations, D197N and H273Y, which were detected in contemporary influenza B viruses during routine surveillance. In vitro characterisation of the D197N and H273Y variants assessed NA enzyme activity and affinity, and cell culture replication, while ferret infection studies assessed viral replicability and transmissibility in comparison with recently circulating NAI-sensitive wild type viruses.
Enzymatic analysis revealed that the D197N variant had impaired NA enzyme function, but had comparable replication kinetics to wild type viruses both in vitro and in ferrets. The transmission efficiency of the D197N variant was slightly reduced between co-housed ferrets compared to the equivalent wild type virus. The H273Y variant had similar NA enzyme function to its wild type, but had delayed replication in vitro, and reduced transmission efficiency between co-housed ferrets.
The results show that both resistance-conferring mutations, D197N and H273Y, confer a fitness cost in influenza B viruses. The in vitro and in vivo data suggest that the fitness cost of the H273Y mutation is greater than that of the D197N mutation, and highlights the need to carefully monitor for the emergence of the D197N mutation in influenza B viruses.