Background
The large consumption of neuraminidase inhibitors (
NAI
s) for the treatment of influenza virus infections places Japan at risk of becoming the epicenter of the global spread of
NAI
‐resistant viruses.
Objective
To clarify
NA
amino acid mutations of epidemic influenza viruses in Japan and their related
NAI
resistance.
Methods
A total of 1791 samples, including 396 A/H1N1pdm09, 1117 A/H3N2, and 278 B isolates, were collected to determine of their 50% inhibitory concentration (
IC
50
) values by
NAI
s (oseltamivir, zanamivir, peramivir, and laninamivir) during the Japanese seasons from 2011‐2012 to 2016‐2017. Then, 380 samples including 49 A/H1N1pdm09, 251 A/H3N2, and 80 B isolates were sequenced for the entire
NA
genes.
Results
Neuraminidase inhibitor‐resistant A/H1N1pdm09 viruses were detected at a frequency of 1.3% (5/396 isolates) in the epidemic seasons. None of the A/H3N2 and B viruses developed resistance to any of the four
NAI
s during the six seasons. Only five and 13
AA
mutations were detected in the
NA
catalytic sites of A/H1N1pdm09 and A/H3N2 viruses, respectively. No mutations were observed in the catalytic sites of B viruses. Four of the five mutations in the catalytic sites of A/H1N1pdm09 consisted of H275Y, which was related to high resistance to oseltamivir and peramivir. Most (10/13) of the catalytic site mutations in A/H3N2 were associated with
MDCK
‐passaged induction (D151G/N). Finally, no mutations related to substantial
NAI
resistance were detected in the A/H3N2 and B viruses examined.
Conclusion
These findings suggest that the
NA
catalytic sites of influenza viruses are well preserved. Even in Japan, no spread of
NAI
‐resistant viruses has been observed, and A/H1N1pdm09 viruses carrying H275Y remain limited.