Consecutive influenza surveillance of neuraminidase mutations and neuraminidase inhibitor resistance in Japan

BACKGROUND: The large consumption of neuraminidase inhibitors (NAIs) 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 NAIs (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 NAIs 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.