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Article

Influenza PA Substitutions and Genetic Diversity of A(H1N1)pdm09, A(H3N2), and B/Victoria Viruses in Japan During the 2023–2024 Season

by
Nanjun Lee
1,*,
Julian W. Tang
2,3,
Irina Chon
1,
Fujio Kakuya
4,
Ryuta Terao
4,
Takashi Kawashima
5,
Isamu Sato
6,
Naoki Kodo
7,
Eitaro Suzuki
8,
Hironori Masaki
9,
Norichika Asoh
10,
Yutaka Shirahige
11,
Hirotsune Hamabata
12,
Tsutomu Tamura
13,
Keita Wagatsuma
1,14,
Yuyang Sun
1,
Jiaming Li
1,
Tri Bayu Purnama
1,
Yusuke Ichikawa
1,
Hisami Watanabe
13 and
Reiko Saito
1add Show full author list remove Hide full author list
1
Division of International Health (Public Health), Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
2
Department of Respiratory Sciences, University of Leicester, Leicester LE1 7RH, UK
3
Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK
4
Furano Kyokai Hospital, Furano 076-8765, Japan
5
Kawashima Medical Clinic, Shibukawa 377-0008, Japan
6
Yoiko Pediatric Clinic, Niigata 950-0983, Japan
7
Kodo Pediatrics, Uji 611-0013, Japan
8
Suzuki Pediatric Clinic, Ube 755-0151, Japan
9
Masaki Respiratory Medicine Clinic, Nagasaki 850-0841, Japan
10
Juzenkai Hospital, Nagasaki 852-0812, Japan
11
Shirahige Clinic, Nagasaki 850-0003, Japan
12
Awase-Daichi Clinic, Okinawa City 904-2172, Japan
13
Infectious Diseases Research Center of Niigata University in Myanmar (IDRC), Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
14
Institute for Research Administration, Niigata University, Niigata 951-8510, Japan
 
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*
Author to whom correspondence should be addressed.
Viruses 2026, 18(1), 13; https://doi.org/10.3390/v18010013 (registering DOI)
Submission received: 27 November 2025 / Revised: 18 December 2025 / Accepted: 19 December 2025 / Published: 21 December 2025
(This article belongs to the Special Issue Influenza and Other Respiratory Viruses: Prevention, Diagnosis, Treatment: 3rd Edition)
Versions Notes

Abstract

We characterized influenza A(H1N1)pdm09, A(H3N2), and B/Victoria viruses circulating in Japan during 2023–2024, focusing on lineage placement relative to WHO-recommended vaccine strains and on baloxavir resistance (PA/I38T substitutions). We enrolled 210 outpatients with influenza-like illness across eight clinics in six prefectures (October 2023–September 2024). Of these, 209 had an analyzable pre-treatment respiratory specimen for RT-PCR; hemagglutinin (HA) and neuraminidase (NA) genes were sequenced by next-generation sequencing (NGS). PA/I38T substitutions that confer baloxavir resistance were assessed by cycling-probe RT-PCR, Sanger sequencing, and NGS. HA phylogenies were constructed with global datasets and WHO vaccine reference strains. Of 209 pre-treatment specimens, 181 were influenza-positive (A(H1N1)pdm09 44.2%, A(H3N2) 37.6%, B/Victoria 18.2%); 51 follow-up specimens were collected ≈4–5 days after baloxavir or neuraminidase inhibitor therapy. HA phylogeny placed A(H1N1)pdm09 in clades 5a.2a/5a.2a.1 with predominance of subclade D.2. A(H3N2) clustered exclusively in clade 2a.3a.1 (J lineage, mostly J.1), indicating a mismatch with the season’s A/Darwin/9/2021 vaccine component and supporting the subsequent J-lineage update. All B/Victoria genomes fell within V1A.3a.2 on a C.5 backbone (C.5.1 and C.5.7). No PA/I38T variant was detected in any pre-treatment specimen. Post-baloxavir, PA/I38T emerged in one A(H3N2) case (confirmed by all three methods) and in one B/Victoria case detected by NGS only (minority variant in a low-load sample). NA genes showed no substitutions associated with reduced susceptibility to laninamivir (e.g., E119A, G147E). During 2023–2024, A(H1N1)pdm09 and B/Victoria remained genetically aligned with their vaccine components, whereas A(H3N2) shifted to the J lineage, consistent with the 2024–2025 vaccine update. Although pre-treatment PA/I38T was absent, low-frequency on-therapy selection was observed, including a rare PA/I38T in influenza B/Victoria detected by NGS, suggesting the value of deep sequencing when viral loads are low. These integrated genomic–clinical data support vaccine strain realignment for H3N2 and continued monitoring of baloxavir resistance in outpatient care.
Keywords: influenza A(H1N1)pdm09; influenza A(H3N2); influenza B/Victoria; hemagglutinin gene; phylogenetic analysis; vaccine strain mismatch; PA/I38T; antiviral resistance influenza A(H1N1)pdm09; influenza A(H3N2); influenza B/Victoria; hemagglutinin gene; phylogenetic analysis; vaccine strain mismatch; PA/I38T; antiviral resistance

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MDPI and ACS Style

Lee, N.; Tang, J.W.; Chon, I.; Kakuya, F.; Terao, R.; Kawashima, T.; Sato, I.; Kodo, N.; Suzuki, E.; Masaki, H.; et al. Influenza PA Substitutions and Genetic Diversity of A(H1N1)pdm09, A(H3N2), and B/Victoria Viruses in Japan During the 2023–2024 Season. Viruses 2026, 18, 13. https://doi.org/10.3390/v18010013

AMA Style

Lee N, Tang JW, Chon I, Kakuya F, Terao R, Kawashima T, Sato I, Kodo N, Suzuki E, Masaki H, et al. Influenza PA Substitutions and Genetic Diversity of A(H1N1)pdm09, A(H3N2), and B/Victoria Viruses in Japan During the 2023–2024 Season. Viruses. 2026; 18(1):13. https://doi.org/10.3390/v18010013

Chicago/Turabian Style

Lee, Nanjun, Julian W. Tang, Irina Chon, Fujio Kakuya, Ryuta Terao, Takashi Kawashima, Isamu Sato, Naoki Kodo, Eitaro Suzuki, Hironori Masaki, and et al. 2026. "Influenza PA Substitutions and Genetic Diversity of A(H1N1)pdm09, A(H3N2), and B/Victoria Viruses in Japan During the 2023–2024 Season" Viruses 18, no. 1: 13. https://doi.org/10.3390/v18010013

APA Style

Lee, N., Tang, J. W., Chon, I., Kakuya, F., Terao, R., Kawashima, T., Sato, I., Kodo, N., Suzuki, E., Masaki, H., Asoh, N., Shirahige, Y., Hamabata, H., Tamura, T., Wagatsuma, K., Sun, Y., Li, J., Purnama, T. B., Ichikawa, Y., ... Saito, R. (2026). Influenza PA Substitutions and Genetic Diversity of A(H1N1)pdm09, A(H3N2), and B/Victoria Viruses in Japan During the 2023–2024 Season. Viruses, 18(1), 13. https://doi.org/10.3390/v18010013

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