Antigenic drift originating from changes to the lateral surface of the neuraminidase head of influenza A virus.

• Project/Area Number: 18K07141
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yamayoshi Seiya 東京大学, 医科学研究所, 特任准教授 (50529534)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: インフルエンザウイルス / NA蛋白質 / 抗原性 / ヒトモノクローナル抗体 / 抗体 / ADCC活性 / 抗原性変化 / NA / ヒト / ADCC / ヒト抗体

Outline of Final Research Achievements

The reason for accumulation of amino acid substitutions at the lateral surface of the NA head remains unknown. Here, we isolated anti-NA monoclonal antibodies (mAbs) from individuals infected with A(H1N1)pdm09 virus. We found that amino acid mutations on the lateral surface of the NA head abolished the binding of these mAbs. These mAbs activated Fcγ receptor (FcγR)-mediated signaling pathways in effector cells and protected mice from lethal challenge infection via their FcγR-mediated antiviral activity. Serological analysis of individuals who were infected with A(H1N1)pdm09 virus revealed that some possessed or acquired the anti-NA lateral surface antibodies upon infection. We also found antigenic drift on the lateral surface of the NA head between 2009 isolates and 2015 isolates.

Academic Significance and Societal Importance of the Research Achievements

NA蛋白質の側面領域を認識し、ウイルスのシアリダーゼ活性を阻害しない抗体も免疫細胞を活性化することで生体におけるウイルス増殖を抑制し、感染防御に寄与することが明らかになった。また、NA蛋白質側面のアミノ酸変異の蓄積が感染防御活性を持つ抗体の選択圧により引き起こされていることを示した。これにより、今後のワクチン株の選定の際、HA蛋白質の抗原性のみでなく、NA蛋白質の抗原性についても考慮することで、より効果の高いワクチン株の選定に資すると考える。

Research Products

• [Journal Article] A(H1N1)pdm09ウイルスのHA蛋白質とNA蛋白質の抗原性変化 (2021)
  • Author(s): 安原敦洋、山吉誠也
  • Journal Title: インフルエンザ［その他の呼吸器感染症］ Volume: 22 Pages: 31-37
  • NAID: 40022525012
• [Journal Article] インフルエンザワクチンの現状と今後 (2020)
  • Author(s): 山吉誠也
  • Journal Title: 臨床免疫・アレルギー科 Volume: 73 Pages: 140-146
• [Journal Article] Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice. (2020)
  • Author(s): Kiso M, Yamayoshi S, Kawaoka Y
  • Journal Title: Commun Biol Volume: 3(1) Issue: 1 Pages: 219-219
  • DOI: 10.1038/s42003-020-0952-y
  • Peer Reviewed / Open Access
• [Journal Article] Antigenic drift originating from changes to the lateral surface of the neuraminidase head of influenza A virus. (2019)
  • Author(s): 4.Yasuhara A, Yamayoshi S, Kiso M, Sakai-Tagawa Y, Koga M, Adachi E, Kikuchi T, Wang IH, Yamada S, Kawaoka Y.
  • Journal Title: Nat Microbiol. Volume: 4(6) Issue: 6 Pages: 1024-1034
  • DOI: 10.1038/s41564-019-0401-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic and antigenic characterisation of influenza A(H3N2) viruses isolated in Yokohama during the 2016/17 and 2017/18 influenza seasons (2019)
  • Author(s): Kawakami Chiharu、Yamayoshi Seiya、Akimoto Miki、Nakamura Kazuya、Miura Hideka、Fujisaki Seiichiro、Pattinson David J.、Shimizu Kohei、Ozawa Hiroki、Momoki Tomoko、Saikusa Miwako、Yasuhara Atsuhiro、Usuku Shuzo、Okubo Ichiro、Toyozawa Takahiro、Sugita Shigeo、Smith Derek J.、Watanabe Shinji、Kawaoka Yoshihiro
  • Journal Title: Eurosurveillance Volume: 24 Issue: 6 Pages: 1800467-1800467
  • DOI: 10.2807/1560-7917.es.2019.24.6.1800467
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of Mouse Monoclonal Antibodies Against the HA of A(H7N9) Influenza Virus. (2019)
  • Author(s): Ito M, Yamayoshi S, Murakami K, Saito K, Motojima A, Nakaishi K, Kawaoka Y.
  • Journal Title: Viruses Volume: 11 Issue: 2 Pages: 149-149
  • DOI: 10.3390/v11020149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Subclade 2.2.1-Specific Human Monoclonal Antibodies That Recognize an Epitope in Antigenic Site A of Influenza A(H5) Virus HA Detected between 2015 and 2018 (2019)
  • Author(s): Okuda Moe、Yamayoshi Seiya、Uraki Ryuta、Ito Mutsumi、Hamabata Taiki、Kawaoka Yoshihiro
  • Journal Title: Viruses Volume: 11 Issue: 4 Pages: 321-321
  • DOI: 10.3390/v11040321
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Current and future influenza vaccines (2019)
  • Author(s): Yamayoshi Seiya、Kawaoka Yoshihiro
  • Journal Title: Nature Medicine Volume: 25 Issue: 2 Pages: 212-220
  • DOI: 10.1038/s41591-018-0340-z
  • Peer Reviewed
• [Journal Article] Antibody-free digital influenza virus counting based on neuraminidase activity (2019)
  • Author(s): Tabata Kazuhito V.、Minagawa Yoshihiro、Kawaguchi Yuko、Ono Mana、Moriizumi Yoshiki、Yamayoshi Seiya、Fujioka Yoichiro、Ohba Yusuke、Kawaoka Yoshihiro、Noji Hiroyuki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1067-1067
  • DOI: 10.1038/s41598-018-37994-6
  • Peer Reviewed / Open Access
• [Journal Article] Isolation and Characterization of Human Monoclonal Antibodies That Recognize the Influenza A(H1N1)pdm09 Virus Hemagglutinin Receptor-Binding Site and Rarely Yield Escape Mutant Viruses (2018)
  • Author(s): Yasuhara Atsuhiro、Yamayoshi Seiya、Ito Mutsumi、Kiso Maki、Yamada Shinya、Kawaoka Yoshihiro
  • Journal Title: Frontiers in Microbiology Volume: 9 Pages: 2660-2660
  • DOI: 10.3389/fmicb.2018.02660
  • Peer Reviewed / Open Access
• [Presentation] インフルエンザウイルスからあなたを守る抗体の話 (2019)
  • Author(s): 山吉誠也
  • Organizer: 第14回ラブラボ
  • Invited
• [Presentation] インフルエンザウイルスのHAおよびNA蛋白質に対するヒトモノクローナル抗体の性状解析 (2019)
  • Author(s): 山吉誠也
  • Organizer: 第33回インフルエンザ交流の会シンポジウム
  • Invited
• [Presentation] Human monoclonal antibodies that recognize the HA of both influenza B lineages (2019)
  • Author(s): Yamayoshi S, Yasuhara A, Kiso M, Kawaoka Y
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] Antigenic drift originating from changes to the lateral surface of the neuraminidase head of influenza A virus. (2019)
  • Author(s): Atsuhiro Yasuhara, Seiya Yamayoshi, Maki Kiso, Yuko Sakai-Tagawa, Michiko Koga, Eisuke Adachi, Tadashi Kikuchi, I-Hsuan Wang, Shinya Yamada, and Yoshihiro Kawaoka
  • Organizer: OPTIONS X for the Control of Influenza
  • Int'l Joint Research
• [Presentation] The potential of human monoclonal antibodies that recognize the influenza A(H1N1)pdm09 virus hemagglutinin receptor-binding site as anti-influenza agents. (2018)
  • Author(s): Yasuhara A, Yamayoshi S, Kiso M, Yamada S, Kawaoka Y
  • Organizer: 17th Negative Strand Virus Meeting 2018
  • Int'l Joint Research
• [Presentation] Human monoclonal antibodies against influenza virus (2018)
  • Author(s): Yamayoshi S, Kawaoka Y
  • Organizer: MEDLAB Asia Pacific & Asia Health Exhibition & Congress 2018
  • Int'l Joint Research / Invited
• [Presentation] Differences in the ease with which mutant viruses escape from human monoclonal antibodies against the HA stem of influenza A virus (2018)
  • Author(s): S. Yamayoshi, A. Yasuhara, M. Ito, R. Uraki, Y. Kawaoka
  • Organizer: 第66回日本ウイルス学会学術集会