Neuraminidase-mediated influenza virus egg growth without hemagglutinin antigenic changes

• Project/Area Number: 18K07139
• 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: Yamada Shinya 東京大学, 医科学研究所, 助教 (90466839)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: インフルエンザ / ワクチン / 抗原性 / H3N2

Outline of Final Research Achievements

Vaccination is one of the major strategies to control influenza. However, upon repeated passaging during vaccine production, H3N2 viruses acquire hemagglutinin (HA) mutations that allow them to recognize egg receptors, resulting in changes in antigenicity. Consequently, the effectiveness of the vaccine is appreciably reduced. Here, we show that mutations in neuraminidase (NA) confer efficient replication in eggs to recent human H3N2 viruses without the acquisition of egg-adaptive HA mutations at the major antigenic sites. The mutant NA allowed viruses to aggregate chicken red blood cells, suggesting the mutant NA serves as a receptor-binding protein in place of HA. The amino acid residues located in major antigenic sites remain unchanged during passages in eggs, demonstrating the potential to generate H3N2 vaccine viruses that would not change HA antigenicity during vaccine production, suggesting a potential new approach for the development of high-efficacy influenza vaccines.

Academic Significance and Societal Importance of the Research Achievements

近年のインフルエンザワクチンは流行株に対する効果的な免疫を誘導できないことが大きな社会問題となっているが、本研究はその問題の解決策になりえるものであり、社会的意義は大きいものと考える。

Research Products

• [Journal Article] Soluble Recombinant Hemagglutinin Protein of H1N1pdm09 Influenza Virus Elicits Cross-Protection Against a Lethal H5N1 Challenge in Mice. (2019)
  • Author(s): Yamada S, Yasuhara A, Kawaoka Y.
  • Journal Title: Front Microbiol. Volume: 4(10) Pages: 1268-1273
  • DOI: 10.3389/fmicb.2019.02031
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Influenza Virus Polymerase Mutation Stabilizes a Foreign Gene Inserted into the Virus Genome by Enhancing the Transcription/Replication Efficiency of the Modified Segment. (2019)
  • Author(s): 2.Furusawa Y, Yamada S, da Silva Lopes TJ, Dutta J, Khan Z, Kriti D, van Bakel H, Kawaoka Y.
  • Journal Title: mBio. Volume: 10(5) Issue: 5
  • DOI: 10.1128/mbio.01794-19
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A humanized MDCK cell line for the efficient isolation and propagation of human influenza viruses. (2019)
  • Author(s): Kosuke Takada, Chiharu Kawakami, Shufang Fan, Shiho Chiba, Gongxun Zhong, Chunyang Gu, Kohei Shimizu, Sara Takasaki, Yuko Sakai-Tagawa, Tiago J. S. Lopes, Jayeeta Dutta, Harm van Bakel, Zenab Khan, Divya Kriti, Shinya Yamada, Tokiko Watanabe, Masaki Imai, Yoshihiro Kawaoka
  • Journal Title: Nature Microbiology Volume: 印刷中 Issue: 8 Pages: 1268-1273
  • DOI: 10.1038/s41564-019-0433-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] 鶏卵での増殖過程でHAの抗原性変化を伴わないH3N2インフルエンザウイルスの作出 (2020)
  • Author(s): 山田晋弥, 千葉志穂, 安原敦洋, 高田光輔, 柳本周, Ryan McBride, Charli Worth, Andrew J. Thompson, Tiago J.S. Lopes, 山吉誠也, James C. Paulson, 河岡義裕
  • Organizer: 第9回 Negative Strand Virus-Japan symposium
• [Presentation] 鶏卵での増殖過程でHAの抗原性変化を伴わないH3N2インフルエンザウイルスの作出 (2020)
  • Author(s): 山田晋弥、安原敦洋、高田光輔、柳本周、千葉志穂、Ryan McBride、 Charli Worth、Andrew J. Thompson、Tiago J.S. Lopes、山吉誠也、 James C. Paulson、河岡義裕
  • Organizer: 9th Negative strand virus-Japan
• [Patent(Industrial Property Rights)] RECOMBINANT INFLUENZA VIRUSES WITH STABILIZED HA FOR REPLICATION IN EGGS (2018)
  • Inventor(s): 河岡義裕、山田晋弥、千葉志穂
  • Industrial Property Rights Holder: 河岡義裕、山田晋弥、千葉志穂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018