Development of the next generation anti-influenza virus VHH antibody with high cross-reactivity

• Project/Area Number: 16K09943
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Juntendo University
• Principal Investigator: Yamamoto Norio 順天堂大学, 医学部, 准教授 (40323703)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: インフルエンザ / インフルエンザウイルス / 中和抗体 / 感染症 / ウイルス

Outline of Final Research Achievements

Influenza viruses easily change their genomes and it would be valuable to develop an antibody that can neutralize a wide variety of influenza viruses. In this research, based on the property of camelid VHH antibodies, we attempted to develop effective VHH antibodies against a broad range of influenza viruses. As a result, a VHH antibody was obtained that could strongly neutralize both A(H1N1)pdm09 and A(H1N1) viruses. This VHH antibody was effective not only in cell experiments but also in animal experiments against A(H1N1)pdm09 and A(H1N1) viruses. This VHH antibody was suggested to be applicable as a therapeutic drug for influenza.

Academic Significance and Societal Importance of the Research Achievements

インフルエンザウイルスは非常に変異しやすい性質を持っているため、抗ウイルス薬に対する耐性ウイルスの出現が問題となる。本研究では、インフルエンザウイルスの保存性が高い領域を標的とし、幅広いウイルスを中和できるVHH抗体の開発を試みた。このVHH抗体は、構造的にかなり異なるA(H1N1)pdm09ウイルスとA(H1N1)ウイルスの両方を強く中和することができたことから、幅広いウイルスに対応可能な抗体であると考えられる。また、異なるウイルスで保存され、変化しにくい領域に作用することから、変異に対しても強い中和抗体であると期待できる。本抗体はインフルエンザによる健康被害の低減に役立つものと考えられる。

Research Products

• [Int'l Joint Research] Novartis Vaccines and Diagnostics(ドイツ)
• [Journal Article] Comparison of suspension MDCK cells, adherent MDCK cells, and LLC‐MK2 cells for selective isolation of influenza viruses to be used as vaccine seeds (2019)
  • Author(s): Harada Yuichi、Takahashi Hitoshi、Trusheim Heidi、Roth Bernhard、Mizuta Katsumi、Hirata‐Saito Asumi、Ogane Teruko、Odagiri Takato、Tashiro Masato、Yamamoto Norio
  • Journal Title: Influenza and Other Respiratory Viruses Volume: 14 Issue: 2 Pages: 204-209
  • DOI: 10.1111/irv.12694
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systematic evaluation of suspension MDCK cells, adherent MDCK cells, and LLC-MK2 cells for preparing influenza vaccine seed virus (2019)
  • Author(s): Nakamura Kazuya、Harada Yuichi、Takahashi Hitoshi、Trusheim Heidi、Bernhard Roth、Hamamoto Itsuki、Hirata-Saito Asumi、Ogane Teruko、Mizuta Katsumi、Konomi Nami、Konomi Yasushi、Asanuma Hideki、Odagiri Takato、Tashiro Masato、Yamamoto Norio
  • Journal Title: Vaccine Volume: 37 Issue: 43 Pages: 6526-6534
  • DOI: 10.1016/j.vaccine.2019.08.064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CpG ODN G9.1 as a novel nasal ODN adjuvant elicits complete protection from influenza virus infection without causing inflammatory immune responses (2019)
  • Author(s): Tateishi Koichiro、Fujihashi Kohtaro、Yamamoto Norio、Hasegawa Hideki、Ainai Akira、Sato Kayoko、Iho Sumiko、Yamamoto Saburo、Maeyama Jun-ichi、Odagiri Takato、Asanuma Hideki
  • Journal Title: Vaccine Volume: 37 Issue: 36 Pages: 5382-5389
  • DOI: 10.1016/j.vaccine.2019.07.032
  • Peer Reviewed / Open Access
• [Journal Article] Administration of plasmacytoid dendritic cell-stimulative lactic acid bacteria is effective against dengue virus infection in mice. (2019)
  • Author(s): Suzuki H, Tsuji R, Sugamata M, Yamamoto N, Yamamoto N, Kanauchi O.
  • Journal Title: Int J Mol Med. Volume: 43 Pages: 426-434
  • DOI: 10.3892/ijmm.2018.3955
  • Peer Reviewed
• [Journal Article] Identification of a novel gene associated with high-level β-lactam resistance in heterogeneous vancomycin-intermediate Staphylococcus aureus strain Mu3 and methicillin-resistant S. aureus strain N315. (2019)
  • Author(s): Matsuo M, Yamamoto N, Hishinuma T, Hiramatsu K
  • Journal Title: Antimicrob Agents Chemother. Volume: 63 Issue: 2 Pages: 1-12
  • DOI: 10.1128/aac.00712-18
  • Peer Reviewed
• [Journal Article] Genetic and transcriptomic analyses of ciprofloxacin-tolerant Staphylococcus aureus isolated by the Replica Plating Tolerance Isolation System (REPTIS) (2019)
  • Author(s): Matsuo M, Hiramatsu M, Singh M, Sasaki T, Hishinuma T, Yamamoto N, Morimoto Y, Kirikae T, Hiramatsu K
  • Journal Title: Antimicrob Agents Chemother. Volume: 63 Issue: 2 Pages: 1-16
  • DOI: 10.1128/aac.02019-18
  • Peer Reviewed
• [Journal Article] Induction of anti-viral genes mediated by humoral factors upon stimulation with Lactococcus lactis strain plasma results in repression of dengue virus replication in vitro. (2018)
  • Author(s): Tsuji R, Yamamoto N, Yamada S, Fujii T, Yamamoto N, Kanauchi O.
  • Journal Title: Antiviral Res. Volume: 160 Pages: 101-108
  • DOI: 10.1016/j.antiviral.2018.10.020
  • Peer Reviewed
• [Journal Article] Spread of GES-5 carbapenemase-producing Pseudomonas aeruginosa clinical isolates in Japan due to clonal expansion of ST235 (2018)
  • Author(s): Hishinuma Tomomi、Tada Tatsuya、Kuwahara-Arai Kyoko、Yamamoto Norio、Shimojima Masahiro、Kirikae Teruo
  • Journal Title: PLOS ONE Volume: 13 Issue: 11 Pages: 1-9
  • DOI: 10.1371/journal.pone.0207134
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] インフルエンザウイルス感染における細胞表層ヘパラン硫酸の関与 (2019)
  • Author(s): 御子神拓樹、臼井麻琴、阿部史弥、渡辺マコ、築地 信、山本典生、東 伸昭
  • Organizer: 第20回Pharmaco-Hematologyシンポジウム
• [Presentation] Evaluation of effectiveness and safety of CpG-ODN G9.1 as mucosal adjuvant for nasal influenza vaccines (2019)
  • Author(s): Koichiro Tateishi, Kayoko Sato, Eita Sasaki, Takuo Mizukami, Junichi Maeyama, Sumiko Iho, Saburo Yamamoto, Norio Yamamoto, Kohtaro Fujihashi, Hideki Asanuma
  • Organizer: 第12回次世代アジュバント研究会
• [Presentation] Lactococcus lactis JCM 5805含有食品摂取が免疫因子およびウイルス反応性に与える影響 (2018)
  • Author(s): 藤井 敏雄、山本 典生
  • Organizer: 第92回日本感染症学会学術講演会・第66回日本化学療法学会総会 合同学会
• [Presentation] Cyclosporin A誘導体によるインフルエンザウイルス増殖抑制効果の解析 (2018)
  • Author(s): 前田 護友、平松 啓一、切替 照雄、山本 典生
  • Organizer: 第92回日本感染症学会学術講演会・第66回日本化学療法学会総会 合同学会、岡山コンベンションセンター
• [Presentation] Assessment of G9.1-induced innate immune responses for the development of safe nasal influenza vaccines (2018)
  • Author(s): Koichiro Tateishi, Kayoko Sato, Eita Sasaki, Takuo Mizukami, Junichi Maeyama, Sumiko Iho, Saburo Yamamoto, Norio Yamamoto, Kohtaro Fujihashi, Hideki Asanuma
  • Organizer: 第47回日本免疫学会学術集会