Innovative viral vaccine strategy promoting broad-reactive neutralizing antibodies.

• Project/Area Number: 19H03491
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Masato Kubo 東京理科大学, 研究推進機構生命医科学研究所, 教授 (40277281)
• Co-Investigator(Kenkyū-buntansha): 宮内 浩典 国立研究開発法人理化学研究所, 生命医科学研究センター, 副チームリーダー (50619856)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: インフルエンザ / ワクチン / 広域中和抗体 / B細胞 / T細胞 / B細胞抗原決定基 / T細胞抗原決定基

Outline of Research at the Start

インフルエンザによるパンデミック感染は人類の最大級の脅威とも言える。これを防ぐ最も有効な手段はワクチンである。本研究は、株が異なるウイルスや不連続抗原変異を起こしたウイルスに対しても有効性が見込める広域中和抗体に着目し、この抗体を人為的に誘導できるユニバーサルワクチンの開発を目指している。この目的を達成するため、本研究計画ではこの広域中和抗体が生み出される肺での微小環境を解明するとともに、広域中和抗体が認識する抗原決定基を明らかにしていく。

Outline of Final Research Achievements

Influenza viruses are a major public health problem, and vaccines offer the effective protective strategy against influenza virus infection. The goal of this proposal is to develop a vaccine with efficacy against newly emerged variant viruses. It has been reported that inactivated vaccines is narrow compared to potential breadth of virus infection. In contrast, live attenuated vaccines (LAV) have the advantage of inducing broadly reactive neutralizing antibodies. Analysis of this mechanism showed that the broadly reactive neutralizing antibodies induced by LAV could recognize a common epitope present in different H1N1 viral strains, and B cells were already set up in pre-existing B cell repertoires. Normally, this common epitope is hidden in native form, so that sufficient amounts of broadly reactive antibodies are not produced, but when the common epitope is exposed during the viral replication process, these B cells are amplified by TFH-derived IL-4 in the secondary lymphoid tissues.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、生ワクチンが持つ広域中和抗体を効率よく産生できる優位性が示された。この成果は現行、流行が起こっている新型コロナウイルスでも活用することが期待でき、社会的貢献度は非常に高い。しかしながら、弱毒生ワクチンの問題点は、副反応にあることは容易に予想できる。そのため、ウイルスが持つ生物特性を利用した新しいワクチン戦略の構築が、これから現れる変異体に対するワクチン戦略として必要となる。本研究は、そのヒントになる情報を提供できたと考えている。

Research Products

• [Journal Article] A Basophil-Neuronal Axis Promotes Itch (2021)
  • Author(s): Wang,F., Trier, A. M., Li, F., Kim, S., Chen, Z., Chai, J. N., Mack, M. R., Morrison, S. A., Hamilton, J. D., Baek, J., Yang, T. B., Ver Heul, A. M., Hu, A. Z., Xie, Z., Dong, X., Kubo, M., Hu, H., Hsieh, C. S., Dong, X., Liu, Q., Margolis, D. J., Ardeleanu, M., Miller, M. J., Kim, B. S.
  • Journal Title: Cell Volume: 184(2) Issue: 2 Pages: 422-440
  • DOI: 10.1016/j.cell.2020.12.033
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Influenza virus infection expands the breadth of antibody responses through IL-4 signal in B cells. (2021)
  • Author(s): Miyauchi, K., Adachi, Y., Tonouchi, K., Yajima, T., Harada, Y., Fukuyama, H., Deno, S., Iwakura, Y., Yoshimura, A., Hasegawa, H., Yugi, K., Fujii, S., Ohara, O., Takahashi, Y., Kubo, M.
  • Journal Title: Nature Communication Volume: 18;12(1) Pages: 3789-3789
  • Peer Reviewed
• [Journal Article] ２．論文標題 Involvement of activation of mast cells via IgE signaling and epithelial cell-derived cytokines in the pathogenesis of pollen-food allergy syndrome in a novel murine model (2021)
  • Author(s): Kato, Y., Morikawa, T., Kato, E., Yoshida, K., Imoto, Y., Sakashita, M., Osawa, Y., Takabayashi, T., Kubo, M., Miura, K., Noguchi, E., Fujieda, S.
  • Journal Title: The Journal of Immunology Volume: 206 Issue: 12 Pages: 1-12
  • DOI: 10.4049/jimmunol.2000518
  • Peer Reviewed
• [Journal Article] IL-33 Signaling in Sensory Neurons Promotes Dry Skin Itch (2021)
  • Author(s): １．著者名 Trier, A. M., Mack, M. R., Tamari, M., Ver Heul, A. M., Avraham O., Fredman, A., Guo, J., Dehner, C., Oetjen,L. K., Zhao, Y., Feng, J., Kubo, M., Gereau, R. W., Coble, D., Cavalli, V., Davidson, S., Hu, H., Liu, Q., and Kim, B. S.
  • Journal Title: The Journal of Allergy and Clinical Immunology Volume: - Issue: 4 Pages: 1473-1480.e6
  • DOI: 10.1016/j.jaci.2021.09.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Essential role of STAT3 signaling in hair follicle homeostasis (2021)
  • Author(s): Miyauchi, K., Ki, S., Ukai, M., Suzuki, Y., Inoue, K., Suda, W., Matsui, T., Ito,Y., Honda, K., Koseki, H., Ohara, O., Tanaka, R. J., Okada-Hatakeyama, M., Kubo, M.
  • Journal Title: Frontiers in Immunology Volume: -
  • DOI: 10.3389/fimmu.2021.663177
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The regulation of DOCK family proteins on T and B cells. (2021)
  • Author(s): Chen, Y., Chen, Y., Yin, W., Han, H., Miller, H., Li, J., Herrada, A. A., Kubo, M., Sui, Z., Gong, Q., Liu. C.
  • Journal Title: J. Leukoc. Biol. Volume: 109(2) Issue: 2 Pages: 383-394
  • DOI: 10.1002/jlb.1mr0520-221rr
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diurnal Rhythmicity Programs of Microbiota and Transcriptional Oscillation of Circadian Regulator, NFIL3 (2020)
  • Author(s): Kubo Masato
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 1-1
  • DOI: 10.3389/fimmu.2020.552188
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced Cell Division Is Required for the Generation of Memory CD4 T Cells to Migrate Into Their Proper Location. (2020)
  • Author(s): Sarkander, J., Hojyo, S., Mursell, M., Yamasaki, Y., Wu, TY., Tumes, DJ., Miyauchi, K., Tran, CL., Zhu, J., Löhning, M., Hutloff, A., Mashreghi, MF., Kubo, M., Radbruch, A., Tokoyoda, K
  • Journal Title: Frontiers in Immunology Volume: 10:3113. Pages: 0-1
  • DOI: 10.3389/fimmu.2019.03113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Breadth of Antibody Responses during Influenza Virus Infection and Vaccination (2020)
  • Author(s): Kubo Masato、Miyauchi Kosuke
  • Journal Title: Trends in Immunology Volume: 41 Issue: 5 Pages: 394-405
  • DOI: 10.1016/j.it.2020.03.005
  • Peer Reviewed
• [Journal Article] Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity (2020)
  • Author(s): Tanaka, S. Ise, W. Inoue, T. Ito, A. Ono, C. Shima, Y. Sakakibara, S. Nakayama, M. Fujii, K. Miura, I. Sharif, J. Koseki, H. Koni, P. A. Raman, I. Li, Q. Z. Kubo, M. Fujiki, K. Nakato, R. Shirahige, K. Araki, H. Miura, F. Ito, T. Kawakami, E. Baba, Y. Kurosaki, T.
  • Journal Title: Nature Immunology Volume: 21 Issue: 8 Pages: 950-961
  • DOI: 10.1038/s41590-020-0700-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical Role of TSLP Receptor on CD4 T Cells for Exacerbation of Skin Inflammation (2020)
  • Author(s): Kitajima Masayuki、Kubo Masato、Ziegler Steven F.、Suzuki Harumi
  • Journal Title: The Journal of Immunology Volume: - Issue: 1 Pages: 27-35
  • DOI: 10.4049/jimmunol.1900758
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tumor-infiltrating CD62L+PD-1-CD8 T cells retain proliferative potential via Bcl6 expression and replenish effector T cells within the tumor (2020)
  • Author(s): Gong Yu、Suzuki Toshihiro、Kozono Haruo、Kubo Masato、Nakano Naoko
  • Journal Title: PLOS ONE Volume: 15 Issue: 8 Pages: 0237646-0237646
  • DOI: 10.1371/journal.pone.0237646
  • Peer Reviewed
• [Journal Article] Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury. (2020)
  • Author(s): Sakai R, Ito M, Komai K, Iizuka-Koga M, Matsuo K, Nakayama T, Yoshie O, Amano K, Nishimasu H, Nureki O, Kubo M, Yoshimura A.
  • Journal Title: Cell Mol Immunol. Volume: Sep Issue: 5 Pages: 11-11
  • DOI: 10.1038/s41423-020-00547-x
  • Peer Reviewed / Open Access
• [Journal Article] Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease. (2020)
  • Author(s): Sasaki, T., Yajima, T., Shimaoka, T., Ogawa, S., Saito, T., Yamaoka, K., Takeuchi, T., Kubo, M.
  • Journal Title: Int. Immunol Volume: 32(3) Issue: 3 Pages: 163-174
  • DOI: 10.1093/intimm/dxz073
  • Peer Reviewed
• [Journal Article] Selective suppression of oral allergen-induced anaphylaxis by Allergin-1 on basophils in mice (2019)
  • Author(s): Lin Yu-Hsien、Tahara-Hanaoka Satoko、Nagai Kei、Yoshikawa Soichiro、Kubo Masato、Shibayama Shiro、Karasuyama Hajime、Shibuya Akira
  • Journal Title: International Immunology Volume: 32 Issue: 3 Pages: 213-219
  • DOI: 10.1093/intimm/dxz075
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interstitial-resident memory CD8+ T cells sustain frontline epithelial memory in the lung. (2019)
  • Author(s): Takamura, S., Kato, S., Motozono, C., Shimaoka, T., Ueha, S., Matsuo, K., Miyauchi, K., Masumoto, T., Katsushima, A., Nakayama, T., Tomura, M., Matsushima, K., Kubo, M. & Miyazawa, M.
  • Journal Title: J Exp Med. Volume: 216 Issue: 12 Pages: 2736-2747
  • DOI: 10.1084/jem.20190557
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis (2019)
  • Author(s): Nishida K, Hasegawa A, Yamasaki S, Uchida R, Ohashi W, Kurashima Y, Kunisawa J, Kimura S, Iwanaga T, Watarai H, Hase K, Ogura H, Nakayama M, Kashiwakura J, Okayama Y, Kubo M, Ohara O, Kiyono H, Koseki H, Murakami M, Hirano T
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10842-10842
  • DOI: 10.1038/s41598-019-47132-5
  • Peer Reviewed / Open Access
• [Journal Article] IL-33-induced atopic dermatitis-like inflammation in mice is mediated by group 2 innate lymphoid cells in concert with basophils (2019)
  • Author(s): Imai Y, Yasuda K, Nagai M, Kusakabe M, Kubo M, Nakanishi K, Yamanishi K
  • Journal Title: J Invest Dermatol Volume: 139 Issue: 10 Pages: 2185-2194
  • DOI: 10.1016/j.jid.2019.04.016
  • Peer Reviewed
• [Journal Article] The basophil‐IL‐4‐mast cell axis is required for food allergy (2019)
  • Author(s): Kashiwakura Jun‐Ichi、Ando Tomoaki、Karasuyama Hajime、Kubo Masato、Matsumoto Kenji、Matsuda Tadashi、Kawakami Toshiaki
  • Journal Title: Allergy Volume: 74 Issue: 10 Pages: 1992-1996
  • DOI: 10.1111/all.13834
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ウイルス感染によって誘導されるIL-4依存的な広域中和抗体産生 (2021)
  • Author(s): 宮内浩典、久保允人
  • Organizer: 第85回日本インターフェロン・サイトカイン学会学術集会
• [Presentation] 【コアテーマ枠】新型コロナウイルスの交差反応性抗体の検出システムに関する研究開発 (2021)
  • Author(s): 久保允人
  • Organizer: COVID-19チャレンジ2020研究成果報告会、東京理科大学
• [Presentation] Role of germinal center response in the antibody responses against SARS-CoV-2 spike protein (2021)
  • Author(s): Miyauchi, K., Hashimoto, R., Takayama K., and Kubo, M.
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] NFIL3 is an important switcher to control ILC2 and ILC1 function (2021)
  • Author(s): Bohio, A. A., Miyauchi, K., and Kubo, M.
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research
• [Presentation] ROLE OF SARS-CoV-2 SPIKE PROTEIN CROSS-REACTIVE CTL EPITOPES IN T CELL IMMUNITY (2021)
  • Author(s): Abubakar, S. D., Miyauchi, K., Kubo, M.
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research
• [Presentation] 「理研と理科大がともに描く科学研究の近未来」新興感染症に対するワクチン戦略 (2021)
  • Author(s): 久保允人
  • Organizer: 第1回理化学研究所－東京理科大学合同シンポジウム
  • Invited
• [Presentation] 自然免疫細胞とアレルギー (2021)
  • Author(s): 久保允人
  • Organizer: 日本アレルギー学会 第7回総合アレルギー講習会
  • Invited
• [Presentation] ２型サイトカインとアレルギー性気道炎症横浜ベイシェラトン＆タワーズ (2021)
  • Author(s): 久保允人
  • Organizer: 横浜Type2炎症疾患フォーラム
  • Invited
• [Presentation] 「2型アレルギー炎症の基礎」 (2021)
  • Author(s): 久保允人
  • Organizer: 日本アレルギー学会第60回専門医認定教育セミナー
  • Invited
• [Presentation] 免疫細胞に宿る記憶の理解とその制御に資する医療シリーズの創出 (2021)
  • Author(s): 久保允人
  • Organizer: AMED免疫記憶ワークショップ
  • Invited
• [Presentation] 「新型コロナウイルスとワクチン」 (2021)
  • Author(s): 久保允人
  • Organizer: こうよう会長野県支部「講演会及び就職・進学説明会」
  • Invited
• [Presentation] 「２型アレルギー炎症とIL-4シグナル」 (2021)
  • Author(s): 久保允人
  • Organizer: Triple allergic cross seminar in Hansin
  • Invited
• [Presentation] 変異ウイルスに強いワクチンの開発を目指して (2021)
  • Author(s): 久保允人
  • Organizer: 鳥取大学医学部免疫学セミナー
  • Invited
• [Presentation] 「Recent advances of IgE, mast cells, and basophile」 (2021)
  • Author(s): 久保允人
  • Organizer: 第50回日本免疫学会学術集会
  • Invited
• [Presentation] Different immunodominance of influenza virus between infection and vaccination (2021)
  • Author(s): Masato Kubo
  • Organizer: The 5th International ImmunologicalMemory and Vaccine Forum(5th IIMVF)
  • Int'l Joint Research / Invited
• [Presentation] A pathogenic role of IL-13 in anaphylaxis (2021)
  • Author(s): T.Sasaki, M. Kubo
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research / Invited
• [Presentation] IgG4関連疾患の炎症はIgG4抗体と細胞傷害性T細胞の協調的作用により起こる、 (2020)
  • Author(s): 佐々木貴紀、久保允人
  • Organizer: 第8回筑波大学・東京理科大学合同リトリート（Zoom）口頭とポスター発表
  • Invited
• [Presentation] アレルギー性炎症における2型サイトカインの役割 (2020)
  • Author(s): 久保允人
  • Organizer: 重症喘息講演会
  • Invited
• [Presentation] アレルギー気道炎 症における2型サイトカインの役割 (2020)
  • Author(s): 久保允人
  • Organizer: Science Exchange Meeting in Kagoshima 2020
  • Invited
• [Presentation] ADの病態におけるIL4/IL13の役割、ADの病態におけるIL-4の重要性 (2020)
  • Author(s): 久保允人
  • Organizer: 第50回日本皮膚免疫アレルギー学会総会学術大会スポンサードシンポジウム
  • Invited
• [Presentation] IL-4,IL-13の基礎について～アレルギー疾患におけるType2炎症にお ける働きから～ (2020)
  • Author(s): 久保允人
  • Organizer: デュピクセント発売記念 1周年記念講演会 in 東京
  • Invited
• [Presentation] Role of IL-13 in production of figh-affinity IgE (2019)
  • Author(s): 久保允人
  • Organizer: 6.第48回日本免疫学会学術集会 第1回JSI-JSA joint symposium
  • Int'l Joint Research / Invited
• [Presentation] NKT exhaustion療法はアナフェラキシーを抑制する (2019)
  • Author(s): 久保允人
  • Organizer: 5.神奈川・湘南ヘルスイノベーションパークセミナー「各拠点における産学公連携の取組み」
  • Invited
• [Presentation] アレルギー性炎症における2型サイトカインの役割 (2019)
  • Author(s): 久保允人
  • Organizer: 第2回日本眼科アレルギー学会
  • Invited
• [Presentation] 適応免疫におけるヘルパーT細胞の役割 (2019)
  • Author(s): 久保允人
  • Organizer: 免疫学会サマースクール
  • Invited
• [Presentation] Role of type 2 Follicular Helper T cells in anaphylaxis (2019)
  • Author(s): Masato Kubo
  • Organizer: The 10th anniversary of the discovery of Bcl6 in Tfh cells
  • Int'l Joint Research / Invited
• [Presentation] Role of cytokine signal in atopic dermatitis (2019)
  • Author(s): Masato Kubo
  • Organizer: The 118th Annual Meeting of the Japanese Dermatological Association
  • Int'l Joint Research / Invited