Investigation of antigen and route of administration for the development of human norovirus vaccine.

• Project/Area Number: 19H03702
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Osaka University
• Principal Investigator: SATO Shintaro 大阪大学, 微生物病研究所, 特任准教授(常勤) (80447333)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
• Keywords: ヒトノロウイルス / ワクチン開発 / 腸管上皮細胞 / 粘膜免疫 / iPS細胞

Outline of Research at the Start

本研究計画では、ヒトノロウイルス（HuNoV）ワクチン開発を念頭に置き、その抗原としてウイルス様粒子と、これまでは検討することができなかった不活化全粒子の優位性を比較するとともに、投与経路として注射型と経粘膜型の優位性も比較検討する。実験には申請者らが最近樹立に成功したヒトiPS細胞株由来の腸管上皮細胞と、この細胞で増殖、精製したHuNoVの感染性粒子を用いる。
免疫担当細胞のHuNoV認識における、抗原取り込みに特化した上皮細胞であるM細胞の関与を検討し、経粘膜型ワクチンにおいてM細胞に標的化することの有用性も検討する。

Outline of Final Research Achievements

With the aim of developing an effective vaccine against human norovirus (HuNoV), we planned to 1) compare virus-like particles (VLPs) and inactivated whole particles as vaccine antigens and 2) compare injectable and transmucosal forms as routes of administration. However, the in vitro growth efficiency of viral whole particles was not improved beyond our initial expectations, and we only evaluated (2) when VLPs were used as antigens. As a result, VLPs were able to induce the production of antigen-specific serum IgG in both injectable and oral forms, and oral administration without the addition of adjuvant was further confirmed to produce serum IgG and IgA with neutralizing activity and secretory IgA in the intestinal lavage fluid.

Academic Significance and Societal Importance of the Research Achievements

HuNoVのin vitro増殖系が確立されたことで、VLPをワクチン抗原とした場合に中和活性を有した特異的抗体が産生されることが研究室で簡便に行えるようになった。第一世代のHuNoVワクチンはほとんどがVLPを抗原とする注射型であるが、VLPの大量調整が可能なのであれば、経口接種によりアジュバントの添加無しに中和活性を有した血清IgG、IgA、分泌型IgA産生が確認されたことから、投与経路としてはやはり経粘膜の方が効率的であるということを示すことが出来た。

Research Products

• [Journal Article] SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response (2022)
  • Author(s): Tsuji Shunya、Minami Shohei、Hashimoto Rina、Konishi Yusuke、Suzuki Tatsuya、Kondo Tamae、Sasai Miwa、Torii Shiho、Ono Chikako、Shichinohe Shintaro、Sato Shintaro、et al.
  • Journal Title: Nature Aging Volume: 2 Issue: 2 Pages: 115-124
  • DOI: 10.1038/s43587-022-00170-7
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal commensal microbiota and cytokines regulate Fut2 ⁺ Paneth cells for gut defense (2022)
  • Author(s): Kamioka Mariko、Goto Yoshiyuki、Nakamura Kiminori、Yokoi Yuki、Sugimoto Rina、Ohira Shuya、Kurashima Yosuke、Umemoto Shingo、Sato Shintaro、Kunisawa Jun、Takahashi Yu、Domino Steven E.、Renauld Jean-Christophe、Nakae Susumu、Iwakura Yoichiro、Ernst Peter B.、Ayabe Tokiyoshi、Kiyono Hiroshi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 3 Pages: 1-10
  • DOI: 10.1073/pnas.2115230119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion (2021)
  • Author(s): Okumura Shintaro、Konishi Yusuke、Narukawa Megumi、Sugiura Yuki、Yoshimoto Shin、Arai Yuriko、Sato Shintaro、Yoshida Yasuo、Tsuji Shunya、Uemura Ken、Wakita Masahiro、Matsudaira Tatsuyuki、Matsumoto Tomonori、Kawamoto Shimpei、Takahashi Akiko、Itatani Yoshiro、Miki Hiroaki ら
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5674-5674
  • DOI: 10.1038/s41467-021-25965-x
  • Peer Reviewed / Open Access
• [Journal Article] The gut microbiota induces Peyer’s-patch-dependent secretion of maternal IgA into milk (2021)
  • Author(s): Usami Katsuki、Niimi Kanae、Matsuo Ayumi、Suyama Yoshihisa、Sakai Yoshifumi、Sato Shintaro、Fujihashi Kohtaro、Kiyono Hiroshi、Uchino Saeka、Furukawa Mutsumi、Islam Jahidul、etc
  • Journal Title: Cell Reports Volume: 36 Issue: 10 Pages: 109655-109655
  • DOI: 10.1016/j.celrep.2021.109655
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of gene expression and activation of transcription factors in organoid-derived monolayer intestinal epithelial cells and organoids (2021)
  • Author(s): Takahashi Yu、Inoue Yu、Kuze Keitaro、Sato Shintaro、Shimizu Makoto、Kiyono Hiroshi、Yamauchi Yoshio、Sato Ryuichiro
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 85 Issue: 10 Pages: 2137-2144
  • DOI: 10.1093/bbb/zbab136
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Antibody-Fragment?Producing Rice for Neutralization of Human Norovirus (2021)
  • Author(s): Sasou Ai、Yuki Yoshikazu、Kurokawa Shiho、Sato Shintaro、Goda Yuki、Uchida Masao、Matsumoto Naomi、Sagara Hiroshi、Watanabe Yuji、Kuroda Masaharu、Sakon Naomi、Sugiura Kotomi、Nakahashi-Ouchida Rika、Ushijima Hiroshi、Fujihashi Kohtaro、Kiyono Hiroshi
  • Journal Title: Frontiers in Plant Science Volume: 12 Pages: 639953-639953
  • DOI: 10.3389/fpls.2021.639953
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alcohol abrogates human norovirus infectivity in a pH-dependent manner (2020)
  • Author(s): Sato Shintaro、Matsumoto Naomi、Hisaie Kota、Uematsu Satoshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15878-15878
  • DOI: 10.1038/s41598-020-72609-z
  • NAID: 120006891639
  • Peer Reviewed / Open Access
• [Journal Article] Metagenome Data on Intestinal Phage-Bacteria Associations Aids the Development of Phage Therapy against Pathobionts (2020)
  • Author(s): Fujimoto Kosuke、Kimura Yasumasa、Shimohigoshi Masaki、Satoh Takeshi、Sato Shintaro、Tremmel Georg、Uematsu Miho、Kawaguchi Yunosuke、Usui Yuki、Nakano Yoshiko、Hayashi Tetsuya、Kashima Koji、Yuki Yoshikazu、Yamaguchi Kiyoshi、Furukawa Yoichi、Kakuta Masanori、Akiyama Yutaka、Yamaguchi Rui、Crowe Sheila E. et al
  • Journal Title: Cell Host & Microbe Volume: 28 Issue: 3 Pages: 380-389
  • DOI: 10.1016/j.chom.2020.06.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A heterodimeric antibody fragment for passive immunotherapy against norovirus infection (2020)
  • Author(s): Yuki Yoshikazu、Kurokawa Shiho、Sato Shintaro、Sasou Ai、Matsumoto Naomi、Suzuki Akio、Sakon Naomi、Goda Yuki、Takeyama Natsumi、Miyoshi Tatsuya、Marcotte Harold、Tanaka Tomoyuki、Hammarstrom Lennart、Kiyono Hiroshi
  • Journal Title: The Journal of Infectious Diseases Volume: － Issue: 3 Pages: 470-478
  • DOI: 10.1093/infdis/jiaa115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteoprotegerin-dependent Mcell self-regulation balances gut infection and immunity. (2020)
  • Author(s): Kimura S, Nakamura Y, Kobayashi N, Shiroguchi K, KawakamiE, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, KaishoT, Iwanaga T, Hase K.
  • Journal Title: Nat Commun Volume: 11 Issue: 1 Pages: 234-234
  • DOI: 10.1038/s41467-019-13883-y
  • Peer Reviewed / Open Access
• [Journal Article] Persistent colonization of non-lymphoid tissue-resident macrophages by Stenotrophomonas maltophilia (2019)
  • Author(s): Takahashi Ichiro, Hosomi Koji, Nagatake Takahiro, Tobou Hirokazu, Yamamoto Daiki, Hayashi Ikue, Kurashima Yosuke, Sato Shintaro, Shibata Naoko, Goto Yoshiyuki, Maruyama Fumito, Nakagawa Ichiro, Kuwae Asaomi, Abe Akio, Kunisawa Jun, Kiyono Hiroshi
  • Journal Title: International Immunology Volume: 32 Issue: 2 Pages: 133-141
  • DOI: 10.1093/intimm/dxz071
  • NAID: 120006888456
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A role for the CCR5?CCL5 interaction in the preferential migration of HSV-2-specific effector cells to the vaginal mucosa upon nasal immunization (2019)
  • Author(s): Joo Sunyi、Suwanto Aldina、Sato Ayuko、Nakahashi-Ouchida Rika、Mori Hiromi、Uchida Yohei、Sato Shintaro、Kurashima Yosuke、Yuki Yoshikazu、Fujihashi Kohtaro、Kawaguchi Yasushi、Kiyono Hiroshi
  • Journal Title: Mucosal Immunology Volume: 12 Issue: 6 Pages: 1391-1403
  • DOI: 10.1038/s41385-019-0203-z
  • Peer Reviewed / Open Access
• [Journal Article] Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses (2019)
  • Author(s): Nagai M、Noguchi R、Takahashi D、Morikawa T、Koshida K、Komiyama S、Ishihara N、Yamada T、Kawamura YI.、Muroi K、Hattori K、Kobayashi N、Fujimura Y、Hirota M、Matsumoto R、Aoki R、Tamura-Nakano M、Sugiyama M、Katakai T、Sato S、Takubo K、Dohi T、Hase K
  • Journal Title: Cell Volume: 178 Issue: 5 Pages: 1072-1087
  • DOI: 10.1016/j.cell.2019.07.047
  • Peer Reviewed
• [Journal Article] Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice (2019)
  • Author(s): Kimura Shunsuke、Kobayashi Nobuhide、Nakamura Yutaka、Kanaya Takashi、Takahashi Daisuke、Fujiki Ryoji、Mutoh Mami、Obata Yuuki、Iwanaga Toshihiko、Nakagawa Tomoo、Kato Naoya、Sato Shintaro、Kaisho Tsuneyasu、Ohno Hiroshi、Hase Koji
  • Journal Title: The Journal of Experimental Medicine Volume: 216 Issue: 4 Pages: 831-846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed / Open Access
• [Presentation] Human norovirus propagation in human induced pluripotent stem cell-derived intestinal epithelial cells (2020)
  • Author(s): Shitnaro Sato
  • Organizer: Keystone Symposia - Tissue Organoids as Models of Host Physiology and Pathophysiology of Disease (J1)
  • Int'l Joint Research
• [Presentation] Human norovirus propagation in human induced pluripotent stem cell-derived intestinal epithelial cells (2019)
  • Author(s): Shitnaro Sato
  • Organizer: 19th International Congress of Mucosal Immunology
  • Int'l Joint Research
• [Book] Mucosal Vaccines, 2nd ed. - Innovation for Preventing Infections Diseases (2020)
  • Author(s): H.Kiyono & D.W.Pascual (eds.)
  • Total Pages: 915
  • Publisher: ACADEMIC PRESS, INC.
  • ISBN: 9780128119242
• [Patent(Industrial Property Rights)] ヒトノロウイルスGII.2特異的抗体 (2022)
  • Inventor(s): 幸 義和、清野 宏、佐藤 慎太郎
  • Industrial Property Rights Holder: 幸 義和、清野 宏、佐藤 慎太郎
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-044887
  • Filing Date: 2022