Development of molecular bases of next generation vaccine: Approach from antigen depot delivery system

• Project/Area Number: 17K08254
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Showa Pharmaceutical University (2020); St. Marianna University School of Medicine (2017-2019)
• Principal Investigator: Asai Daisuke 昭和薬科大学, 薬学部, 准教授 (10423485)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ワクチン / 徐放 / DDS / 注射ゲル / エラスチン / 生体材料 / 生分解材料 / アジュバント / 抗原徐放 / バルクゲル / インジェクタブルポリマー / 人工エラスチン / 破傷風トキソイド / 破傷風 / 感染症 / 免疫学 / バイオテクノロジー / 生体生命情報学

Outline of Final Research Achievements

Vaccines typically contain an antigen, delivery system (vehicle) and adjuvant, all of which contribute to the induction of a potent immune response. Consequently, design of new vaccines is difficult, because the contributions and interactions of these components are not easy to identify. We selected recombinant elastin-like polypeptides with periodic cysteine residues (cELPs) as carriers and tetanus toxoid (Ttd) as an antigen. After subcutaneous injection of the mixture, cELP rapidly formed a disulfide cross-linked hydrogel in situ, within which Ttd is physically incorporated, affording a biodegradable antigen depot. A single injection induced high levels of tetanus antibody with high avidity for at least 20 weeks in mice. The ability of this system to separately identify the contribution of sustained antigen release to antibody induction should be helpful for rational design of next-generation vaccines.

Academic Significance and Societal Importance of the Research Achievements

新型コロナウイルス感染症に対するワクチン開発競争において、わが国は世界に遅れをとったとの一般認識が定着しつつある。ワクチン接種対象者が健常者であるために、接種後の副反応に過敏になり、ワクチン開発に係る政策は遅れをとってきた。地球規模での人口増加や途上国開拓が進むにつれ、新型コロナウイルス感染症のような新興感染症は今後も発生する可能性が高い。新規材料を用いた基礎研究の展開により得られた当該研究事業の成果は、ワクチン開発に対して抗原送達システムからの貢献に資すると期待される。

Research Products

• [Journal Article] Synthesis and Anti-HIV Activity of Sulfated Oligosaccharide-Branched β-CD (2020)
  • Author(s): Mingxue, B, Chaolumen, B, Asai, D, Miyazaki, K, Yoshida, T
  • Journal Title: Journal of Fiber Science and Technology Volume: 76 Issue: 1 Pages: 63-71
  • DOI: 10.2115/fiberst.2020-0006
  • NAID: 130007789674
  • ISSN: 2189-7654
  • Year and Date: 2020-01-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design of substrates and inhibitors of G protein-coupled receptor kinase 2 (GRK2) based on its phosphorylation reaction (2020)
  • Author(s): J.H. Kang, R. Toita, T. Kawano, M. Murata, and D. Asai
  • Journal Title: Amino Acids Volume: 52 Issue: 6-7 Pages: 863-870
  • DOI: 10.1007/s00726-020-02864-x
  • Peer Reviewed
• [Journal Article] Role of a long-chain alkyl group in sulfated alkyl oligosaccharides with high anti-HIV activity revealed by SPR and DLS (2020)
  • Author(s): Bai Mingxue, Bai Chaolumen, K. Miyazaki, Daisuke Asai, Hiromu Takemura, T. Yoshida
  • Journal Title: Carbohydr. Polym. Volume: 245 Pages: 116518-116518
  • DOI: 10.1016/j.carbpol.2020.116518
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Blood retention and antigenicity of polycarboxybetaine-modified liposomes (2020)
  • Author(s): T. Ryujin, T. Shimizu, R. Miyahara, D. Asai, R. Shimazu, T. Yoshikawa, A. Kishimura, T. Mori, T. Ishida, and Y. Katayama
  • Journal Title: Int. J. Pharm. Volume: 586 Pages: 119521-119521
  • DOI: 10.1016/j.ijpharm.2020.119521
  • Peer Reviewed
• [Journal Article] Elucidation of anti-HIV mechanism of sulfated cellobiose－polylysine dendrimers by SPR and DLS (2020)
  • Author(s): Song Weiyue, Li Yin, T. Kanamoto, D. Asai, H. Takemura, H. Nakashima, K. Miyazaki,T, Yoshida
  • Journal Title: Carbohydr. Res. Volume: 495 Pages: 108084-108084
  • DOI: 10.1016/j.carres.2020.108084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantification of antitumor, antiviral and neuroprotective activity of twenty Kampo preparations (2020)
  • Author(s): H. Shi, K. Fukuchi, D. Asai, S. Terakubo, H. Takemura, and H. Sakagami
  • Journal Title: New Food Industry Volume: 62 Pages: 599-607
  • Open Access / Int'l Joint Research
• [Journal Article] Quantification of the Ability of Natural Products to Prevent Herpes Virus Infection (2020)
  • Author(s): Fukuchi Kunihiko、Sakagami Hiroshi、Sugita Yoshiaki、Takao Koichi、Asai Daisuke、Terakubo Shigemi、Takemura Hiromu、Ohno Hirokazu、Horiuchi Misaki、Suguro Madoka、Fujisawa Tomohiro、Toeda Kazuki、Oizumi Hiroshi、Yasui Toshikazu、Oizumi Takaaki
  • Journal Title: Medicines Volume: 7 Issue: 10 Pages: 64-64
  • DOI: 10.3390/medicines7100064
  • Peer Reviewed / Open Access
• [Journal Article] Rapid virus inactivation by alkaline extract of leaves of Sasa sp. (2020)
  • Author(s): H. Sakagami, K. Fukuchi, D. Asai, S. Terakubo, H. Takemura, M. Horiuchi, T. Fujisawa, M.
  • Journal Title: New Food Industry Volume: 62 Pages: 785-790
  • NAID: 40022397008
  • Open Access
• [Journal Article] Effect of Fetal Bovine Serum Concentration on Lysophosphatidylcholine-mediated Proliferation and Apoptosis of Human Aortic Smooth Muscle Cells (2020)
  • Author(s): Asai, D, Kawano, T, Murata, M, Nakashima, H, Toita, R, Kang, J.H
  • Journal Title: Journal of Oleo Science Volume: 69 Issue: 3 Pages: 255-260
  • DOI: 10.5650/jos.ess19268
  • NAID: 130007804109
  • ISSN: 1345-8957, 1347-3352
  • Peer Reviewed / Open Access
• [Journal Article] A high-affinity peptide substrate for G protein-coupled receptor kinase 2 (GRK2) (2019)
  • Author(s): Daisuke Asai, Masaharu Murata, Riki Toita, Takahito Kawano, Hideki Nakashima, Jeong-Hun Kang
  • Journal Title: Amino acids Volume: 51 Issue: 6 Pages: 973-976
  • DOI: 10.1007/s00726-019-02735-0
  • Peer Reviewed
• [Journal Article] Suppression of lysophosphatidylcholine-induced human aortic smooth muscle cell calcification by protein kinase A inhibition (2019)
  • Author(s): Riki Toita, Daisuke Asai, Kentaro Otani, Takahito Kawano, Masaharu Murata, Jeong-Hun Kang
  • Journal Title: Lipids Volume: 54 Issue: 8 Pages: 465-470
  • DOI: 10.1002/lipd.12178
  • Peer Reviewed
• [Journal Article] Injectable polypeptide hydrogel depot system for assessment of the immune-response-inducing efficacy of sustained antigen release alone (2019)
  • Author(s): Asai, D, Fukuda, T, Morokuma, K, Funamoto, D, Yamaguchi, Y, Mori, T, Katayama, Y, Shibayama, K, Nakashima, H
  • Journal Title: Macromol. Biosci. Volume: 19 Issue: 10
  • DOI: 10.1002/mabi.201900167
  • Peer Reviewed
• [Journal Article] A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells (2018)
  • Author(s): Koichi Sasaki, Yoshiki Miyashita, Daisuke Asai, Daiki Funamoto, Kazuki Sato, Yoko Yamaguchi, Yuji Mishima, Tadafumi Iino, Shigeo Takaishi, Jun Nagano, Akihiro Kishimura, Takeshi Mori and Yoshiki Katayama
  • Journal Title: Medicinal Chemistry Communications Volume: 印刷中 Issue: 5 Pages: 783-788
  • DOI: 10.1039/c8md00010g
  • Peer Reviewed
• [Journal Article] Pathogenic viruses commonly present in the oral cavity and relevant antiviral compounds derived from natural products. (2018)
  • Author(s): Asai, D. and Nakashima, H.
  • Journal Title: Medicines(Basel) Volume: 5 Issue: 4 Pages: 120-120
  • DOI: 10.3390/medicines5040120
  • Peer Reviewed / Open Access
• [Journal Article] In situ depot formation of anti-HIV fusion-inhibitor peptide in recombinant protein polymer hydrogel (2017)
  • Author(s): Asai, D., Kanamoto, T., Takenaga, M., and Nakashima, H.
  • Journal Title: Acta Biomater. Volume: 64 Pages: 116-125
  • DOI: 10.1016/j.actbio.2017.10.024
  • Peer Reviewed
• [Journal Article] Role of amino acid residues surrounding the phosphorylation site in peptide substrates of G protein-coupled receptor kinase 2 (GRK2) (2017)
  • Author(s): Asai, D., Nakashima, H., and Kang, J.-H.
  • Journal Title: Biomed. Adv. Volume: Editors' Picks (in July 2017) Pages: 22-22
  • Open Access
• [Presentation] 抗体産生および抗体特性に及ぼす抗原徐放単独寄与の解明 (2019)
  • Author(s): 浅井大輔、福田靖、諸熊一則、船本大起、山口優子、森健、片山佳樹、柴山恵吾、中島秀喜
  • Organizer: 第35回日本ＤＤＳ学会学術集会
• [Presentation] 近接双性イオンポリマーの低抗原性の評価 (2019)
  • Author(s): 龍神尭昌、宮原涼、浅井大輔、岸村顕広、森健、片山佳樹
  • Organizer: 第56回化学関連支部合同九州大会
• [Presentation] 次世代ワクチンの基盤開発研究：インジェクタブルゲル抗原製剤を用いたアプローチ (2019)
  • Author(s): 浅井大輔、福田靖、諸熊一則、船本大起、山口優子、森健、片山佳樹、柴山恵吾、中島秀喜
  • Organizer: 第41回日本バイオマテリアル学会大会
• [Presentation] 注射型抗HIVペプチドデポ製剤の開発 (2017)
  • Author(s): 浅井大輔, 金本大成, 寺久保繁美, Ashutosh Chilkoti, 武永美津子, 中島秀喜
  • Organizer: 第33回日本DDS学会学術集会
• [Presentation] Protection from off-target ADCC by using peptide inhibitors (2017)
  • Author(s): Mori, T., Sasaki, K., Miyashita, Y., Asai, D., Harada, M., Kishimura, A. and Katayama, Y.
  • Organizer: The 2nd international symposium on biofunctional chemistry (ISBC2017)
  • Int'l Joint Research
• [Book] ペプチド医薬品のスクリーニング・安定化・製剤化技術, 第7章 ペプチド医薬品の製剤化技術 第２節 抗HIVペプチドのデポ製剤化 (2017)
  • Author(s): 浅井大輔, 中島秀喜
  • Total Pages: 587
  • Publisher: (株)技術情報協会
• [Remarks] 抗微生物薬の送達手法開発（聖マリアンナ医科大学 微生物学教室HP）
  • URL: http://www.marianna-u.ac.jp/microbiology/office/003334.html
• [Remarks] 聖マリアンナ医科大学微生物学教室
  • URL: http://www.marianna-u.ac.jp/microbiology/office/003334.html