Development of the novel rabies vaccine by using gene-deficient virus

• Project/Area Number: 23380179
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied veterinary science
• Research Institution: Gifu University
• Principal Investigator: SUGIYAMA Makoto 岐阜大学, 応用生物科学部, 教授 (80196774)
• Co-Investigator(Kenkyū-buntansha): ITO Naoto 岐阜大学, 応用生物科学部, 准教授 (20334922)
• Co-Investigator(Renkei-kenkyūsha): INOUE Satoshi 国立感染症研究所, 獣医科学部, 室長 (90213157)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000); Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 狂犬病ウイルス / ワクチン / 増殖欠損ウイルス / Mタンパク質 / Pタンパク質 / 狂犬病ワクチン / 遺伝子操作 / 遺伝子欠損 / 弱毒化変異

Research Abstract

The aim of this study was to generate a replication-defective (M gene-deficient) rabies virus strain by gene manipulation and to examine the potency of the strain as a rabies vaccine. Our preliminary data strongly suggested that the M gene-deficient virus could not sufficiently propagate in Vero cells stably expressing M protein. We generated a mixture of P- and M-gene deficient viruses by gene manipulation and examined the potency as a rabies vaccine. Theoretically, P- and M-gene deficient viruses will not produce progeny viruses unless the two different viruses infect an identical cell and complement the gene defect of each other. In fact, we found that the mixture of the P- and M-gene deficient viruses has high levels of safety and immunogenicity, indicating that the mixture is a promising candidate as the next-generation rabies vaccine.

Research Products

• [Journal Article] Interaction of Rabies Virus P-Protein With STAT Proteins is Critical to Lethal Rabies Disease. (2014)
  • Author(s): Wiltzer, L, Okada, K, Yamaoka, S, Larrous, F, Kuusisto, HV, Sugiyama, M, Blondel, D, Bourhy, H, Jans, DA, Ito, N, Moseley, GW.
  • Journal Title: Journal of Infectious Diseases Volume: in press Issue: 11 Pages: 1744-1753
  • DOI: 10.1093/infdis/jit829
  • Peer Reviewed
• [Journal Article] Interaction of Rabies Virus P-Protein With STAT Proteins is Critical to Lethal Rabies Disease (2013)
  • Author(s): Wiltzer, L, Okada, K, Yamaoka, S, Larrous, F, Kuusisto, HV, Sugiyama, M, Blondel, D, Bourhy, H, Jans, DA, Ito, N, Moseley, GW
  • Journal Title: J. Infect. Dis Volume: (in press)
  • Peer Reviewed
• [Journal Article] Involvement of the rabies virus phosphoprotein gene in neuroinvasiveness (2013)
  • Author(s): Yamaoka, S, Ito, N, Ohka, S, Kaneda, S, Nakamura, H, Agari, T, Masatani, T, Nakagawa, K, Okada, K, Okadera, K, Mitake, H, Fujii, T, Sugiyama, M
  • Journal Title: J. Virol Volume: 87(22) Issue: 22 Pages: 12327-38
  • DOI: 10.1128/jvi.02132-13
  • Peer Reviewed
• [Journal Article] Generation of a live rabies vaccine strain attenuated by multiple mutations and evaluation of its safety and efficacy (2012)
  • Author(s): Nakagawa, K, Ito, N, Masatani, T, Abe, M, Yamaoka, S, Ito, Y, Okadera, K, Sugiyama, M
  • Journal Title: Vaccine Volume: 30(24) Issue: 24 Pages: 3610-7
  • DOI: 10.1016/j.vaccine.2012.03.044
  • Peer Reviewed
• [Presentation] Generation of live rabies virus strain with high levels of safety and immunogenicity by mutations in nucleoprotein and glycoprotein (2014)
  • Author(s): Nakagawa, K., Ito, N., Mastani, T., Yamaoka, S., Okadera, K., Okada, K., Sugiyama, M
  • Organizer: The 11th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji Yumebutai International Conference Center, Japan
• [Presentation] Combination of attenuating mutations in rabies virus nucleoprotein and glycoprotein enhances safety of a live vaccine strain (2014)
  • Author(s): Nakagawa, K., Ito, N., Mastani, T., Yamaoka, S., Okadera, K., Okada, K., Sugiyama, M
  • Organizer: 4th Infection and Immunity conference Lorne Mantra
  • Place of Presentation: Australia
• [Presentation] Combination of attenuating mutations in rabies virus nucleoprotein and glycoprotein enhances safety of a live vaccine strain. (2014)
  • Author(s): Keisuke Nakagawa, Naoto Ito, Tatsunori Mastani, Satoko Yamaoka, Kota Okadera, Kazuma Okada, Makoto Sugiyama
  • Organizer: 4th Infection and Immunity conference
  • Place of Presentation: Lorne Mantra, Australia
• [Presentation] N およびG 遺伝子に弱毒化変異を導入した狂犬病生ワクチン候補株の作出 (2012)
  • Author(s): 中川敬介, 伊藤直人, 山岡理子, 岡寺康太, 杉山誠
  • Organizer: 第60回日本ウイルス学会
  • Place of Presentation: 大阪国際会議場
• [Presentation] N およびG 遺伝子に弱毒化変異を導入した狂犬病ウイルス株の弱毒性状の解析 (2012)
  • Author(s): 中川敬介, 伊藤直人, 山岡理子, 岡寺康太, 杉山誠
  • Organizer: 第154回日本獣医学会
  • Place of Presentation: 岩手大学
• [Presentation] Generation of rabies virus strain attenuated by multiple mechanisms (2011)
  • Author(s): Keisuke Nakagawa
  • Organizer: International Union of Microbiological Socienties 2011 Congress
  • Place of Presentation: Sapporo
  • Year and Date: 2011-09-15
• [Presentation] N 遺伝子への変異導入による狂犬病ウイルス弱毒株の作出 (2011)
  • Author(s): 中川敬介, 伊藤直人, 正谷達謄, 山岡理子, 岡寺康太, 杉山誠
  • Organizer: 第152回日本獣医学会
  • Place of Presentation: 大阪府立大学
• [Presentation] Generation of rabies virus strain attenuated by multiple mechanisms (2011)
  • Author(s): Nakagawa, K., Ito, N., Masatani, N., Abe, M. Yamaoka, S., Okadera, K., Sugiyama, M
  • Organizer: XV International Congress of Virology
  • Place of Presentation: Sapporo Convention Center
• [Presentation] NおよびG遺伝子に弱毒化変異を導入した狂犬病ウイルス株の弱毒性状
  • Author(s): 杉山 誠
  • Organizer: 第154回日本獣医学会学術集会
  • Place of Presentation: 盛岡市
• [Presentation] NおよびG遺伝子に弱毒化変異を導入した狂犬病ワクチン候補株の作出
  • Author(s): 杉山 誠
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪市
• [Presentation] 狂犬病ウイルスの病原性発現機序に関する研究
  • Author(s): 伊藤直人
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪市
  • Invited
• [Patent(Industrial Property Rights)] 変異狂犬病ウイルス合成・増殖方法, 並びに狂犬病ワクチン製剤 (2012)
  • Inventor(s): 伊藤直人・杉山誠
  • Industrial Property Rights Holder: 国立大学法人岐阜大学・共立製薬株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-10-17
• [Patent(Industrial Property Rights)] 変異狂犬病ウイルス合成・増殖方法、並びに狂犬病ワクチン製剤 (2012)
  • Inventor(s): 伊藤直人、杉山 誠
  • Industrial Property Rights Holder: 伊藤直人、杉山 誠
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-229854
  • Filing Date: 2012-10-17
• [Patent(Industrial Property Rights)] 変異狂犬病ウイルス及びワクチン (2011)
  • Inventor(s): 伊藤直人・杉山誠
  • Industrial Property Rights Holder: 国立大学法人岐阜大学・共立製薬株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2011-10-25
• [Patent(Industrial Property Rights)] 変異狂犬病ウイルス合成・増殖方法、並びに狂犬病ワクチン製剤 (2011)
  • Inventor(s): 杉山誠, 伊藤直人
  • Industrial Property Rights Holder: 岐阜大学
  • Industrial Property Number: 2011-234036
  • Filing Date: 2011-10-25