Improvement of rabies post-exposure prophylaxis for category III exposure

• Project/Area Number: 19K08957
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Oita University
• Principal Investigator: Nishizono Akira 大分大学, 医学部, 教授 (70218155)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 狂犬病 / 曝露後発症予防治療 / 抗ウイルス薬 / 脳血液関門 / 曝露後治療 / 血液脳関門 / 免疫グロブリン / カテゴリーIII

Outline of Research at the Start

狂犬病は致死率ほぼ100%のウイルス性脳炎であるが、曝露後治療（PEP）により発症阻止が可能である。しかし、免疫グロブリン（RIG）を使用できないことや頭頸部への曝露等の理由により、「PEPが失敗」するケースがある。そこで本研究では、現状に即した「失敗しないPEP」の確立に向け、RIGの代替としてのPEPにおける抗ウイルス薬投与の有効性、および頭頸部への曝露に関して抗ウイルス薬の血液脳関門を超えて脳内に浸透させる術としてマイクロバブル・経頭蓋的集束超音波併用法の有効性について、ウイルス感染モデルマウスを用いたin vivoイメージングにより評価し、効果の高いPEPレジメンの提案を行う。

Outline of Final Research Achievements

In rabies, which is an incurable disease, severe bites classified as Category III may be fatal even after exposure (PEP) with immunoglobulin preparations (RIG) and continuous rabies vaccines. Effective administration of the antiviral drug Favipiravir was examined for the proposal of PEP regimen which is accessible and more effective for severe bite exposure. In order to update the permeability of the brain blood barrier (BBB) of the drug, modification by cyclodextrin was performed, and the effect was examined, but sufficient results were not obtained. However, it was considered that sufficient prevention effect was obtained by administering favipiravir orally continuously immediately after severe exposure and continuing continuous administration of the vaccine, and it was possible to advocate it as a new PEP regimen.

Academic Significance and Societal Importance of the Research Achievements

当初の研究目的で挙げた、狂犬病発症後の脳血液関門の透過性を上昇させる結果は最終的に得られなかったが、これまでに狂犬病ウイルスに対する抗ウイルス効果を確認できている薬剤ファビピラビルをウイルス曝露直後に経口投与し、その後に狂犬病ワクチンの連続接種を行うことで、抗狂犬病免疫グロブリンの効果と遜色無い、100％での発症予防効果を確認できた。このことは、カテゴリーIIIの重度曝露に対する新たな発症後治療のレジメを提示できたものと考えられ、本研究の最終目的の達成に適うと考えられた。

Research Products

• [Int'l Joint Research] フィリピン熱帯医学研究所/フィリピン農業省/国立サンラザロ病院(フィリピン)
• [Int'l Joint Research] 熱帯医学研究所(フィリピン)
• [Int'l Joint Research] フィリピン熱帯医学研究所/国立サンラザロ病院(フィリピン)
• [Journal Article] Lateral flow devices for samples collected by straw sampling method for postmortem canine rabies diagnosis. (2021)
  • Author(s): Mananggit MR, Manalo DL, Saito N, Kimitsuki K, Garcia AMG, Lacanilao PMT, Ongtangco JT, Velasco CR, Del Rosario MVA, Lagayan MGO, Yamada K, Park CH, Inoue S, Suzuki M, Saito-Obata M, Kamiya Y, Demetria CS, Quiambao BP, Nishizono A.
  • Journal Title: PLoS Negl Trop Dis. Volume: 15 Issue: 12 Pages: e0009891-e0009891
  • DOI: 10.1371/journal.pntd.0009891
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] alidation of serum apolipoprotein A1 in rabies virus-infected mice as a biomarker for the preclinical diagnosis of rabies. (2021)
  • Author(s): Yamada K, Kuribayashi K, Inomata N, Noguchi K, Kimitsuki K, Demetria CS, Saito N, Inoue S, Park CH, Kaimori R, Suzuki M, Saito-Obata M, Kamiya Y, Manalo DL, Quiambao BP, Nishizono A.
  • Journal Title: Microbiol Immunol. Volume: 65 Issue: 10 Pages: 438-448
  • DOI: 10.1111/1348-0421.12929
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Background and descriptive features of rabies-suspected animals in Central Luzon, Philippines. (2021)
  • Author(s): Mananggit MR, Kimitsuki K, Saito N, Garcia AMG, Lacanilao PMT, Ongtangco JT, Velasco CR, Rosario MVD, Lagayan MGO, Yamada K, Park CH, Inoue S, Suzuki M, Saito-Obata M, Kamiya Y, Manalo DL, Demetria CS, Quiambao BP, Nishizono A.
  • Journal Title: Trop Med Health. Volume: 49 Issue: 1 Pages: 59-59
  • DOI: 10.1186/s41182-021-00351-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk factors and protective immunity against rabies in unvaccinated butchers working at dog slaughterhouses in Northern Vietnam. (2021)
  • Author(s): Nguyen AKT, Vu AH, Nguyen TT, Nguyen DV, Ngo GC, Pham TQ, Inoue S, Nishizono A
  • Journal Title: Am J Trop Med Hyg. Volume: 105 Issue: 3 Pages: 788-793
  • DOI: 10.4269/ajtmh.20-1172
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Rabies infected dog at slaughterhouses: A potential risk of rabies transmission via dog trading and butchering activities in Vietnam. (2021)
  • Author(s): Vu AH, Nguyen TT, Nguyen DV, Ngo GC, Inoue S, Nishizono A, Nguyen TD, Anh Kieu Thi Nguyen AKT.
  • Journal Title: Zoonoses Public Health. Volume: 68 Issue: 6 Pages: 630-637
  • DOI: 10.1111/zph.12851
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of the diagnostic accuracy of lateral flow devices as a tool to diagnose rabies in post-mortem animals. (2020)
  • Author(s): Kimitsuki K, Saito N, Yamada K, Park CH, Inoue S, Suzuki M, Obata MS, Kamiya Y, Manalo DL, Demetria CS, Mananggit MR, Quiambao BP, Nishizono A.
  • Journal Title: PLoS Negl Trop Dis. Volume: 14
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and Phenotypic Characterization of a Rabies Virus Strain Isolated from a Dog in Tokyo, Japan in the 1940s. (2020)
  • Author(s): 11.Takahashi T, Inukai M, Sasaki M, Potratz M, Jarusombuti S, Fujii Y, Nishiyama S, Finke S, Yamada K, Sakai H, Sawa H, Nishizono A, Sugiyama M, Ito N.
  • Journal Title: Viruses Volume: 12 Issue: 9 Pages: 914-914
  • DOI: 10.3390/v12090914
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reevaluation of the efficacy of favipiravir against rabies virus using in vivo imaging analysis. (2019)
  • Author(s): Yamada K, Noguchi K, Kimitsuki K, Kaimori R, Saito N, Komeno T, Nakajima N, Furuta Y, Nishizono A.
  • Journal Title: Antiviral Res. Volume: 172 Pages: 104641-104641
  • DOI: 10.1016/j.antiviral.2019.104641
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel bat-associated circovirus identified in northern Hokkaido, Japan. (2019)
  • Author(s): Matsumoto T, Sato M, Nishizono A, Ahmed K.
  • Journal Title: Arch Virol. Volume: 164(8) Issue: 8 Pages: 2179-2182
  • DOI: 10.1007/s00705-019-04286-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 1.One Healthの視点からの狂犬病 Rabies, from the viewpoint of “One Health” (2021)
  • Author(s): 西園晃
  • Organizer: 第62回日本熱帯医学会総会（仙台市, Web)
  • Invited
• [Presentation] 2.Evaluation of a real-time mobile PCR device (PCR1100) in the detection of Rabies Nucleoprotein RNA in Experimentally Infected Samples, (2021)
  • Author(s): Demetria CS, Kawano M, Kimitsuki K, Yahiro T, Saito N, Manalo DL, Chu MYJV, Mauhay J, Quiambao BP and Nishizono A
  • Organizer: 第62回日本熱帯医学会総会（仙台市, Web)
• [Presentation] 3.Characteristics of management and clinical signs of rabies suspected animals in the endemic areas of the Philippines: Data from 2019 to 2021 (2021)
  • Author(s): Kimitsuki K, Saito N, Garcia AMG, Lacanilao PMT, Ongtangco JT, Velasco CR, Rosario MVD, Lagayan MGO, Manalo DL, Demetria CS, Quiambao BP, Nishizono A
  • Organizer: 第62回日本熱帯医学会総会（仙台市, Web)
• [Presentation] 4.Characteristics of human rabies in Metro Manila. the Philippines. 2-year prospective study. (2021)
  • Author(s): Saito N, Kimitsuki K, Yamada K, Ferdinand GD, Rontgene SM, Kamiya Y, Quiambao BP, and Nishizono A
  • Organizer: 第62回日本熱帯医学会総会（仙台市, Web)
• [Presentation] 5.Evaluation of screening RT-PCR assay using RNA extracted from lateral flow device after the use of rabies post-mortem diagnosis for the genome sequencing (2021)
  • Author(s): Saito N, Mauhay JM, Kimitsuki K, Yamada K, Quiambao, BP, and Nishizono A
  • Organizer: 第62回日本熱帯医学会総会（仙台市, Web)
• [Presentation] 6.狂犬病流行国フィリピンにおける狂犬病疑い動物の臨床的特徴 (2021)
  • Author(s): 西園晃, 君付和範, 齊藤信夫, Mananggit MR, Garcia AMG, Lacanilao PMT, Ongtangco JT, Velasco CR, Rosario MVD, Lagayan MGO, Manalo DL, Demetria CS, Quiambao BP.
  • Organizer: 第25回日本渡航医学会学術集会（東京都, Web)
• [Presentation] 7.狂犬病 ～この忘れられた死の病と最新の知見～ (2021)
  • Author(s): 西園晃
  • Organizer: One Health国際フォーラム（福岡市, Web)
  • Invited
• [Presentation] 8.One Healthの視点からの狂犬病 (2021)
  • Author(s): 西園晃
  • Organizer: 第95回日本感染症学会総会 教育講演（東京都, Web)
  • Invited
• [Presentation] Prospective observational study of human rabies in the Philippines (Interium analysis) (2020)
  • Author(s): Nobuo Saito, Kazunori Kimitsuki, Kentaro Yamada, Beatriz Quiambao, Ferdinand Guzman, Solante Rontgene, Motoi Suzuki, Yasuhiko Kamiya, Akira Nishizono,
  • Organizer: グローバルヘルス合同大会
• [Presentation] フィリピン中部ルソン地域におけるイヌ狂犬病診断の現状と迅速診断キットの現場応用の評価 (2020)
  • Author(s): 君付和範, 齊藤信夫, Manalo Daria, Lagayan MariaGlofezita, Manangitt Milagros, Quiambao Beatriz, 西園晃
  • Organizer: グローバルヘルス合同大会
• [Presentation] Illuminating the stealth rabies virus infection with bioluminescence (2020)
  • Author(s): Yamada K, Nishizono A
  • Organizer: 51st US-Japan Cooperative Medical Science Program, Viral Panel Meeting (Bangkok, Thailand)
  • Int'l Joint Research
• [Presentation] Screening and validation of a biomarker candidate applicable to preclinical diagnosis of rabies (2019)
  • Author(s): Yamada K, Kobayashi K, Inomato N, Kaimori R, Kimitsuki K,, Saito N, Nishizono A.
  • Organizer: 第67回日本ウイルス学会学術集会（東京）
• [Book] まるわかりワクチンQ&A 第3版 (2020)
  • Author(s): 中野貴司編
  • Total Pages: 465
  • Publisher: 日本医事新報社
  • ISBN: 9784784944736
• [Book] 海外渡航者のためのワクチンガイドライン/ガイダンス2019 (2019)
  • Author(s): 西園晃
  • Total Pages: 178
  • Publisher: 協和企画
  • ISBN: 9784877942045
• [Remarks] 国立大学法人大分大学医学部微生物学講座（西園研究室）
  • URL: http://www.med.oita-u.ac.jp/biseibut/
• [Remarks] 大分大学グローカル感染症研究センター
  • URL: https://www.oita-glocal.jp/