Study of pneumonia in SARS-CoV-2 reinfection by primate COVID-19 model

• Project/Area Number: 21K19395
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: National Institutes of Biomedical Innovation, Health and Nutrition
• Principal Investigator: Yasutomi Yasuhiro 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 霊長類医科学研究センター, センター長 (90281724)
• Co-Investigator(Kenkyū-buntansha): 浦野 恵美子 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 霊長類医科学研究センター, 主任研究員 (40794988)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: COVID-19 / 霊長類モデル / 再感染 / 肺炎 / mRNAワクチン / 霊長類 / SARS-CoV-2

Outline of Research at the Start

COVID-19は高齢者において重症化することは周知であり、再感染についてもワクチン開発に関連して精査が必要である。このため、有効な動物モデルによる病態や免疫応答の解析が求められている。申請者らはカニクイザルを用いてCOVID-19霊長類モデルを作製することに成功した。霊長類医科学研究センターでは世界的にも極めて貴重な高齢ザルの巨大コロニーを保有している。これら高齢ザルを用いてSARS-CoV-2再感染モデルの検討を行ったところ、初回感染以上に強い肺炎像を示す個体も確認された。本研究では健康若齢個体に加え老齢個体におけるSARS-CoV-2再感染による肺炎の病態の解明を検討する。

Outline of Final Research Achievements

The study with the Wuhan strain demonstrated that the cynomolgus macaque reflects human COVID-19 pathological conditions. We confirmed that re-exposure to the Wuhan strain did not result in PCR re-positivity; however, one elderly monkey developed transient pneumonia with increased levels of various serum cytokines and chemokines such as cytokine storm-like symptoms after re-exposure Wuhan strain. Therefore, we examined reinfection and pathogenesis among VOC strains and evaluate mRNA vaccine efficacy on pulmonary pathology using the COVID-19 cynomolgus macaque model. Re-infection was confirmed between different virus strains and between the same VOC strain in some cases. Analysis using the mRNA vaccine showed inhibition of viral infection against the Wuhan strain, but not against the Omicron BA.5. On the other hand, viral propagation was suppressed in the lungs against both the Wuhan strain and BA.5 in vaccinated-cynomolgus macaques.

Academic Significance and Societal Importance of the Research Achievements

パンデミックとなったCOVID-19に対し、迅速なワクチン開発および積極的なワクチン接種により一定の効果が得られているが、続的な新規変異株の出現と流行により、感染が拡大し長期化している。それらに病原性の解明や現行ワクチンの効果が課題となっている。さらに、感染により誘導される免疫システムの解析は、ワクチン戦略や公衆衛生管理、今後の感染予測において極めて重要な意味を持つ。これらを明らかにするためには、有効な動物モデルを用いた解析が必須であり、本研究で得られた知見は今後のワクチン戦略にも貢献できることが期待され、高い波及効果をもたらす可能性ある。

Research Products

• [Journal Article] Age-related alterations in protein phosphatase 2A methylation levels in brains of cynomolgus monkeys: a pilot study (2023)
  • Author(s): Ando Sana、Sakurai Masashi、Shibutani Shusaku、Kimura Nobuyuki、Shimozawa Nobuhiro、Yasutomi Yasuhiro、Yabe Ryotaro、Ohama Takashi、Sato Koichi
  • Journal Title: The Journal of Biochemistry Volume: － Issue: 6 Pages: 1093-1093
  • DOI: 10.1093/jb/mvad006
  • Peer Reviewed
• [Journal Article] Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates (2023)
  • Author(s): Takahama Shokichi、Ishige Kazuya、Nogimori Takuto、Yasutomi Yasuhiro、Appay Victor、Yamamoto Takuya
  • Journal Title: Molecular Therapy - Methods & Clinical Development Volume: 28 Pages: 99-115
  • DOI: 10.1016/j.omtm.2022.12.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] d-Alanine as a biomarker and a therapeutic option for severe influenza virus infection and COVID-19 (2023)
  • Author(s): Kimura-Ohba Shihoko、Asaka Masamitsu N.、Utsumi Daichi、Takabatake Yoshitsugu、Takahashi Atsushi、Yasutomi Yasuhiro、Isaka Yoshitaka、Kimura Tomonori
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Volume: 1869 Issue: 1 Pages: 166584-166584
  • DOI: 10.1016/j.bbadis.2022.166584
  • Peer Reviewed / Open Access
• [Journal Article] Repeated Intravaginal Inoculation of Zika Virus Protects Cynomolgus Monkeys from Subcutaneous Superchallenge (2022)
  • Author(s): Shofa M, Okamura T, Urano E, Matsuura Y, Yasutomi Y, Saito A.
  • Journal Title: Int J Mol Sci Volume: 23 Issue: 22 Pages: 14002-14002
  • DOI: 10.3390/ijms232214002
  • Peer Reviewed / Open Access
• [Journal Article] Intratracheal trimerized nanobody cocktail administration suppresses weight loss and prolongs survival of SARS-CoV-2 infected mice (2022)
  • Author(s): Nagata Kayoko、Utsumi Daichi、Asaka Masamitsu N.、Maeda Ryota、Shirakawa Kotaro、Kazuma Yasuhiro、Nomura Ryosuke、Horisawa Yoshihito、Yanagida Yohei、Kawai Yugo、Sato Kei、Yamaoka Yutaro、Miyakawa Kei、Ryo Akihide、Yasutomi Yasuhiro、Imura Akihiro、Takaori-Kondo Akifumi
  • Journal Title: Communications Medicine Volume: 2 Issue: 1 Pages: 152-152
  • DOI: 10.1038/s43856-022-00213-5
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Cynomolgus Macaque Model of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Infection by Direct Inoculation of Adult T-Cell Leukemia Patient-Derived Cell Lines for HTLV-1 Infection (2022)
  • Author(s): Urano E, Ueda K, Higuchi Furukawa M, Okamura T, Tanaka Y, Yasutomi Y
  • Journal Title: J Virol Volume: 96 Issue: 22 Pages: 1339-1339
  • DOI: 10.1128/jvi.01339-22
  • Peer Reviewed / Open Access
• [Journal Article] A controlled ovarian stimulation procedure suitable for cynomolgus macaques (2022)
  • Author(s): Shimozawa Nobuhiro、Iwata Takeshi、Yasutomi Yasuhiro
  • Journal Title: Experimental Animals Volume: 71 Issue: 4 Pages: 426-432
  • DOI: 10.1538/expanim.21-0198
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed
• [Journal Article] Comparison of young and elderly COVID-19 cynomolgus macaque models reflecting human COVID-19 pathological conditions (2022)
  • Author(s): Urano E, Okamura T, Kamitani W, Kawaoka Y, Yasutomi Y.
  • Journal Title: J Translational and Regulatory Science (TRS) Volume: 4 Pages: 20-24
• [Journal Article] Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques (2022)
  • Author(s): Nagatake T, Kishino S, Urano E, et al.
  • Journal Title: Mucosal Immunology Volume: 15 Issue: 2 Pages: 289-300
  • DOI: 10.1038/s41385-021-00477-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of young and elderly COVID-19 cynomolgus macaque models reflecting human COVID-19 pathological conditions. (2022)
  • Author(s): Urano E, Okamura T, Kamitani W, Kawaoka Y, Yasutomi Y.
  • Journal Title: J Translational and Regulatory Science Volume: 118
  • Peer Reviewed / Open Access
• [Journal Article] COVID-19 cynomolgus macaque model reflecting human COVID-19 pathological conditions. (2021)
  • Author(s): Urano E, Okamura T, Ono C, Ueno S, Nagata S, Kamada H, Higuchi M, Furukawa M, Kamitani W, Matsuura Y, Kawaoka Y, Yasutomi Y.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 118 Issue: 43 Pages: 1-2
  • DOI: 10.1073/pnas.2104847118
  • Peer Reviewed / Open Access
• [Journal Article] Highly susceptible SARS-CoV-2 model in CAG promoter?driven hACE2-transgenic mice (2021)
  • Author(s): Asaka Masamitsu N.、Utsumi Daichi、Kamada Haruhiko、Nagata Satoshi、Nakachi Yutaka、Yamaguchi Tomokazu、Kawaoka Yoshihiro、Kuba Keiji、Yasutomi Yasuhiro
  • Journal Title: JCI Insight Volume: 6 Issue: 19 Pages: 1-2
  • DOI: 10.1172/jci.insight.152529
  • Peer Reviewed / Open Access
• [Journal Article] ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury (2021)
  • Author(s): Yamaguchi T, Hoshizaki M, Minato T, Nirasawa S, Asaka MN, Niiyama M, Imai M, Uda A, Chan JF, Takahashi S, An J, Saku A, Nukiwa R, Utsumi D, Kiso M, Yasuhara A, Poon VK, Chan CC, Fujino Y, Motoyama S, Nagata S, Penninger JM, Kamada H, Yuen KY, Kamitani W, Maeda K, Kawaoka Y, Yasutomi Y, Imai Y, Kuba Keiji
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 6791-6791
  • DOI: 10.1038/s41467-021-27097-8
  • Peer Reviewed / Open Access / Int'l Joint Research