Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster modelResearch in context
Michihito Sasaki,
Tatsuki Sugi,
Shun Iida,
Yuichiro Hirata,
Shinji Kusakabe,
Kei Konishi,
Yukari Itakura,
Koshiro Tabata,
Mai Kishimoto,
Hiroko Kobayashi,
Takuma Ariizumi,
Kittiya Intaruck,
Haruaki Nobori,
Shinsuke Toba,
Akihiko Sato,
Keita Matsuno,
Junya Yamagishi,
Tadaki Suzuki,
William W. Hall,
Yasuko Orba,
Hirofumi Sawa
Affiliations
Michihito Sasaki
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; Corresponding author. Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
Tatsuki Sugi
Division of Collaboration and Education, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
Shun Iida
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Yuichiro Hirata
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Shinji Kusakabe
Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan
Kei Konishi
Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan
Yukari Itakura
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan
Koshiro Tabata
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan
Mai Kishimoto
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
Hiroko Kobayashi
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
Takuma Ariizumi
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
Kittiya Intaruck
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
Haruaki Nobori
Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan
Shinsuke Toba
Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan
Akihiko Sato
Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan
Keita Matsuno
International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Division of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan
Junya Yamagishi
Division of Collaboration and Education, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan
Tadaki Suzuki
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
William W. Hall
Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; National Virus Reference Laboratory, School of Medicine, University College of Dublin, Ireland; Global Virus Network, Baltimore, Maryland, USA
Yasuko Orba
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan
Hirofumi Sawa
Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan; Global Virus Network, Baltimore, Maryland, USA
Summary: Background: Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals. Methods: We studied the therapeutic effects of monotherapy with the oral antiviral ensitrelvir or the anti-inflammatory corticosteroid methylprednisolone and combination therapy with ensitrelvir and methylprednisolone in a delayed dosing model of hamsters infected with SARS-CoV-2. Findings: Combination therapy with ensitrelvir and methylprednisolone improved respiratory conditions and reduced the development of pneumonia in hamsters even when the treatment was started after 2 days post-infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulation of expression of genes involved in the inflammatory response. Furthermore, we found that the combination treatment is effective in case of infection with either the highly pathogenic delta or circulating omicron variants. Interpretation: Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment from the perspective of lung pathology and host inflammatory responses. Funding: Funding bodies are described in the Acknowledgments section.
