Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2

Munster, Vincent J.; Feldmann, Friederike; Williamson, Brandi N.; Doremalen, Neeltje van; Pérez-Pérez, Lizzette; Schulz, Jonathan; Meade-White, Kimberly; Okumura, Atsushi; Callison, Julie; Brumbaugh, Beniah; Avanzato, Victoria A.; Rosenke, Rebecca; Hanley, Patrick W.; Saturday, Greg; Scott, Dana; Fischer, Elizabeth R.; Wit, Emmie de

doi:10.1101/2020.03.21.001628

Cited by 124 publications

(119 citation statements)

References 35 publications

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“…Here, we investigated the efficacy of remdesivir treatment in our recently established rhesus macaque model of SARS-CoV-2 infection. In this model, infected rhesus macaques develop mild to moderate, transient respiratory disease with pulmonary infiltrates visible on radiographs, and a shedding pattern similar to that observed in COVID-19 patients 9 . Therapeutic treatment of rhesus macaques with remdesivir shortly before the peak of virus replication resulted in a significant clinical improvement, reduction in pulmonary infiltrates, and a reduction in pulmonary pathology.…”

Section: Introductionmentioning

confidence: 59%

“…To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease 9 . Twelve animals were randomly assigned to two groups and inoculated as described previously with a total dose of 2.6x10 6 TCID50 of SARS-CoV-2 strain nCoV-WA1-2020 via intranasal, oral, ocular and intratracheal routes.…”

Section: Methodsmentioning

confidence: 99%

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Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Williamson

Feldmann

Schwarz

et al. 2020

Preprint

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187

203

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Background: Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. Methods:To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy. Results:In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue. Conclusions: Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefitin SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

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Section: Introductionmentioning

confidence: 59%

Section: Methodsmentioning

confidence: 99%

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Williamson

Feldmann

Schwarz

et al. 2020

Preprint

Self Cite

187

203

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“…Similar results regarding viral shedding and tissue and cell tropism were recently also reported following SARS-CoV-2 inoculation in rhesus macaques. However, unlike in our model, SARS-CoV-2 infection in rhesus macaques does result in transient respiratory disease and weight loss (22,23).…”

mentioning

confidence: 77%

Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Rockx

Kuiken

Herfst

et al. 2020

Science

864

927

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The current pandemic coronavirus, severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), was recently identified in patients with an acute respiratory syndrome, coronavirus disease 2019 (COVID-19). To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or Middle East respiratory syndrome (MERS)–CoV and compared the pathology and virology with historical reports of SARS-CoV infections. In SARS-CoV-2–infected macaques, virus was excreted from nose and throat in the absence of clinical signs and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV infection, lung lesions were typically more severe, whereas they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 causes COVID-19–like disease in macaques and provides a new model to test preventive and therapeutic strategies.

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“…Therefore, animal models are urgently expected to be established for this severe COVID-19. Although several models of COVID-19 have recently been reported [5][6][7] , including the non-human primate model, none of model should be considered to be the best one, depending on what questions we are going to answer with the animal models. About 16 years ago, the nonhuman primate models recapitulated several important aspects of SARS [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Comparison of SARS-CoV-2 infections among 3 species of non-human primates

Zhao

et al. 2020

Preprint

149

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COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and new world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C.jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV2 infection, followed by M. fascicularis and C. jacchus. One Sentence Summary:M. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.

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Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2

Cited by 124 publications

References 35 publications

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Comparison of SARS-CoV-2 infections among 3 species of non-human primates

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