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

Abstract

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 benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

Figure 1.. Reduced respiratory disease in rhesus macaques infected with SARS-CoV-2 and treated with remdesivir.

Panel A shows daily clinical scores in animals infected with SARS-CoV-2 and treated with remdesivir (red circles) or vehicle solution (black squares). Panel B shows cumulative radiograph scores. Ventro-dorsal and lateral radiographs were scored for the presence of pulmonary infiltrates by a clinical veterinarian according to a standard scoring system (0: normal; 1: mild interstitial pulmonary infiltrates; 2: moderate pulmonary infiltrates perhaps with partial cardiac border effacement and small areas of pulmonary consolidation; 3: severe interstitial infiltrates, large areas of pulmonary consolidation, alveolar patterns and air bronchograms). Individual lobes were scored and scores per animal per day were totaled and displayed. Panel C shows ventro-dorsal radiographs collected from each animal taken on 7 dpi. Areas of pulmonary infiltration are marked with a circle. Statistical analysis was performed using a 2-way ANOVA with Sidak’s multiple comparisons test. ** P<0.01; *** P< 0.001; **** P< 0.0001

Figure 2.. Viral loads and virus titers in bronchoalveolar lavage fluid.

Panel A shows viral loads and Panel B shows infectious virus titers in BAL collected from rhesus macaques infected with SARS-CoV-2 and treated with remdesivir (red circles) or vehicle solution (black squares). Statistical analysis was performed using a 2-way ANOVA with Sidak’s multiple comparisons test. *** P< 0.001

Figure 3.. Viral loads and virus titers in swabs collected from rhesus macaques infected with SARS-CoV-2 and treated with remdesivir.

Panel A shows viral loads and Panel B shows infectious virus titers in nose, throat and rectal swabs collected daily. Statistical analysis was performed using a 2-way ANOVA with Sidak’s multiple comparisons test. * P<0.05; ** P<0.01

Figure 4.. Viral loads in tissues collected from the respiratory tract on 7 dpi.

Panel A shows viral loads in all six lung lobes collected from rhesus macaques infected with SARS-CoV-2 and treated with remdesivir (red circles) or vehicle solution (black squares), stratified per lung lobe. In panel B, all viral loads were combined. Statistical analysis was performed using an unpaired t test. ***P<0.001. Panel C shows viral loads in other tissues collected throughout the respiratory tract on 7 dpi.

Figure 5.. Pathological changes in lungs of rhesus macaques infected with SARS-CoV-2 and treated with remdesivir.

Panel A shows the area of each individual lung lobe affected by gross lesions as scored by a veterinary pathologist. In panel B, all data from A are combined. Panel C shows the lung weight: bodyweight ratio as an indicator of pulmonary edema. Panel D shows the cumulative histology score. Each lung lobe was scored for the presence of histologic lung lesions on a predetermined scale (0–4); these values were combined per animal and graphed. Data in panel A were analyzed using a 2-way ANOVA with Sidak’s multiple comparisons test; data in panels B-D were analyzed using an unpaired t test. * P<0.05; **** P<0.0001

Figure 6.. Changes to the lungs of rhesus macaques infected with SARS-CoV-2 and treated with remdesivir.

Panel A shows a representative dorsal view of lungs of a remdesivir-treated animal. Panel B shows a representative dorsal view of lungs of a vehicle-treated animal with focally extensive areas of consolidation (circles). Panel C shows minimal subpleural interstitial pneumonia (box) observed in 3 of 6 remdesivir-treated animals. Panel D shows moderate subpleural interstitial pneumonia with edema (box) observed in 5 of 6 vehicle-treated animals. Panel E shows the boxed area from panel C with alveoli lined by type II pneumocytes (arrow) and alveolar spaces containing foamy macrophages (arrowhead). Panel F shows the boxed area from panel E with pulmonary interstitium expanded by edema and moderate numbers of inflammatory cells. Alveoli are lined by type II pneumocytes (arrows). Alveolar spaces are filled with edema (asterisk) and small numbers of pulmonary macrophages (arrowhead). Panel G shows viral antigen in type I pneumocytes (arrow) and type II pneumocytes (arrowhead) of a remdesivir-treated animal. Panel H shows viral antigen in type I pneumocytes (arrow) and macrophage (arrowhead) of a vehicle-treated animal. Magnification C and D: 40x; panel E-H: 200x.