Subcutaneous remdesivir administration prevents interstitial pneumonia in rhesus macaques inoculated with SARS-CoV-2

Abstract

The utility of remdesivir treatment in COVID-19 patients is currently limited by the necessity to administer this antiviral intravenously, which has generally limited its use to hospitalized patients. Here, we tested a novel, subcutaneous formulation of remdesivir in the rhesus macaque model of SARS-CoV-2 infection that was previously used to establish the efficacy of remdesivir against this virus in vivo. Compared to vehicle-treated animals, macaques treated with subcutaneous remdesivir from 12 h through 6 days post inoculation showed reduced signs of respiratory disease, a reduction of virus replication in the lower respiratory tract, and an absence of interstitial pneumonia. Thus, early subcutaneous administration of remdesivir can protect from lower respiratory tract disease caused by SARS-CoV-2.

Keywords: Animal model; Antiviral; COVID-19.

Fig. 1

Clinical disease and replication in the lower respiratory tract of rhesus macaques inoculated with SARS-CoV-2 and treated with subcutaneous remdesivir. Two groups of six rhesus macaques were inoculated with SARS-CoV-2 strain nCoV-WA1-2020. Twelve hours post inoculation, one group was administered 10 mg/kg subcutaneous remdesivir and the other group was treated with an equal volume of vehicle solution (NMP; 0.2 ml/kg). Treatment was continued 12 h after the first treatment, and every 24 h thereafter with a dose of 5 mg/kg remdesivir or equal volume of vehicle solution (0.1 ml/kg). A. Daily clinical scores were obtained using a standardized scoring sheet by a person blinded to the group assignment of the animals. B. Proportion of animals in each group that displayed respiratory signs during daily clinical scoring. C. Ventro-dorsal and lateral radiographs were scored for the presence of pulmonary infiltrates by a clinical veterinarian blinded to the group assignment of the animals according to a standard scoring system. The number of animals with pulmonary infiltrates over time is shown. D. On 1, 3, and 7 dpi, bronchoalveolar lavages were performed and tested for the presence of gRNA (left panel), sgRNA (middle panel) and infectious virus (right panel). E. On 7 dpi, animals were euthanized and tissue samples were collected from all lung lobes and tested for the presence of gRNA (left panel) and sgRNA (right panel). Data in panels A and D were analyzed using a 2-way ANOVA, and data in panel E using a Mann Whitney test; only p-values <0.05 are indicated in the graphs.

Fig. 2

Histological changes in the lungs of rhesus macaques inoculated with SARS-CoV-2 and treated with subcutaneous remdesivir. Two groups of six rhesus macaques were inoculated with SARS-CoV-2 strain nCoV-WA1-2020. Twelve hours post inoculation, one group was administered 10 mg/kg subcutaneous remdesivir and the other group was treated with an equal volume of vehicle solution (NMP; 0.2 ml/kg). Treatment was continued 12 h after the first treatment, and every 24 h thereafter with a dose of 5 mg/kg remdesivir or equal volume of vehicle solution (0.1 ml/kg). On 7 dpi, all animals were euthanized and lung tissue was collected for analysis by a board-certified veterinary pathologist blinded to the group assignment of the animals. A. Lungs from remdesivir-treated rhesus macaques were essentially normal. B. Multifocal interstitial pneumonia with lymphocytic perivascular cuffing in one of the vehicle-treated controls. C. Histological lesion severity was scored per lung lobe according to a standardized scoring system evaluating the presence of interstitial pneumonia, type II pneumocyte hyperplasia, edema and fibrin, and perivascular lymphoid cuffing (score 0–5); these values were combined per lung lobe and graphed. D. Presence of viral antigen was scored per lung lobe according to a standardized scoring system (0–5); these values were combined per lung lobe and graphed. The size bar in panel A and B indicates 200 μm. Statistical analysis was performed on the data in panel C and D using a Mann Whitney test; p-value < 0.05 is indicated in the graph; ns: not significant.