Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

Abstract

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.

Fig. 1.. Clinical signs in AGMs inoculated with a lethal dose of Nipah virus Bangladesh and treated with remdesivir.

Two groups of four AGMs were inoculated intranasally and intratracheally with 10⁵ TCID₅₀ of Nipah virus Bangladesh. At 1 dpi, the groups were treated intravenously with remdesivir (10 mg/kg, red circles) or vehicle solution (2 ml/kg, black squares); treatment was continued for 12 days. After inoculation, the animals were observed twice daily for clinical signs of disease and scored using a predetermined clinical scoring system (A). Survival after inoculation and treatment is indicated in (B). At regular time points after inoculation, clinical examinations were performed, during which respiration rate (C) and oxygen saturation (SPO₂) (D) were determined.

Fig. 2.. Virus replication and serology in AGMs inoculated with a lethal dose of Nipah virus Bangladesh and treated with remdesivir.

Two groups of four AGMs were inoculated intranasally and intratracheally with 10⁵ TCID₅₀ of Nipah virus Bangladesh. At 1 dpi, groups of four animals were treated intravenously with remdesivir (10 mg/kg, red circles) or vehicle solution (2 ml/kg, black squares); treatment was continued for 12 days. During clinical examinations, nose swabs, throat swabs, blood, and serum were collected, and the presence of viral RNA was determined by qRT-PCR [(A), top panels], and infectious virus was determined by virus titration [(A), bottom] in swabs and blood. The presence of IgM and IgG antibodies against Nipah virus was determined using ELISA (B); dotted line indicates lower limit of detection. At the time of necropsy, tissues were collected, and the presence of viral RNA was determined. Nipah virus RNA-positive tissues present in remdesivir-treated animals euthanized at 92 dpi are shown and compared to the same tissues collected from vehicle-treated animals on 7 and 8 dpi (C); underlined tissues were collected from the same animal. Ab, antibody.

Fig. 3.. Presence of Nipah virus in the cerebrum of one AGM inoculated with Nipah virus Bangladesh and treated with remdesivir.

At 92 dpi, all surviving animals were euthanized, and brain tissue was collected for histopathologic analysis. (A) Mononuclear perivascular cuffing and edema [hematoxylin and eosin (H&E), cerebrum, ×5]. (B) Neuronal necrosis, gliosis, and mononuclear perivascular cuffing (H&E, cerebrum, 20×). (C) Representative scattered granular staining in areas of parenchymal inflammation (arrowhead) with occasional intracellular neuronal staining (arrows) (IHC assay targeting whole Nipah virus antigen, cerebrum, ×20). Targeted antigen in red. (D) Staining of neuronal cell body and processes (IHC assay, cerebrum, ×40).