Combination therapy with remdesivir and monoclonal antibodies protects nonhuman primates against advanced Sudan virus disease
Robert W. Cross, Zachary A. Bornholdt, Abhishek N. Prasad, Courtney Woolsey, Viktoriya Borisevich, Krystle N. Agans, Daniel J. Deer, Dafna M. Abelson, Do H. Kim, William S. Shestowsky, Lioudmila A. Campbell, Elaine Bunyan, Joan B. Geisbert, Natalie S. Dobias, Karla A. Fenton, Danielle P. Porter, Larry Zeitlin, Thomas W. Geisbert
Robert W. Cross, Zachary A. Bornholdt, Abhishek N. Prasad, Courtney Woolsey, Viktoriya Borisevich, Krystle N. Agans, Daniel J. Deer, Dafna M. Abelson, Do H. Kim, William S. Shestowsky, Lioudmila A. Campbell, Elaine Bunyan, Joan B. Geisbert, Natalie S. Dobias, Karla A. Fenton, Danielle P. Porter, Larry Zeitlin, Thomas W. Geisbert
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Research Article Virology

Combination therapy with remdesivir and monoclonal antibodies protects nonhuman primates against advanced Sudan virus disease

Abstract

A major challenge in managing acute viral infections is ameliorating disease when treatment is delayed. Previously, we reported the success of a 2-pronged mAb and antiviral remdesivir therapeutic approach to treat advanced illness in rhesus monkeys infected with Marburg virus (MARV). Here, we explored the benefit of a similar combination therapy for Sudan ebolavirus (Sudan virus; SUDV) infection. Importantly, no licensed anti-SUDV therapeutics currently exist, and infection of rhesus macaques with SUDV results in a rapid disease course similar to MARV with a mean time to death of 8.3 days. When initiation of therapy with either remdesivir or a pan-ebolavirus mAb cocktail (MBP431) was delayed until 6 days after inoculation, only 20% of macaques survived. In contrast, when remdesivir and MBP431 treatment were combined beginning 6 days after inoculation, significant protection (80%) was achieved. Our results suggest that combination therapy may be a viable treatment for patients with advanced filovirus disease that warrants further clinical testing in future outbreaks.

Authors

Robert W. Cross, Zachary A. Bornholdt, Abhishek N. Prasad, Courtney Woolsey, Viktoriya Borisevich, Krystle N. Agans, Daniel J. Deer, Dafna M. Abelson, Do H. Kim, William S. Shestowsky, Lioudmila A. Campbell, Elaine Bunyan, Joan B. Geisbert, Natalie S. Dobias, Karla A. Fenton, Danielle P. Porter, Larry Zeitlin, Thomas W. Geisbert

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Figure 3

Pathology of the liver, spleen, and lung of SUDV-challenged rhesus macaques.

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Pathology of the liver, spleen, and lung of SUDV-challenged rhesus macaq...
Representative photomicrographs of IHC for anti-SUDV VP 40 antigen (brown) in liver (A, E, I, M, and Q), spleen (C, G, K, O, and S), and lung (D, H, L, P, and T). All photomicrographs were taken at 20× original magnification. H&E staining of the spleen (B, F, J, N, and R) and gross images of the liver (U, V, W, and X. D5-CTRL (A–D). IHC positivity of sinusoidal lining cells, Kupffer cells, and rarely, hepatocytes (A); marked disruption of normal splenic architecture with fibrin accumulation, hemorrhage, and lymphocytolysis of the white pulp (B); IHC-positive mononuclear cells within the red and white pulp of the spleen (C); IHC-positive mononuclear cells within the alveolar septa (black arrow) and alveolar macrophages (white arrow) (D). No appreciable immunolabeling or lesions noted in the liver, spleen, or lung of D5-RDV-4 (E–H), D6-RDV-2 (I–L), D6-MBP-1 (M–P), and D6-COMB-3 (Q–T). Necrotizing hepatitis described as multifocal to coalescing hepatic pallor in D6-COMB-5 that succumbed from SUDV infection (U). No appreciable gross lesions noted in the liver of representative animals at the study endpoint for D6-RDV-2 (V), D6-MBP-1 (W), and D6-COMB-3 (X).