Efficacy of COVID-HIGIV in animal models of SARS-CoV-2 infection

Abstract

In late 2019 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China and quickly spread into a worldwide pandemic. It has caused millions of hospitalizations and deaths, despite the use of COVID-19 vaccines. Convalescent plasma and monoclonal antibodies emerged as major therapeutic options for treatment of COVID-19. We have developed an anti-SARS-CoV-2 immunoglobulin intravenous (Human) (COVID-HIGIV), a potential improvement from using convalescent plasma. In this report the efficacy of COVID-HIGIV was evaluated in hamster and mouse models of SARS-CoV-2 infection. COVID-HIGIV treatment in both mice and hamsters significantly reduced the viral load in the lungs. Among COVID-HIGIV treated animals, infection-related body weight loss was reduced and the animals regained their baseline body weight faster than the PBS controls. In hamsters, COVID-HIGIV treatment reduced infection-associated lung pathology including lung inflammation, and pneumocyte hypertrophy in the lungs. These results support ongoing trials for outpatient treatment with COVID-HIGIV for safety and efficacy evaluation (NCT04910269, NCT04546581).

Conflict of interest statement

AJ, DB, DT and SK are employees of Emergent BioSolutions. JL, VM, JK and DF (employees of Vaccine and Infectious Disease Organization (VIDO)), and RH and MF (employees of University of Maryland School of Medicine) received funding from Emergent BioSolutions to conduct the work described.

© 2022. The Author(s).

Figures

Figure 1

COVID-HIGIV treatment improves the clinical signs of SARS-CoV-2 infection in mice. Five groups of mice transduced with adenovirus carrying human ACE2 (N = 18) were challenged i.n. with SARS-CoV-2 (WA-1 strain), four groups were treated with different dosages of COVID-HIGIV (6.26, 25, 100 and 400 mg/kg dose) 6 h post infection, and the fifth group was PBS treatment control. An age matched sham infected group (N = 6) was also included as controls. Body weights for all surviving animals were collected each day until the end of the study. Figures represent (A) mean percent body weight, (B) mean percent peak body weight loss relative to the baseline weight on study day 0 before infection.

Figure 2

COVID-HIGIV treatment dose dependently reduced the live virus load in the mouse lungs. Five groups of mice transduced with adenovirus carrying human ACE2 (N = 18) were challenged i.n. with SARS-CoV-2 (WA-1 strain), four groups were treated with different dosages of COVID-HIGIV (6.26, 25, 100 and 400 mg/kg dose) 6 h post infection, and the fifth group was PBS treatment control. Six animals from each group were sacrificed on 2 and 4 dpi to harvest lung for ‘plaque forming unit assay’ for live virus load. Figures represent live virus load (A) 2 dpi, (B) 4 dpi. Statistical comparison was made using One-way ANOVA followed by Dunnett’s pairwise comparison with PBS treated group as control group. P values are reported as * < 0.05, ** < 0.01.

Figure 3

COVID-HIGIV treatment at dose ≥ 400 mg/kg significantly reduced clinical signs of SARS-CoV-2 infection in hamsters. Four groups of Hamsters (N = 18) were challenged i.n. with SARS-CoV-2 (1 × 105 TCID50 in 100 mL; strain—SARS-CoV-2/Canada/ON/VIDO-01/2020), three groups were treated with different dosages of COVID-HIGIV (100, 400 and 800 mg/kg dose) 6 h before infection, and the fourth group was PBS treatment control. Body weights for all surviving animals were collected each day until the end of the study. Figures represent (A) mean percent body weight, (B) mean percent peak body weight loss relative to the baseline weight on study day 0 before infection. Statistical comparison was made using Nested One-way ANOVA followed by Dunnett’s pairwise comparison with PBS treated group as control group P values are reported as * < 0.05, ** < 0.01 and *** < 0.001.

Figure 4

COVID-HIGIV treatment at dose ≥ 400 mg/kg significantly reduced SARS-CoV-2 virus sub-genomic RNA (sg-RNA) in hamster lungs. Four groups of Hamsters (N = 18) were challenged i.n. with SARS-CoV-2 (1 × 105 TCID50 in 100 mL; strain—SARS-CoV-2/Canada/ON/VIDO-01/2020), three groups were treated with different dosages of COVID-HIGIV (100, 400 and 800 mg/kg dose) 6 h before infection, and the fourth group was PBS treatment control. Nine animals from each group were sacrificed at 3 dpi to harvest lung for sg-RNA load by RT-qPCR. Viral sg-RNA load was estimated in the four lobes of right lung (cranial, caudal middle and accessory lobes) and single lobe of the left lung. Viral load for entire right lung was extrapolated by the average viral loads for all four right lung lobes. Similarly, total lung viral load was extrapolated by the average viral loads for all four lobes from right lung and the single lobe from the left lung. Statistical comparison was made using One-way ANOVA followed by Dunnett’s pairwise comparison with PBS treated group as control group. P values are reported as ** < 0.01 and *** < 0.001.

Figure 5

COVID-HIGIV treatment at dose ≥ 400 mg/kg significantly reduced SARS-CoV-2 live virus load in hamster lungs. Four groups of Hamsters (N = 18) were challenged i.n. with SARS-CoV-2 (1 × 105 TCID50 in 100 mL; strain—SARS-CoV-2/Canada/ON/VIDO-01/2020), three groups were treated with different dosages of COVID-HIGIV (100, 400 and 800 mg/kg dose) 6 h before infection, and the fourth group was PBS treatment control. Nine animals from each group were sacrificed at 3 dpi to harvest lung for live virus load estimation by ‘tissue culture infection dose assay’. Live virus load was estimated in the four lobes of right lung (cranial, caudal middle and accessory lobes) and single lobe of the left lung. Viral load for entire right lung was extrapolated by the average viral loads for all four right lung lobes. Similarly, total lung viral load was extrapolated by the average viral loads for all four lobes from right lung and the single lobe from the left lung. Statistical comparison was made using One-way ANOVA followed by Dunnett’s pairwise comparison with PBS treated group as control group. P values are reported as * < 0.05, ** < 0.01 and *** < 0.001.

Figure 6

COVID-HIGIV treatment at dose ≥ 400 mg/kg significantly reduced SARS-CoV-2 infection induced lung pathology in hamsters. Four groups of Hamsters (N = 18) were challenged i.n. with SARS-CoV-2 (1 × 105 TCID50 in 100 mL; strain—SARS-CoV-2/Canada/ON/VIDO-01/2020), three groups were treated with different dosages of COVID-HIGIV (100, 400 and 800 mg/kg dose) 6 h before infection, and the fourth group was PBS treatment control. Nine animals from each group were sacrificed at 10 dpi to harvest left lung for histopathology. Left lobe of the lung was fixed in paraformaldehyde and embedded in wax before sectioning at 5 µm thickness and staining with H&E for light microscopic examination at ×4  magnification. Pathology scoring was performed by the pathologist in a blinded manner.