Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model

Abstract

COVID-19, caused by SARS-CoV-2 infection, is currently among the most important public health concerns worldwide. Although several effective vaccines have been developed, there is an urgent clinical need for effective pharmaceutical treatments for treatment of COVID-19. Ivermectin, a chemical derivative of avermectin produced by Streptomyces avermitilis, is a macrocyclic lactone with antiparasitic activity. Recent studies have shown that ivermectin inhibits SARS-CoV-2 replication in vitro. In the present study, we investigated the in vivo effects of ivermectin in a hamster model of SARS-CoV-2 infection. The results of the present study demonstrate oral administration of ivermectin prior to SARS-CoV-2 infection in hamsters was associated with decreased weight loss and pulmonary inflammation. In addition, the administration of ivermectin reduced pulmonary viral titers and mRNA expression level of pro-inflammatory cytokines associated with severe COVID-19 disease. The administration of ivermectin rapidly induced the production of virus-specific neutralizing antibodies in the late stage of viral infection. Zinc concentrations leading to immune quiescence were also significantly higher in the lungs of ivermectin-treated hamsters compared to controls. These results indicate that ivermectin may have efficacy in reducing the development and severity of COVID-19 by affecting host immunity in a hamster model of SARS-CoV-2 infection.

Fig. 1

Prophylactic administration of ivermectin prevents weight loss in a hamster model of SARS-CoV-2 infection. a Schematic of the experimental design. b Bodyweight change in Syrian hamsters following SARS-CoV-2 infection. Both vehicle-treated and ivermectin (IVM)-treated hamsters (n = 6 per group) were infected by intranasal injection of 5 × 10⁴ plaque-forming units (PFU) of SARS-CoV-2 followed by assessments for bodyweight change. Hamsters without viral infection, n = 3 per group. Data are presented as the means ± SEM. *P < 0.05 by Student’s t test

Fig. 2

Prophylactic administration of ivermectin reduces the severity of pulmonary disease in a hamster model of SARS-CoV-2 infection. a Hematoxylin and eosin staining of the lungs on days 0, 3, 6 and 10 after SARS-CoV-2 infection. Bar = 50 μm. b Magnified image of hematoxylin and eosin staining of lungs 6 days after SARS-CoV-2 infection; the area enclosed by the square in (a) is magnified. Bar = 25 μm.　c Viral titers in infected lungs. Lungs from vehicle-treated or IVM-treated hamsters infected with SARS-CoV-2 on days 0, 3, 6 and 10 (n = 5 per group) were homogenized and virus titers were quantified by plaque assay in VeroE6/TMPRSS2 cells. N.D., not detected. Data are presented as the means ± SEM. *P < 0.05 by Student’s t-test

Fig. 3

Prophylactic administration of ivermectin inhibits pulmonary inflammatory cytokine expression following SARS-CoV-2 infection. a Il6, (b) Tnf, (c) Il10, and (d) Irf7 mRNA expression levels in lungs of vehicle-treated or IVM-treated hamsters (n = 5 per group) after SARS-CoV-2 infection. Data are presented as the means ± SEM of duplicates. *P < 0.05 by Student’s t-test

Fig. 4

Prophylactic administration of ivermectin reduces the severity of pathological changes associated with SARS-CoV-2 infection. a Plasma titers of neutralizing antibodies on day 0 and 10 in vehicle-treated or IVM-treated hamsters (n = 5 per group) infected with SARS-CoV-2. Neutralizing antibody titers are expressed as a reciprocal of the highest dilution of the test plasma that completely inhibited the cytopathic effect. b Zinc concentrations in lungs from vehicle-treated or IVM-treated hamsters (n = 5 per group) after SARS-CoV-2 infection. Data are presented as the means ± SEM of duplicates. *P < 0.05 by Student’s t-test