Antiviral therapies are urgently needed to treat and limit the development of severe
COVID-19 disease.
Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 μM. These limited in vitro results triggered the investigation of
ivermectin as a treatment option to alleviate
COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of
ivermectin to treat
COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of
ivermectin is too low to exert a strong
antiviral effect. Here, we performed a head-to-head comparison of the
antiviral activity of
ivermectin and the structurally related, but metabolically more stable
moxidectin in multiple in vitro models of
SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both
moxidectin and
ivermectin exhibited
antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both
moxidectin and
ivermectin failed to inhibit
SARS-CoV-2 infection, even at concentrations of 10 μM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of
ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans.