Minimal impact of ivermectin on immune response and transcriptional profiles in naïve adults with mild COVID-19

Ivermectin (IVM), an antiparasitic, was tested in clinical trials as a potential treatment for COVID-19 due to its in vitro antiviral properties and hypothetical immunomodulatory effects. In this study, we explored the immunomodulatory effects of IVM in a clinical trial involving 24 mild COVID-19 patients who received IVM within 48 hours of symptom onset. The IVM group showed a trend towards lower viral loads post-treatment, and a significantly shorter duration of hyposmia/anosmia. We comprehensively analyzed immune responses by measuring antibody levels, cytokine profiles, immune cell subsets over 28 days and whole blood gene expression. The IVM group had increased levels of IgG against the SARS-CoV-2 nucleocapsid and IL-1RA, an anti-inflammatory cytokine. IVM did not affect the kinetics of SARS-CoV-2 T cells, despite a slight decrease in naive CD4+ T cells. Additionally, gene expression analysis showed a decrease in innate and antiviral responses and an increase of adaptive responses over time that were stronger in the placebo compared to the IVM group. In conclusion, despite some differences in IVM treated participants, our detailed analyses do not support significant immunomodulatory effects, reinforcing evidence that IVM is unlikely to be an effective treatment for COVID-19. Overall design: Gene expression profile analysis of RNA-Seq data from 72 whole blood samples of 24 COVID-19 patients, collected at three timepoints: treatment day (D1), 4 days post-treatment (D4), and 7 days post-treatment (D7). Patients were randomly assigned (1:1) to receive a single oral dose of ivermectin (400 µg/kg) or placebo.