Comparing Ghanaians with mild vs severe COVID-19 reveals a diminished antiviral response in Ghanaians with severe COVID-19 marked by downregulation of antiviral genes OAS1, CCL8, SAMD9L, HLA-A, CXCL11, ISG15, IL32, and IFIT2, and suppression of antiviral immune response pathways. Here, ISG15 is linked to COVID-19.