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Understanding who is at risk of progression to severe coronavirus disease 2019 (COVID-19) is key to clinical decision making and effective treatment. We study correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ClinicalTrials.gov04545060). Laboratory parameters identify study participants at greater risk of severe disease, including a high neutrophil-to-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test, and whole-blood transcriptome profiles. Sotrovimab treatment is associated with normalization of NLR and the transcriptomic profile and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provides the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identify a 10-gene signature with similar predictive accuracy. We identify markers of risk for disease progression and demonstrate that normalization of these parameters occurs with antibody treatment of established infection.