Identifying molecular signatures underpinning treatment responses to novel therapeutics influencing COVID-19 outcomes.

COVID-19 continues to present ongoing global health challenges driven by diverse immune responses and heterogeneous clinical outcomes. The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. To better understand their molecular mechanisms, we conducted a mechanistic follow-up study, integrating transcriptomic and clinical data from 65 patients and applying cellular deconvolution, differential expression, coexpression, and pathway enrichment analyses to uncover treatment-specific immune responses. Each therapy induced transcriptional shifts and modulated distinct immune pathways implicated in severe disease. Bemcentinib primarily modulated myeloid cell populations and inflammatory signalling; zilucoplan enhanced B-cell signalling and lymphocyte-associated pathways; and tozorakimab exerted broad immune and cellular responses across immune cell types. Co-expression analysis revealed gene networks associated with clinical improvement, each driven by distinct treatment-specific hub genes, indicating diverse regulatory mechanisms across treatments. Improved outcomes correlated with gene expression shifts in 4 key immunological pathways: B-cell signalling, antiviral defense, innate inflammation, and platelet/coagulation activity. In contrast, nonresponders had persistent dysregulation of 1 or more of these gene signatures. Our findings define molecular signatures of treatment response and failure in COVID-19, providing mechanistic insight into how distinct therapies modulate the immune system. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19.