Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments

AbstractThe role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored. Here, we show that patients treated with various anti-SARS-CoV-2 mAb regimens develop evasive Spike mutations with remarkable speed and high specificity to the targeted mAb-binding sites. Mutations develop more frequently in immunocompromised patients and strongly correlate not only with the neutralizing capacity of the therapeutic mAbs, but also with an anti-inflammatory and healing-promoting host milieu. Machine-learning models based on soluble host-derived biomarkers identified patients at high risk of developing escape mutations against therapeutic mAbs with high accuracy. While our data demonstrate that host-driven immune and non-immune responses are essential for development of mutant SARS-CoV-2, these data could also support point-of-care decision making in reducing the risk of mAb treatment failure and improving mitigation strategies for possible dissemination of escape SARS-CoV-2 mutants.