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In The Journal of clinical investigation ; h5-index 129.0

BACKGROUND : The role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored.

METHODS : In a prospective, observational, monocentric ORCHESTRA cohort study, conducted between March 2021 and November 2022, mild-to-moderately ill COVID-19 patients (n=204) receiving bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were longitudinally studied over 28 days for viral loads, de novo Spike mutations, mAb kinetics, seroneutralization against infecting variants of concern, and T-cell immunity. Additionally, a machine learning-based circulating immune-related (CIB) biomarker profile predictive of evasive Spike mutations was constructed and confirmed in an independent dataset (n=19) that included patients receiving sotrovimab or tixagevimab/cilgavimab.

RESULTS : Patients treated with various mAbs developed evasive Spike mutations with remarkable speed and high specificity to the targeted mAb-binding sites. Immunocompromised patients receiving mAb therapy not only continued to display significantly higher viral loads, but also showed higher likelihood of developing de novo Spike mutations. Development of escape mutants also strongly correlated with neutralizing capacity of the therapeutic mAbs and T-cell immunity, suggesting immune pressure as an important driver of escape mutations. Lastly, we showed that an anti-inflammatory and healing-promoting host milieu facilitates Spike mutations, where 4 CIBs identified patients at high risk of developing escape mutations against therapeutic mAbs with high accuracy.

CONCLUSIONS : Our data demonstrate that host-driven immune and non-immune responses are essential for development of mutant SARS-CoV-2. These data 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.

Gupta Akshita, Konnova Angelina, Smet Mathias, Berkell Matilda, Savoldi Alessia, Morra Matteo, Van Averbeke Vincent, De Winter Fien Hr, Peserico Denise, Danese Elisa, Hotterbeekx An, Righi Elda, De Nardo Pasquale, Tacconelli Evelina, Malhotra-Kumar Surbhi, Kumar-Singh Samir


COVID-19, Cellular immune response