Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments
Akshita Gupta, … , Surbhi Malhotra-Kumar, Samir Kumar-Singh
Akshita Gupta, … , Surbhi Malhotra-Kumar, Samir Kumar-Singh
Published February 9, 2023
Citation Information: J Clin Invest. 2023;133(6):e166032. https://doi.org/10.1172/JCI166032.
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Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments

Abstract

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 biomarker (CIB) profile predictive of evasive Spike mutations was constructed and confirmed in an independent data set (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 antiinflammatory 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 nonimmune 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.Funding The ORCHESTRA project/European Union’s Horizon 2020 research and innovation program.

Authors

Akshita Gupta, Angelina Konnova, Mathias Smet, Matilda Berkell, Alessia Savoldi, Matteo Morra, Vincent Van averbeke, Fien H.R. De Winter, Denise Peserico, Elisa Danese, An Hotterbeekx, Elda Righi, mAb ORCHESTRA working group, Pasquale De Nardo, Evelina Tacconelli, Surbhi Malhotra-Kumar, Samir Kumar-Singh

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Figure 2

De novo SARS-CoV-2 S RBD mutations evolving under mAb pressure.

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De novo SARS-CoV-2 S RBD mutations evolving under mAb pressure. (A) Sche...
(A) Schematic quaternary structure of the SARS-CoV-2 S RBD protein when bound to the human (h)ACE2 receptor (PDB: 6M0J). Key RBD-binding sites of bamlanivimab, etesevimab, and sotrovimab are highlighted in the protein structure with corresponding colors. Binding sites common to all mAbs, including casirivimab and imdevimab, are indicated in red, whereas hACE2 is highlighted in blue. (B) SARS-CoV-2 genomes longitudinally isolated from patients receiving mAb therapy were screened for the emergence of de novo mutations resulting in amino acid substitutions in the S RBD region. Most commonly, escape mutants occurred in residues harbored within the respective mAb binding site. Pt, patient. (C) Patients developing S RBD mutations were found to harbor significantly higher viral loads at all time points. Cross-sectional statistical comparisons were performed using the Mann-Whitney test. Lines represent smoothed conditional means and shaded areas display 95% CIs for all measured time points. ***P < 0.005. For more details on nonsynonymous de novo changes and sample numbers, see Supplemental Figures 1 and 7 and Supplemental Table 4.