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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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Clinical Research and Public Health Article has an altmetric score of 110

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

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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 3

Temporal evolution of anti-N, anti-S, and anti-RBD serology titers in patients receiving mAb therapies.

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Temporal evolution of anti-N, anti-S, and anti-RBD serology titers in pa...
(A) Natural immunity was assessed based on anti-N titers, revealing a gradual increase through D28. High anti-S and anti-RBD titers due to therapeutic mAb administration persisted from D2 to D28 in patients in all treatment groups. (B) Similarly, high anti-S and anti-RBD titers were observed in patients carrying Omicron subvariants (BA.1, BA1+R346K, or BA.2) receiving sotrovimab monotherapy. Red, green, and blue dotted lines indicate SARS-CoV-2 WHO reference standard values for low, medium, and high antibody titers, respectively. Line graphs in A and B represent conditional means and shaded areas displaying 95% CIs for all measured time points. Linear mixed models were utilized to investigate evolution of antibody titers over time for different mAbs, with asterisks indicating significance of the slopes of the curves. **P < 0.01, ***P < 0.001. For more details on serology in patients with or without vaccination and sample numbers, see Supplemental Table 5 and Supplemental Figure 7.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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