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

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 1

Immunocompromised and Omicron-infected COVID-19 patients display higher viral loads after mAb administration.

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Immunocompromised and Omicron-infected COVID-19 patients display higher ...
RT-qPCR detection of SARS-CoV-2 was performed on nasopharyngeal swab samples collected on D0, D2, and D7 from patients treated with different therapeutic mAbs. (A) A steady increase in Ct values was observed over 7 days for all mAb-treated groups. Box-and-whisker plots indicate median (middle line), 25th and 75th percentiles (box boundary), and 5th and 95th percentiles (whiskers). All data points, including outliers, are displayed. (B) Overall, patients carrying Omicron (BA.1, BA1+R346K, or BA.2) displayed higher viral loads than patients carrying Alpha subvariants (B.1.1.7 or Q4). (C) Immunocompromised patients carried higher viral loads, irrespective of the infecting SARS-CoV-2 variant and mAb treatment. Line graphs in B and C represent smoothed conditional means, with shaded areas displaying 95% CIs for all measured time points. Cross-sectional and longitudinal statistical comparisons were performed using Mann-Whitney followed by Bonferroni’s post hoc correction. *P < 0.05; **P < 0.01; ***P < 0.001. NS, nonsignificant; D0, sample collected prior to mAb infusion; D2, 2 ± 1 days after mAb infusion; D7, 7 ± 2 days after mAb infusion. A limited number of nasopharyngeal swab samples were collected on D28 (n = 9) across all 4 mAb therapy groups and were therefore excluded from this analysis. See Supplemental Tables 2 and 3 for details on Ct values at each time point.