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.
View: Text | PDF
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

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

×

Figure 5

Longitudinal T cell responses in patients receiving mAb therapy.

Options: View larger image (or click on image) Download as PowerPoint
Longitudinal T cell responses in patients receiving mAb therapy. Evoluti...
Evolution of IFN-γ and CD154 expression in SARS-CoV-2 S– and Nucleocapsid–stimulated CD4+ T cells in patients was studied over 28 days after receiving bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab. (A) Patients receiving sotrovimab therapy show a consistent significant increase in T cell expression during the first 28 days after mAb administration. For the utilized gating strategy, refer to Supplemental Figure 8. (B) Patients with de novo mutations in the SARS-CoV-2 S RBD region show an increased T cell expression compared with those without. Linear mixed models were utilized to investigate evolution of Th cell immunity over time between the different mAb groups. Regression curves represent smoothed conditional means and shaded areas display 95% CIs for all measured time points, with asterisks on lines representing the significance of the slopes. Vertical lines with asterisks represent the significance of pairwise comparisons between patients with or without de novo mutations before mAb treatment (D0) and after 28 days of treatment (D28). *P < 0.05; **P < 0.01; ***P < 0.001.