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

TLDR

The role of host immunity in driving the emergence of evasive SARS‑CoV‑2 Spike mutations under monoclonal antibody pressure remains largely unexplored. The study aims to inform point‑of‑care decisions that reduce monoclonal antibody treatment failure and mitigate the spread of escape SARS‑CoV‑2 mutants. The authors conducted a prospective observational cohort of 204 COVID‑19 patients treated with different monoclonal antibodies, monitoring viral loads, Spike mutations, antibody kinetics, neutralization, and T‑cell immunity over 28 days, and developed a machine‑learning circulating‑immune‑biomarker profile that predicts emergence of evasive Spike mutations. Patients receiving monoclonal antibodies rapidly acquired Spike mutations at the targeted binding sites, especially immunocompromised individuals with higher viral loads, and the emergence of escape mutants correlated with therapeutic neutralizing capacity and T‑cell immunity, underscoring host immune pressure and a pro‑inflammatory milieu as key drivers of mutation development.

Abstract

BackgroundThe role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored.MethodsIn 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.ResultsPatients 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.ConclusionsOur 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.FundingThe ORCHESTRA project/European Union's Horizon 2020 research and innovation program.