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Introduction The coronavirus replication machinery encodes proofreading functions that result in fewer errors compared with other RNA viruses; however, multiple SARS-CoV-2 variants of concern (VOCs) have emerged throughout the pandemic [...], 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 healingpromoting 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.

People living with HIV (PLWH) despite having an appreciable depletion of CD4+ T‐cells show a good severe acute respiratory syndrome coronavirus 2 vaccination response. The underlying mechanism(s) are currently not understood. We studied serological and polyfunctional T‐cell responses in PLWH receiving anti‐retroviral therapy stratified on CD4+ counts as PLWH‐high (CD4 ≥ 500 cells/mm3) and PLWH‐low (<500 cells/mm3). Responses were assessed longitudinally before the first vaccination (T0), 1‐month after the first dose (T1), 3‐months (T2), and 6‐months (T3) after the second dose. Expectedly, both PLWH‐high and ‐low groups developed similar serological responses after T2, which were also non‐significantly different from age and vaccination‐matched HIV‐negative controls at T3. The immunoglobulin G titers were also protective showing a good correlation with angiotensin‐converting enzyme 2‐neutralizations (R = 0.628, p = 0.005). While surface and intracellular activation analysis showed no significant difference at T3 between PLWH and controls in activated CD4+CD154+ and CD4+ memory T‐cells, spike‐specific CD4+ polyfunctional cytokine expression analysis showed that PLWH preferentially express interleukin (IL)‐2 (p < 0.001) and controls, interferon‐γ (p = 0.017). CD4+ T‐cell counts negatively correlated with IL‐2‐expressing CD4+ T‐cells including CD4+ memory T‐cells (Spearman ρ: −0.85 and −0.80, respectively; p < 0.001). Our results suggest that the durable serological and CD4+ T‐cell responses developing in vaccinated PLWH are associated with IL‐2‐mediated CD4+ T‐cell activation that likely compensates for CD4+ T‐cell depletion in PLWH. [ABSTRACT FROM AUTHOR]