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The role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored. Here, we show that patients treated with various anti-SARS-CoV-2 mAb regimens develop evasive Spike mutations with remarkable speed and high specificity to the targeted mAb-binding sites. Mutations develop more frequently in immunocompromised patients and strongly correlate not only with the neutralizing capacity of the therapeutic mAbs, but also with an anti-inflammatory and healing-promoting host milieu. Machine-learning models based on soluble host-derived biomarkers identified patients at high risk of developing escape mutations against therapeutic mAbs with high accuracy. While our data demonstrate that host-driven immune and non-immune responses are essential for development of mutant SARS-CoV-2, these data could 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.
RESUMO
BackgroundRecent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting SARS-CoV-2 varies according to the Variant of Concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. MethodsThe MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with early COVID-19. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was COVID-19 progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. ResultsOverall, 319 patients were included. Among 141 patients infected with Delta, no disease progression was recorded and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.895). Among 170 patients infected with Omicron (80.6% BA.1, 19.4% BA.1.1), two disease progressions were recorded in the bamlanivimab/etesevimab group and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared to bamlanivimab/etesevimab and casirivimab/imdevimab (HR 0.526 and HR 0.451, 95% CI 0.359 - 0.77 and 95% CI 0.303 - 0.669, p 0.001 and 0.0001, respectively). ConclusionsThese results confirm the in-vitro data of superiority of sotrovimab versus casirivimab/imdevimab and bamlanivimab/etesivamab in reducing the time to recovery in patients infected with Omicron BA.1 and BA.1.1, while no difference was detected in Delta infections. Casirivimab/imdevimab seems to maintain a role in preventing severe COVID-19 in the Omicron population. Adaptive clinical trials comparing mAbs by VOC should be pursued to promptly inform clinical recommendations. FundingThis trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Unions Horizon 2020 research and innovation programme under grant agreement No 101016167. Clinical trial numberNCT05205759
RESUMO
Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocytosis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely impeding the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell RNA-seq analysis of more than 150.000 immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of COVID-19 patients and healthy controls, and integrated it with clinical, immunological and functional ex vivo data. We unveiled an immune signature of disease severity that correlated with the accumulation of naive lymphoid cells in the lung and an expansion and activation of myeloid cells in the periphery. Moreover, we demonstrated that myeloid-driven immune suppression is a hallmark of COVID-19 evolution and arginase 1 expression is significantly associated with monocyte immune regulatory features. Noteworthy, we found monocyte and neutro-phil immune suppression loss associated with fatal clinical outcome in severe patients. Additionally, our analysis discovered that the strongest association of the patients clinical outcome and immune phenotype is the lung T cell response. We found that patients with a robust CXCR6+ effector memory T cell response have better outcomes. This result is line with the rs11385942 COVID-19 risk allel, which is in proximity to the CXCR6 gene and suggest effector memory T cell are a primary feature in COVID-19 patients. By systemically quantifying the viral landscape in the lung of severe patients, we indeed identified Herpes-Simplex-Virus 1 (HSV-1) as a potential opportunistic virus in COVID-19 patients. Lastly, we observed an unexpectedly high SARS-CoV-2 viral load in an immuno-compromised patient, allowing us to study the SARS-CoV-2 in-vivo life cycle. The development of myeloid dysfunctions and the impairment of lymphoid arm establish a condition of immune paralysis that supports secondary bacteria and virus infection and can progress to "immune silence" in patients facing death.
