Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections:The ORCHESTRA Prospective Cohort Study

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p &lt; 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05–0.27, p &lt; 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08–5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03–1.08, p &lt; 0.001), and male gender (aOR:1.97, 95%CI: 1.04–3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p &lt; 0.001) in immunocompromised and elderly patients &gt;75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.</p

Clinical efficacy of different monoclonal antibody regimens among non-hospitalised patients with mild to moderate COVID-19 at high risk for disease progression: a prospective cohort study

This study aimed to compare the clinical progression of COVID-19 in high-risk outpatients treated with the monoclonal antibodies (mAb) bamlanivimab, bamlanivimab-etesevimab and casirivimab-imdevimab. This is an observational, multi-centre, prospective study conducted from 18 March to 15 July 2021 in eight Italian tertiary-care hospitals including mild-to-moderate COVID-19 outpatients receiving bamlanivimab (700&nbsp;mg), bamlanivimab-etesevimab (700-1400&nbsp;mg) or casirivimab-imdevimab (1200-1200&nbsp;mg). All patients were at high risk of COVID-19 progression according to Italian Medicines Agency definitions. In a patient subgroup, SARS-CoV-2 variant and anti-SARS-CoV-2 serology were analysed at baseline. Factors associated with 28-day all-cause hospitalisation were identified using multivariable multilevel logistic regression (MMLR) and summarised with adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 635 outpatients received mAb: 161 (25.4%) bamlanivimab, 396 (62.4%) bamlanivimab-etesevimab and 78 (12.2%) casirivimab-imdevimab. Ninety-five (15%) patients received full or partial SARS-CoV-2 vaccination. The B.1.1.7 (Alpha) variant was detected in 99% of patients. Baseline serology showed no significant differences among the three mAb regimen groups. Twenty-eight-day all-cause hospitalisation was 11.3%, with a significantly higher proportion (p 0.001) in the bamlanivimab group (18.6%), compared to the bamlanivimab-etesevimab (10.1%) and casirivimab-imdevimab (2.6%) groups. On MMLR, aORs for 28-day all-cause hospitalisation were significantly lower in patients receiving bamlanivimab-etesevimab (aOR 0.51, 95% CI 0.30-0.88 p 0.015) and casirivimab-imdevimab (aOR 0.14, 95% CI 0.03-0.61, p 0.009) compared to those receiving bamlanivimab. No patients with a history of vaccination were hospitalised. The study suggests differences in clinical outcomes among the first available mAb regimens for treating high-risk COVID-19 outpatients. Randomised trials are needed to compare efficacy of mAb combination regimens in high-risk populations and according to circulating variants

How storytelling can combat vaccine hesitancy: a transdisciplinary approach

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Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics

Summary Therapy resistance remains a major clinical challenge for the management of metastatic melanoma. Here we show that activation of the Integrated Stress Response (ISR), which we show is common in drug-tolerant and resistant melanoma, promotes selective synthesis of mitochondrial proteins in the cytosol. Since mitochondrial translation adapts to the influx of nuclear-encoded mitochondrial proteins, ISR activation indirectly enhances mitochondrial translation and makes these cells highly vulnerable to mitochondrial translation inhibitors. Treatment of melanoma with mitoribosome-targeting antibiotics, induces proteotoxic stress and significantly compromises the growth of NRAS -mutant and immunotherapy-resistant skin melanoma as well as uveal melanoma. Additionally, a triple BRAFi/MEKi/Tigecycline combination reduces intratumour heterogeneity by abrogating emergence of dedifferentiated drug-tolerant cells, and delayed or even prevented the development of resistance in BRAF V600E PDX models. Consistently, a melanoma patient exposed to Doxycycline, a mitoribosome-targeting antibiotic commonly used to treat infections, experienced a complete and long-lasting response of a treatment-resistant lesion. Significance Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF -mutant melanoma, and a therapeutic option to target NRAS -driven and immunotherapy-resistant cutaneous melanoma and uveal melanomas.status: publishe

Uprooting Deeper Causes of Belgium's Lack of Pandemic Preparedness in the Covid-19 Crisis

The challenge of the Coronavirus Pandemic Preparedness project was to explore gaps in the way Belgium addressed the COVID-19 pandemic as a path forward for learning how to be better prepared in the probable event of a future pandemic. A pandemic is more than just a health crisis; well-intentioned efforts to contain an epidemic resulted in mental health problems, an economic downturn and the impairment of learning, among other issues. To understand a complex or "wicked" problem, such as a pandemic, we deployed a transdisciplinary approach, engaging experts and stakeholders from a variety of fields. At the end of March 2021, we organised an online co-creation workshop on behalf of the transdisciplinary research team at the Institute for the Future (1), inviting societal actors to participate in a multilevel brainstorming discussion. The purpose of the workshop was to identify deeper causes underlying the gaps in Belgian pandemic preparedness, building upon earlier work of the research team. We engaged stakeholders from different sectors of society in interactive exercises to verify and challenge the work of the research team. As a result, our team unearthed plausible missing elements within the deeper causes underlying the Belgian lack of preparedness for the pandemic. The majority of gaps identified by the stake holders could be traced to deeper causes interwoven in our society's fabric. Some key areas where improvement was suggested were greater political willingness to tackle more complex problems, an expansion of transdisciplinary knowledge and education across our institutions and trust-building among citizens, government and the scientific community. Our findings are summarised and presented in a short video output. These findings can be taken up to formulate future objectives for pandemic preparedness in Belgium. This can in turn serve to create a more resilient and sustain- able society

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

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 (CIB) biomarker profile predictive of evasive Spike mutations was constructed and confirmed in an independent dataset (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 anti-inflammatory 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 non-immune 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

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections: The ORCHESTRA Prospective Cohort Study

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p &lt; 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05-0.27, p &lt; 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08-5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03-1.08, p &lt; 0.001), and male gender (aOR:1.97, 95%CI: 1.04-3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p &lt; 0.001) in immunocompromised and elderly patients &gt;75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories