Casirivimab + imdevimab accelerates symptom resolution linked to improved COVID-19 outcomes across susceptible antibody and risk profiles

The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in millions of infections and deaths globally. The severity of COVID-19 varies widely among individuals, ranging from asymptomatic infection to severe respiratory distress and death. Risk factors for severe disease include age, obesity, and metabolic disorders. While the immunological response to SARS-CoV-2 is crucial for viral clearance, excessive inflammation can contribute to symptoms and tissue damage. Early in the pandemic, distinguishing COVID-19 symptoms from other respiratory viruses was challenging, but loss of taste/smell emerged as a distinguishing feature. Studies have explored the relationship between immune response and clinical outcomes, but data linking immune response to symptom evolution remains inconclusive. This study aimed to address this gap by evaluating the effect of CAS + IMD treatment on symptom resolution in high-risk COVID-19 patients, considering baseline antibody responses and risk factors for severe disease. Understanding the interplay between symptoms, antibody responses, and clinical outcomes is crucial for developing effective treatment strategies.

Existing literature highlights the variability in COVID-19 symptom presentation and the challenges in early diagnosis. Loss of taste/smell has been identified as a potential distinguishing symptom. Studies have begun to uncover the relationship between immune response and clinical outcomes, with innate and adaptive immunity playing critical roles in viral clearance and symptom development. However, the specific links between immune responses, symptom evolution, and resolution remain unclear. Previous studies have explored the effectiveness of CAS + IMD in reducing hospitalization and death in high-risk patients, but detailed analysis of its impact on individual symptom resolution and its interaction with baseline antibody profiles has been limited.

This secondary analysis utilized data from a placebo-controlled Phase I/II/III clinical trial (COV-2067, NCT04425629) evaluating CAS + IMD in high-risk symptomatic outpatients with COVID-19. The study included patients with a positive SARS-CoV-2 test and symptoms with onset ≤ 7 days before randomization. Patients completed a daily electronic diary (Symptoms Evolution of COVID-19) to track 23 symptoms. The primary endpoint of the Phase III trial was the proportion of patients with ≥1 COVID-19-related hospitalization or death by day 29. Baseline antibody profiles (IgA, IgG, neutralizing antibodies [NAbs]) and viral load were assessed. A two-step approach was used to analyze longitudinal symptom data. Step one involved fitting logistic regression models for each symptom, considering treatment, age, sex, BMI, and baseline viral load. Step two involved smoothing the probability differences between treatment arms to estimate treatment effects over time. Hierarchical clustering grouped symptoms with similar trajectories. Cox regression models assessed the association between symptoms and hospitalization/death. Subgroup analyses explored the impact of age, sex, BMI, viral load, and antibody profiles on symptom resolution. The study also examined patients who seroconverted late.

CAS + IMD significantly reduced the probability of 17 out of 23 symptoms compared to placebo. Symptom resolution was faster and more pronounced in patients without baseline antibodies or NAbs. Five symptoms (dyspnea, cough, fever, fatigue, loss of appetite) strongly predicted hospitalization/death. Treatment effects were greater in older patients, those with obesity, and those with high baseline viral load. Patients lacking early antibody responses showed a greater treatment benefit. Even patients who seroconverted late still benefited from treatment. The analysis revealed three symptom clusters based on response to treatment: early, mid-cycle, and delayed responders. IgG antibodies were identified as a crucial factor in symptom resolution and improved outcomes. The study demonstrated that early administration of CAS + IMD is critical in improving the course of the illness, especially in those with weak early antibody responses.

This study's findings demonstrate that CAS + IMD accelerates symptom resolution in high-risk COVID-19 patients, particularly in those with weak early antibody responses. The identification of five symptoms strongly associated with poor outcomes provides valuable clinical insights for risk stratification. The greater treatment benefit observed in patients with risk factors for severe disease underscores the importance of targeted antibody therapy for high-risk individuals. The finding that even late seroconverters benefit from CAS + IMD suggests the importance of timely treatment. The results support the critical role of IgG in resolving COVID-19 symptoms and improving outcomes. The study's findings have implications for clinical management and highlight the potential of CAS + IMD in improving COVID-19 outcomes.

This secondary analysis of a clinical trial demonstrates that CAS + IMD treatment significantly accelerates COVID-19 symptom resolution and improves outcomes, especially in patients lacking early or robust antibody responses. The identification of key symptoms predictive of hospitalization and death provides valuable clinical information for risk assessment and management. These findings underscore the importance of early administration of CAS + IMD in high-risk individuals. Further research should explore the contribution of T cells and non-neutralizing antibodies to overall immune response to COVID-19.

This study is a secondary analysis of an existing clinical trial, which limits the generalizability of the findings. The study population was primarily enrolled before the emergence of Omicron variants, potentially limiting the applicability to current circulating variants. The reliance on self-reported symptom data through an electronic diary could introduce potential bias. The study did not investigate the mechanism of action through which CAS + IMD improves antibody responses, nor the mechanisms through which the specific symptoms are reduced.