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

The study investigates how treatment with the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) affects the evolution and resolution of individual COVID-19 symptoms in high-risk outpatients and how these symptom changes relate to clinical outcomes (hospitalization or death). It also examines how baseline SARS-CoV-2 antibody profiles—including IgA, IgG, and neutralizing antibodies (NAbs)—and established risk factors (age, obesity, viral load) modify treatment effects. Contextually, COVID-19 presents with heterogeneous symptomatology and outcomes, with older age, obesity, and cardiometabolic comorbidities linked to severe disease. While immune responses, particularly neutralizing antibodies, are associated with protection, their relationship to symptom trajectories and outcomes during acute infection and in the presence of exogenous neutralizing antibodies remains incompletely defined. The purpose is to delineate symptom-level treatment effects, identify symptom clusters and their timing, link symptom dynamics to outcomes, and determine how endogenous antibody status influences CAS + IMD efficacy.

Prior work has characterized COVID-19 clinical features and risk factors (age, obesity, cardiometabolic disease) and identified distinctive symptoms (e.g., loss of taste/smell). Studies have linked immune responses to outcomes, showing that early and robust adaptive responses—especially neutralizing antibodies—predict protection from severe disease, while delayed NAb production correlates with mortality. Vaccination studies further demonstrate NAb titers predict protection from symptomatic infection. However, few analyses have assessed the evolution of individual symptoms, their clustering over time, and their association with outcomes, nor have they integrated baseline antibody class/NAb status with symptom resolution and treatment response. CAS + IMD has shown efficacy in outpatients in reducing viral load and clinical events, and mechanistic/preclinical work established potent neutralization and reduced mutational escape with antibody cocktails. This study extends the literature by linking symptom trajectories and clinical outcomes to baseline antibody profiles and by quantifying how exogenous highly neutralizing IgG (CAS + IMD) modifies these relationships in high-risk outpatients.

Design and population: Secondary analysis of data from COV-2067 (NCT04425629), an adaptive, seamless, randomized, double-blind, placebo-controlled Phase I/II/III trial of CAS + IMD in symptomatic outpatients with confirmed SARS-CoV-2 infection. Participants were ≥18 years, had a positive RT-qPCR or antigen test ≤72 h prior to randomization, symptom onset ≤7 days, and oxygen saturation ≥93% on room air. The analysis focused on patients with ≥1 risk factor for severe COVID-19 (e.g., age ≥50 years, BMI ≥30 kg/m2). Patients were enrolled prior to the emergence of Omicron-lineage variants. Interventions: Phase I/II randomized 1:1:1 to placebo or single IV CAS + IMD 2400 mg or 8000 mg. Phase III randomized 1:1:1 to placebo, CAS + IMD 1200 mg, or CAS + IMD 2400 mg. Doses were pooled for analysis given similar efficacy. Symptom assessment: Patients completed the Symptoms Evolution of COVID-19 (SE-C19) electronic diary daily, rating 23 symptoms (none [0], mild [1], moderate [2], severe [3]). Symptom data from day 1 (baseline) through day 15 were analyzed (most symptoms resolved by day 16). Antibody and virology assessments: Baseline composite serostatus was determined using EuroImmun anti-S1 IgA, EuroImmun anti-S1 IgG, and Abbott anti-N IgG assays. Seronegative was defined as all three negative; seropositive as any positive; an “other” category was used for missing/borderline results. Seroconversion at day 29 was assessed by anti-N IgG only. Neutralizing antibody titers were measured at baseline in seropositive patients using the IMMUNO-COV assay. Nasopharyngeal swab RT-qPCR quantified viral load (log10 copies/mL) at baseline. Analysis population: All randomized patients with positive baseline NP RT-qPCR, ≥1 risk factor for hospitalization, and symptom data at baseline plus ≥1 follow-up day between days 2–15. Data across study phases and CAS + IMD doses were pooled. Statistical methods: A two-step approach modeled symptom presence over time. Step 1: For each symptom and day (days 1–15), logistic regression estimated least-squares mean probabilities including covariates: treatment (placebo vs CAS + IMD), age, sex, BMI, and baseline viral load (log10). Step 2: Treatment effect trajectories were obtained by smoothing the daily probability differences (CAS + IMD minus placebo). Global 95% confidence bands were constructed via bootstrap (300 replications). A symptom had a significant treatment effect if the upper bound of the 95% band was below 0 for ≥2 consecutive days. Hierarchical clustering with gap statistics grouped symptoms by similarity of treatment trajectories; median onset day (first day upper 95% CI <0) and median day of maximal effect were derived per cluster. Cox proportional hazards models (time-varying) assessed associations between individual symptoms and time to first COVID-19-related hospitalization or all-cause death through day 29, adjusting for baseline symptom score, daily change from baseline, treatment, age, sex, baseline BMI, and baseline viral load. Subgroup analyses (two-step method) examined treatment effects by age (<50 vs ≥50), sex, BMI (<30 vs ≥30 kg/m2), baseline viral load (≤107 vs >107 copies/mL), baseline serology (seronegative vs seropositive), IgA/IgG status, NAb status, and seroconversion among baseline seronegatives by day 29. Spearman correlations and multivariable regression explored relationships between antibody classes and NAbs. Analyses were conducted in R (v4.1.2).

- Baseline antibody profile: • 67.8% (2589/3816) were seronegative; 29.5% (1124/3816) seropositive for at least one assay. • Among seropositives: IgA (anti-S) 89.6% (1007/1124), IgG (anti-S) 38.0% (427/1124), IgG (anti-N) 40.3% (453/1124). Anti-S IgG and anti-N IgG concordance: 92.6%. • Among baseline seronegatives with day 29 data (2291; 88.5%), 84.2% (1929) seroconverted (anti-N IgG), 15.8% (362) remained seronegative. • Neutralizing antibodies (NAbs): 64.0% (721/1124) of seropositives were NAb-positive. NAb positivity was 41.7% (222/532) in IgA-only vs 91.4% (427/467) in dual IgA+IgG positives. IgG correlated more strongly with NAbs than IgA (multivariable P = 3.16e-14). • Risk factors and antibodies: Older age, male sex, immunocompromised status, and high baseline viral load were associated with lower NAb positivity; high viral load also associated with ~30% lower seropositivity, ~60% lower NAb positivity among seropositives, and ~1 log lower mean NAb titers. - Baseline antibodies and outcomes/viral load: • Placebo arm: hospitalization/death proportions were 4.5% (39/860) in seronegatives; 3.9% (7/181) in IgA-only; 0.7% (1/167) in dual IgA+IgG (≈86.7% risk reduction vs seronegatives). • Baseline viral load (log10 copies/mL): seronegative 7.17 (SD 1.46); IgA-only 5.77 (SD 1.59); dual IgA+IgG 4.36 (SD 1.42). Among seropositives, NAb+ 4.70 (SD 1.44) vs NAb− 6.81 (SD 1.46). - Treatment effects on symptoms: • CAS + IMD significantly reduced 17/23 symptoms versus placebo (cough, fatigue, body aches, loss of appetite, chills, headache, feeling feverish, altered or loss of taste/smell, shortness of breath/difficulty breathing, diarrhea, nausea, sputum/phlegm, pressure/tightness in chest, sore throat, dizziness, chest pain, vomiting). No significant reduction for sneezing, stomachache, runny nose, confusion, rash, red/watery eyes. • Symptom clusters by timing of effect: Cluster 1 (early: headache, diarrhea, vomiting, feeling feverish, body aches, chills) median onset day 3, maximal effect day 4; Cluster 2 (mid: pressure/tightness in chest, chest pain, loss of appetite, nausea, fatigue, dizziness) onset day 4, maximal day 8; Cluster 3 (delayed: cough, sputum/phlegm, sore throat, loss of taste/smell, shortness of breath) onset day 5, maximal day 11. - Symptoms linked to hospitalization/death (Cox models): Five symptoms independently associated with outcomes after Bonferroni adjustment—shortness of breath, cough, feeling feverish, fatigue, loss of appetite. • Per 1-point higher baseline severity: cough HR 3.20 (P<0.001), fatigue HR 2.12 (P<0.001), feeling feverish HR 2.67 (P<0.001), loss of appetite HR 1.92 (P<0.001), shortness of breath HR 2.06 (P=0.001). • Per 1-point decrease from baseline (improvement): cough HR 0.31 (P<0.001), fatigue HR 0.51 (P=0.011), feeling feverish HR 0.47 (P=0.001), loss of appetite HR 0.56 (P=0.043), shortness of breath HR 0.34 (P<0.001). • Composite of cough + feeling feverish showed the strongest association (baseline 1-point increase: 4.54-fold higher risk; 1-point improvement: 0.78-fold lower risk). - Subgroup treatment effects on the five key symptoms: • Greater benefits in patients ≥50 years (especially cough, feeling feverish), in those with obesity (notably dyspnea), and in those with high baseline viral load (>10^7 copies/mL). Effects comparable by sex. - Antibody profile and treatment response: • Larger treatment effects in baseline seronegative vs seropositive patients across key symptoms. • Among seropositives, significant benefit in NAb-negative patients; no difference in NAb-positive patients. • Baseline seronegatives who seroconverted by day 29 still benefited from CAS + IMD; in placebo recipients, late seroconverters showed little difference in symptom evolution vs non-converters.

The study demonstrates that providing exogenous, highly neutralizing anti–SARS-CoV-2 IgG (CAS + IMD) accelerates resolution of a broad range of acute COVID-19 symptoms in high-risk outpatients, particularly those lacking early endogenous antibody responses or presenting with high viral load. It identifies five symptoms—shortness of breath, cough, feeling feverish, fatigue, and loss of appetite—whose baseline severity and subsequent improvement are strongly and independently associated with hospitalization/death. Faster improvement of these symptoms following CAS + IMD treatment likely reflects rapid viral neutralization and reduced inflammatory burden, translating into reduced risk of severe outcomes. Baseline antibody status modifies treatment response: patients who are seronegative or lack neutralizing capacity derive the greatest symptomatic benefit; those already NAb-positive show limited additional symptom improvement, consistent with endogenous neutralization already underway. The findings reinforce the central role of neutralizing IgG in resolving acute infection and suggest early administration of CAS + IMD can rescue patients with delayed or inadequate humoral responses. Differences in treatment effects across age, obesity, and viral load strata align with observed lower seropositivity and NAb titers in these high-risk groups, providing a mechanistic link between host factors, antibody responses, symptom trajectories, and outcomes. By clustering symptom trajectories, the study shows temporally distinct patterns of response to neutralizing therapy, with early systemic and constitutional symptoms responding first, followed by gastrointestinal and energy-related symptoms, and later respiratory and sensory symptoms. This temporal mapping provides clinically useful markers for monitoring therapeutic response and prognosis.

CAS + IMD significantly reduced 17 of 23 COVID-19 symptoms and accelerated resolution across three temporal symptom clusters, with the most pronounced benefits in patients at higher risk (older age, obesity, high viral load) and those lacking early endogenous neutralizing antibodies. Resolution of five key symptoms—shortness of breath, cough, feeling feverish, fatigue, and loss of appetite—was independently associated with reduced hospitalization/death, and CAS + IMD hastened improvement in these symptoms, especially among seronegative and NAb-negative patients. The data underscore the pivotal role of neutralizing IgG in resolving acute COVID-19 and support early administration of highly neutralizing monoclonal antibodies to improve symptom trajectories and outcomes in high-risk outpatients. Future research should evaluate generalizability across emerging variants, further dissect the roles of T cells and non-neutralizing antibodies in symptom resolution, assess mucosal immunity contributions (particularly IgA), and determine whether potent neutralizing IgG therapy can mitigate effects of low-titer or potentially misdirected pre-existing antibodies.

- The analysis is secondary and observational within a randomized trial framework; symptom trajectory analyses rely on modeling assumptions and bootstrapping, with wider variance noted for certain symptoms (e.g., feeling feverish in some subgroups). - Symptom data are self-reported via eDiary, potentially introducing reporting bias and variability. - Symptom trajectory analyses were limited to the first 15 days, though clinical outcomes were tracked to day 29. - The cohort was enrolled before Omicron-lineage variants; findings may not fully generalize to newer variants with differing clinical phenotypes and immune escape. - Baseline NAbs were measured in serum and not classified by antibody isotype; serum assays may underestimate contributions of mucosal IgA. - Affinity maturation and timing of endogenous responses could not be fully characterized beyond day-29 seroconversion. - The study did not evaluate whether CAS + IMD can counteract potentially misdirected or enhancing pre-existing antibodies.