Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19

The ineffectiveness of neutralizing monoclonal antibodies (nmAbs) in hospitalized COVID-19 patients remains a significant research question. While some trials have shown limited or no benefit, a deeper understanding of the dynamics of virologic and immunologic biomarkers could reveal why. This study aimed to address this gap by examining the impact of nmAb treatment on the trajectories of several key biomarkers in hospitalized patients. The investigation focused on early changes in viral load (measured by plasma nucleocapsid antigen, N-Ag), the body's immune response (anti-nucleocapsid antibodies), and markers of systemic inflammation (C-reactive protein, interleukin-6, and D-dimer). Understanding these trajectories is crucial for informing treatment strategies, refining future antiviral therapies, and developing more effective prognostic tools for clinical trials. The Therapeutics for Inpatients with COVID-19 (TICO) trials, a platform of randomized controlled trials, provided a large, well-characterized dataset suitable for such an analysis. Previous studies focused largely on baseline measurements. This research provides a unique opportunity to track the changes in these biomarkers over a five-day period, offering a more nuanced perspective on the efficacy of nmAb treatment in hospitalized COVID-19 patients and potentially highlighting the subgroups that may benefit most.

Previous studies evaluating nmAb treatment in hospitalized COVID-19 patients have yielded mixed results. Some studies suggested a potential benefit for specific patient subgroups, including those with low baseline anti-spike antibody titers, high plasma N-Ag concentrations, or those requiring high levels of respiratory support. However, the overall clinical benefit of nmAbs in hospitalized patients has been unclear. A major limitation in previous research has been the focus primarily on baseline measurements of virologic and immunologic markers. The dynamic interplay between viral load, immune response, and inflammation during the early stages of hospitalization remains poorly understood. This lack of longitudinal data has hampered the ability to draw definitive conclusions about the mechanisms of action and clinical significance of nmAb treatment.

This study analyzed data from the TICO/ACTIV-3 trials, a platform of four international, blinded, randomized, placebo-controlled trials evaluating different nmAbs in hospitalized COVID-19 patients. A total of 2254 adult patients with laboratory-confirmed SARS-CoV-2 infection, symptoms for ≤12 days, and no organ failure were enrolled between August 2020 and September 2021. Patients were randomized to receive one of the four nmAbs (bamlanivimab, sotrovimab, amubarvimab-romlusevimab, or tixagevimab-cilgavimab) or a placebo. Remdesivir was provided as standard of care. The primary analysis included 2149 participants with baseline and at least one follow-up sample (days 1, 3, or 5). Key laboratory measurements included plasma N-Ag (using the Quanterix SARS-CoV-2 N Protein Antigen assay), anti-N Ab (BioRad Platelia SARS-CoV-2 Total Ab assay), anti-S Ab neutralizing activity (GenScript SARS-CoV-2 cPass assay), CRP, IL-6, and D-dimer. Longitudinal differences between treatment and placebo groups were assessed using linear mixed models, adjusting for baseline values, oxygen requirement, and study stratum. Subgroup analyses were performed to examine whether the treatment effect varied across different baseline characteristics. The association between nmAb treatment and the day 5 pulmonary ordinal scale was evaluated using proportional odds models. Statistical analyses were conducted using SAS (version 9.4) and R (version 4.1).

The analysis of 2149 participants revealed a significant reduction in plasma N-Ag levels in the nmAb group compared to the placebo group. Specifically, the nmAb group exhibited a 20% lower average plasma N-Ag level across days 1, 3, and 5 (95% CI, 12%-27%; P < .001). Furthermore, the rate of decline in plasma N-Ag was steeper in the nmAb group (P < .001 for treatment by day interaction). This indicates a clear antiviral effect of nmAb treatment as measured by plasma N-Ag. However, no significant differences were observed between the nmAb and placebo groups in the trajectories of anti-N Ab, CRP, IL-6, or D-dimer. There was also no significant difference in the day 5 pulmonary ordinal scale, suggesting that the reduction in viral load, as measured by plasma N-Ag, did not translate into clinically meaningful improvements in pulmonary status within the first 5 days of hospitalization. Subgroup analyses revealed a consistent pattern across various baseline factors, including age, sex, comorbidities, viral variant, and baseline biomarker levels. The reduction in plasma N-Ag with nmAb treatment was observed across almost all subgroups, but there were no corresponding differences in other biomarker trajectories or the day 5 pulmonary ordinal scale.

The findings confirm an antiviral effect of nmAb treatment in hospitalized COVID-19 patients, as evidenced by the significant reduction in plasma N-Ag levels. This effect was consistent across various subgroups, suggesting that the antiviral effect is not dependent on specific baseline characteristics. However, the lack of corresponding improvements in inflammatory markers or clinical outcomes raises important questions. Two possible explanations are offered: 1) the antiviral effect of nmAbs may not be sufficiently potent to add clinical benefit when given in conjunction with remdesivir, or 2) inflammation, rather than viral burden, may be the primary driver of disease progression in hospitalized COVID-19 patients. The study's findings highlight the complex interplay between viral load and inflammation in COVID-19 pathogenesis and the need for more potent antivirals or more effective immunomodulatory strategies.

This large, randomized, placebo-controlled trial confirms an antiviral effect of nmAbs on plasma N-Ag in hospitalized COVID-19 patients, but this effect did not translate into clinically significant improvements in early pulmonary status. The lack of impact on inflammation or clinical outcomes suggests that either more potent antivirals or more effective immunomodulatory therapies are needed for hospitalized patients. Future research should explore the timing of nmAb administration and the potential benefits of combination therapies targeting both viral replication and inflammation. The absence of blunting of the endogenous immune response is reassuring for the potential use of nmAbs against future SARS-CoV-2 variants or emerging pathogens.

The use of plasma N-Ag as a proxy for viral replication may not be entirely specific. Pooling data from four different nmAbs assumes similar properties, which might not be entirely accurate. The widespread use of remdesivir could have influenced the nmAb treatment effect. The generalizability of the findings to contemporary patients with high vaccination rates and Omicron variant infections is uncertain. Finally, the numerous subgroup analyses were exploratory and did not adjust for the potential inflation of type I error.