Long-term anti-SARS-CoV-2 antibody trajectories after neutralizing monoclonal antibody treatment

Abstract

Background: Neutralizing monoclonal antibodies (nMAbs) have been used to treat COVID-19 and are increasingly being used to treat other infections. However, there is concern that by neutralizing the SARS-CoV-2 virus, nMAbs may decrease the availability of antigens to the immune system, potentially impairing the endogenous polyclonal immune response and decreasing long-term immune protection.

Methods: We compared 28 and 90-day anti-SARS-CoV-2 spike protein neutralization activity and anti-SARS-CoV-2 nucleocapsid response for patients hospitalized with COVID-19 infection randomized to receive nMAbs or placebo in the large platform ACTIV-3/TICO trials. We pooled results from four trials of anti-spike nMAbs. For most tested agents, measurements of the spike protein response reflect both the therapeutic and endogenous immune response. Anti-nucleocapsid levels reflect only the endogenous immune response. Data are summarized as mean differences in percent binding inhibition (anti-spike) and signal-to-cutoff (S/C) ratio (anti-nucleocapsid). Linear mixed effects models were fit to compare the longitudinal trajectory between treatment and placebo groups.

Results: Of 2,254 participants in the ACTIV-3/TICO trials modified intention-to-treat population, 2,149 (95.3%) had antibody measures at baseline and at least 1 follow-up day (day 1, 3, or 5) and were included in this analysis. Antibody measures were available for 1,556 (72.4%) participants at day 28 and 1,429 (66.5%) participants at day 90. In participants who received nMAbs, anti-spike neutralization activity was higher at day 28 (mean difference in percent binding inhibition: 7.1% [95%CI: 5.3, 8.9], p < 0.001) and day 90 (mean difference in percent binding inhibition: 7.2% [95% CI: 5.4, 9.0], p < 0.001). Anti-nucleocapsid response was similar at day 28 (mean difference in S/C ratio: 0.02 [95%CI: -0.11, 0.15], p = 0.75) and day 90 (mean difference in S/C ratio: 0.08 [95% CI: -0.05, 0.21], p = 0.22). Similar patterns were observed in all trials.

Conclusions: In patients hospitalized with COVID-19, treatment with nMAbs did not decrease long-term anti-nucleocapsid response compared to placebo, suggesting neutralizing therapies do not suppress the endogenous humoral immune response in this population.

Fig 1. Study Flow Diagram.

Study flow diagram for the pooled analysis. There were 96 deaths in the active groups and 93 deaths in the placebo groups through Day 90. Red box = participants included in the treatment groups. Blue box = participants included in the placebo groups. Of note, in some cases a placebo participant was used as a control for multiple trials [–11,26]. Due to shared placebos, more participants were randomized to active treatment than placebo.

Fig 2. Antibody and antigen responses after treatment with nMAb vs placebo, day 1-90 (pooled nMAb treatments).

Pooled day 1-90 antibody and antigen responses for randomized controlled trials comparing treatment to placebo, where treatments included: Bamlanivimab (LY-CoV555, Eli Lilly and Company), Sotrovimab (VIR-7831, Vir biotechnology and GlaxoSmithKline), Amubarvimab/ Romlusevimab (BRII-196 and BRII-198, BRII Biosciences), and Tixagevimab/ Cilgavimab (AZD7442, AstraZeneca). Panel A: Anti-SARS-CoV-2 spike protein neutralization activity presented as percent binding inhibition (GenScript, Piscataway, New Jersey), Panel B: Total immunoglobulin (IgG, IgA, and IgM) against the SARS-CoV-2 nucleocapsid antigen presented as signal to cut off (S/C) ratio (BioRad, Hercules, California), Panel C: SARS-CoV-2 nucleocapsid antigen levels presented as pg/mL on a log scale (Quanterix, Billerica, MA). Values in plot are mean + /- standard error. P-values are from a longitudinal model comparing treatment versus placebo groups at each time point, adjusting for baseline level of blood marker. * = p-value < 0.05; ** = p-value <0.001.