Passive immunotherapy for adults hospitalized with COVID-19: An individual participant data meta-analysis of six randomized controlled trials

Abstract

Background: Anti-SARS-CoV-2 monoclonal antibodies (mAb) reduce the risk of hospitalization in outpatients with mild-to-moderate COVID-19. However, the efficacy of treatment with mAbs and other passive immunotherapies in patients hospitalized with severe COVID-19 is not clear. The objective of this study was to assess the clinical effect of passive immunotherapy and its heterogeneity according to baseline endogenous neutralizing antibody status and SARS-CoV-2 antigen level, in adults hospitalized with SARS-CoV-2 infection and severe COVID-19.

Methods and findings: We carried out a two-stage individual participant data meta-analysis of six double-blind, randomized, placebo-controlled trials conducted under the Therapeutics for Inpatients with COVID-19 (TICO) and the similarly designed Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) master protocols. Within each trial, three major outcomes (sustained recovery, mortality, and a composite safety outcome) were compared between treatment and placebo using Fine-Gray and Cox proportional hazards models. Trial-specific treatment differences for each of the three outcomes were pooled using a common effect meta-analysis. A total of 3,079 patients hospitalized for COVID-19 were enrolled in the six trials. Only 18% had received at least one dose of an anti-SARS-CoV-2 vaccine. Overall, the median plasma SARS-CoV-2 antigen level was 1,421 (IQR: 231-4,568) pg/mL, and 51% of patients were endogenous neutralizing antibody positive at study entry. The overall summary estimate of sustained recovery rate ratio (RRR) of the treatment versus placebo group was 1.06 (95% CI [0.99,1.14]), but this varied significantly by antibody serostatus. The RRR was 1.16 (95% CI [1.04,1.29]) among seronegative patients and 0.97 (95% CI [0.88,1.07]) in seropositive patients [p = 0.02 for interaction (the difference in RRR between seropositive and seronegative patients)]. The summary hazard ratio (HR) for mortality comparing treatment to placebo was 0.81 (95% CI [0.64,1.03]) overall, 0.69 (95% CI [0.50,0.95]) in seronegative patients, and 0.96 (95% CI [0.66,1.39]) in seropositive patients (interaction p = 0.18). There was no evidence that the treatment effect on any outcome differed according to antigen level, whether overall or within serostatus subgroups. In regards to the composite safety outcome, the overall summary HR comparing treatment group to placebo was 0.89 (95% CI [0.66,1.21]; Q = 3.47 [p = 0.63], I2 = 0.0%), and it was 0.83 (95% CI [0.70,0.99]) and 1.04 (95% CI [0.86,1.26]) in seronegative and seropositive patients, respectively. The main limitation of the methodology is that these results are limited to the analysis of the six trials in ACTIV-3/TICO and ITAC and are not intended to be a complete summary of all trials of passive immunotherapy.

Conclusions: Passive immunotherapy might be a useful treatment option for hospitalized patients with COVID-19 if administered before the appearance of endogenous antibodies. Development of similar passive immunotherapy could also be especially important during the early stages of a viral pandemic, or as novel viral variants emerge.

Fig 1. Sustained recovery by baseline SARS-CoV-2 neutralizing antibody status.

(a) Forest plot of recovery rate ratio (RRR) comparing treatment arm versus matched placebo by neutralizing antibody status at study entry. (b) Forest plot of the relative recovery rate ratio (rRRR) comparing the estimated treatment effect in neutralizing antibody seropositive versus seronegative patients at study entry.

Fig 2. Mortality by baseline SARS-CoV-2 neutralizing antibody status.

(a) Forest plot of hazard ratio (HR) for mortality comparing treatment arm versus matched placebo by neutralizing antibody status at study entry. (b) Forest plot of the relative hazard ratio (rHR) comparing the estimated treatment effect in neutralizing antibody seropositive versus seronegative patients at study entry.

Fig 3. Pooled recovery rate ratio (RRR) for sustained recovery comparing treatment arm vs. matched placebo by baseline plasma antigen level.

(a) Overall Study, (b) By neutralizing antibody status at study entry. The points show the observed distribution of baseline antigen measurements in patients. The dashed lines represent the 33rd and 66th percentiles of antigen measurements across trials in the respective patient group (overall, seropositive, seronegative); these correspond to the locations of the internal knots for the restricted cubic splines. The dotted lines represent the 10th and 90th percentiles of antigen measurements in the respective group.