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

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 safety outcomes, 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. Why was this study done?: What did the researchers do and find?: What do these findings mean?: The main limitation of this study is that it was conducted before the COVID-19 virus had evolved to later variants, such as the Omicron variant. However, the study still provides insight into treatment approaches during the early phase of an epidemic. In addition, the current analysis focuses on the six trials that were performed using similar methodology and is not intended to represent all trials on passive immunotherapy. An analysis of the effects of passive immunotherapy in hospitalized patients with severe COVID-19 suggests there may be some benefit for patients who have not yet developed SARS-CoV-2-specific antibodies. The findings suggest that passive immunotherapies warrant consideration at the early stage of a pandemic when immunity is not widespread.