Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis
In patients with non-severe covid-19:
Casirivimab-imdevimab (Regen-Cov) probably reduces hospitalisation;
Bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation.
Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n2231 (Published 23 September 2021)Cite this as: BMJ 2021;374:n2231
As of 14 September 2021, more than 225 million people have been infected with SARS-CoV-2, and total deaths have surpassed 4.6 million.1 Because covid-19 represents a significant threat to global health, coordinated international efforts to identify evidence based therapies have resulted in over 2900 registered clinical trials. Approximately 12% of these trials are investigating cellular or antibody-based therapies such as convalescent plasma, intravenous immunoglobulins (IVIg), or antiviral antibodies.2
Given their favourable toxicity profile and historical (though variable) mortality benefit over the years, these harvested and manufactured antiviral antibodies represent attractive therapeutic options for covid-19. Indeed, based on this historical evidence combined with early clinical trial data, several countries have issued authorisation for emergency use of convalescent plasma for the treatment of hospitalised patients with covid-19. Several countries have also authorised the use of antiviral monoclonal antibodies of covid-19.7
Unlike drugs, stem cells, convalescent plasma, and IVIg cannot be manufactured; thus, production is limited by the number of donors. Since these products have established therapeutic applications in the treatment of congenital and acquired diseases,8 one can, in the absence of clear evidence for use in covid-19, anticipate challenges related to resource allocation.
In contrast, monoclonal antibodies are very easily scalable once they are identified, but production can be time consuming.9 Therefore, in the midst of a global pandemic in which resource management is fundamental, timely summaries of available evidence and associated guidelines are crucial.10
A living systematic review is dynamic and captures all relevant data published over time.13 Network meta-analysis, which combines direct and indirect evidence to compare interventions, can provide robust information regarding the relative efficacy of interventions that may not have been compared head-to-head due to feasibility or other constraints.14
Objective To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19).
Design Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data.
Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021).
Study selection Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate.
Methods After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm.
Results As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) −4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD −4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD −3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD −4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative.
Conclusion In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.
Systematic review registration This review was not registered. The protocol established a priori is included as a data supplement.