Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial

Abstract

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

SARS-CoV-2 Infection of Rhesus Macaques Treated Early with Human COVID-19 Convalescent Plasma

“…In addition, histopathologic changes in the lungs ( 23 ) were similar in the animals with and without CP treatment. Although this study was limited by the number of animals that received CP treatment and the mild-to-moderate severity of disease in the model, several recent randomized clinical trials have demonstrated similar findings ( 7 , 8 , 14 ), including several studies that were stopped for futility in hospitalized patients with more severe disease ( 17 , 24 , 25 ).…”

Vaccination of COVID-19 Convalescent Plasma Donors Increases Binding and Neutralizing Antibodies Against SARS-CoV-2 Variants

“…However, based on further findings from observational studies, the beneficial effects of CCP were limited to units with high titers of neutralizing antibodies (nAbs) administered early after infection, and efficacy was not confirmed by recent large randomized trials 3 . For example, the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) study showed no significant beneficial effect in mildly symptomatic treated patients compared to controls 4 , with similar findings in the CONCOR-1 study in hospitalized patients 5 ; both were halted early for futility.…”

A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in rhesus macaques

“…This quantitative determination of a neutralizing titer as a direct mechanistic correlate of protection has implications for estimating the durability of protection conferred by passive immunization with antibodies (Loo et al, 2021) or active immunization with vaccines. The failure to achieve serum neutralizing titers above this threshold likely explains the lack of limited efficacy observed in most clinical trials of COVID-19 convalescent plasma (Begin et al, 2021;Bradfute et al, 2020;Janiaud et al, 2021). Also, this quantitative threshold for correlate of protection sheds light on the somewhat limited magnitude and durability of the humoral immunity component of protection following natural infection or immunization.…”