Potent neutralizing antibodies for severe COVID-19: A randomized clinical trial
2021
Background: Convalescent plasma could be an inexpensive and widely available drug for COVID-19 patients. Reports on its effectiveness are inconclusive. We collected convalescent plasma with high titers of neutralizing anti-SARS-CoV-2 antibodies effectively blocking SARS-CoV-2 infection and assessed their clinical and viro-immunological responses in COVID-19 patients with severe disease. Methods: In a multicentre open-label randomized clinical trial in 14 secondary and academic hospitals in the Netherlands, included patients were admitted for COVID-19 with SARS-CoV-2 detected by PCR and not on mechanical ventilation for >96hours. Convalescent plasma donors were selected based on SARS-CoV-2 plaque reduction neutralization test (PRNT50) result of ≥1:80. Primary outcome was day 60 mortality. Secondary outcomes were disease severity, inflammatory and virological markers. Results: Included patients were 72% male, median 63 years (IQR 56-74) and with median 10 days of symptoms (IQR 6-15) at inclusion when they were randomized to convalescent plasma or standard of care. We found no significant difference in mortality at day 60 by using 300mL of convalescent plasma (median PRNT50 1:640) between the arms after adjustment (OR: 0.95, 95%CI: 0.20-4.67). Improvements in WHO COVID-19 disease severity scores at day 15 (OR: 1.30, 95%CI 0.52-3.32) and time to discharge (HR: 0.88, 95%CI: 0.49-1.60) were also comparable. The vast majority of patients already had potent neutralizing anti-SARS-CoV-2 antibodies at hospital admission and at comparable titers as the carefully selected plasma donors. No effect of convalescent plasma on viral clearance in the respiratory tract, anti- SARS-CoV-2 antibody development or changes in serum pro-inflammatory cytokine levels were observed. After the inclusion of 86 patients and per DSMB recommendation, we decided to interrupt the study for futility. Conclusion: Convalescent plasma treatment in this patient group did not improve survival or disease course, nor did it alter relevant virological and immunological parameters. Together, these data indicate that the variable effectivity observed in trials on convalescent plasma for COVID-19 may be explained by the timing of treatment and varying levels of preexisting anti-SARS-CoV-2 immunity in patients. It also substantiates that convalescent plasma should be studied as early as possible in the disease course or at least preceding the start of an autologous humoral response. (Clinicaltrials.gov: NCT04342182).
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