Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study

Abstract

COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for <10 days were eligible. Participants received either CCP with nAb titers of >1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray's P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher's P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507). IMPORTANCE In this study, in a high-risk population of patients admitted for COVID-19, we found an earlier time to hospital discharge among participants receiving CCP with nAb titers of >1:640 compared with participants receiving CCP with a lower nAb titer and no CCP-related AEs. The significance of our research is in identifying a dose response of CCP and clinical outcomes based on nAb titer. Although limited by a small study size, these findings support further study of high-nAb-titer CCP defined as >1:640 in the treatment of COVID-19.

Keywords: SARS-CoV-2; antibodies; convalescent plasma; coronavirus; immunology; neutralizing antibodies.

FIG 1

Enrollment, randomization, and treatment allocation. Patient flow diagram in the CoVIP study, detailing excluded patients, randomization, and CCP titer received. *, 13 patients randomized to receive high-titer CCP received standard-titer CPP because ABO-compatible high-titer plasma was not available.

FIG 2

Cumulative incidence of hospital discharge by high- versus standard-neutralizing antibody-titer CCP received. Time to hospital discharge from first CCP infusion until day 55, by CCP titer received with death as a competing event, was estimated using the Aalen-Johansen estimator with Gray’s test with rho = 0 (A). Shown are stacked cumulative incidence curves for death, hospital discharge, and remaining hospitalized as competing risks among patients receiving high-titer CCP (B) and standard-titer CCP (C). Deaths are shaded in black, hospital discharge in gray, and remaining hospitalized in blue.

FIG 3

Time to hospital discharge by neutralizing antibody CCP titer received and patient characteristics. Hazard ratios and 95% confidence intervals for hospital discharge from first CCP infusion until day 55 were estimated by the Fine-Gray method, accounting for competing risk of death. Shown are unadjusted estimates for high- versus standard-titer CCP and select patient characteristics fit with separate models. High- versus standard-titer CCP adjusted estimates with adjustment made for each patient characteristic are given in a separate model. Respiratory support measured at baseline contrast is ventilation (i.e., noninvasive or invasive ventilation) versus less than ventilation (i.e., none or low-flow nasal cannula). Comorbidities (any) included diagnosis at baseline of any of the following: hypertension, diabetes, obesity, cardiovascular disease, chronic pulmonary disease, solid tumor, hematologic malignancies, solid organ transplant, and hematologic stem cell transplantation.