Convalescent Plasma for Preventing Critical Illness in COVID-19: a Phase 2 Trial and Immune Profile

Abstract

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring frequent adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting. We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28-day mortality or alter levels of specific antibody responses before and after CIP infusion. In a single-arm phase II study, patients >18 years-old with respiratory symptoms with confirmed COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 h of admission. Levels of SARS-CoV-2 detected by PCR in the respiratory tract and circulating anti-SARS-CoV-2 antibody titers were sequentially measured before and after CIP transfusion. Twenty-nine patients were transfused high titer CIP and 48 contemporaneous comparable controls were identified. All classes of antibodies to the three SARS-CoV-2 target proteins were significantly increased at days 7 and 14 post-transfusion compared with baseline (P < 0.01). Anti-nucleocapsid IgA levels were reduced at day 28, suggesting that the initial rise may have been due to the contribution of CIP. The groups were well-balanced, without statistically significant differences in demographics or co-morbidities or use of remdesivir or dexamethasone. In participants transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298). IMPORTANCE Transfusion of high-titer CIP to non-critically ill patients early after admission with COVID-19 respiratory disease was associated with significantly increased anti-SARS-CoV-2 specific antibodies (compared to baseline) and a non-significant reduction in ICU transfer and death (compared to controls). This prospective phase II trial provides a suggestion that the antiviral effects of CIP from early in the COVID-19 pandemic may delay progression to critical illness and death in specific patient populations. This study informs the optimal timing and potential population of use for CIP in COVID-19, particularly in settings without access to other interventions, or in planning for future coronavirus pandemics.

Keywords: COVID-19; SARS-CoV-2; antibodies; convalescent plasma; respiratory failure.

FIG 1

Swimmer plot depicting clinical timelines of CIP transfused participants and controls. Baseline was the day of index hospital admission. The blue line represents symptomatic days before admission; green lines represent admission to acute hospital care, with intensive care unit stays represented in red. Blank gaps between hospitalizations indicate the patient was discharged then readmitted within the 60 day follow up period. Circles show the date of plasma infusion; triangles indicate that the patient died; “< >” bracket time periods where the patient received mechanical ventilation. Participant 29 in the Convalescent Plasma group was discharged on day 60. *Pictured intensive care unit stays were indicated for higher levels of oxygen therapy including high-flow nasal cannula oxygen, mechanical ventilation, and/or extracorporeal membrane oxygenation.

FIG 2

Effect of CIP on progression to critical illness and survival. Kaplan-Meier curves are shown comparing survival (A) and ICU-free survival (B) in CIP transfused patients vs control. Number of patients remaining at risk are listed along the bottom of each panel. Log-rank P values are listed.

FIG 3

Specific IgG, IgM, and IgA antibodies binding to spike (S), receptor binding domain (RBD), nucleocapsid (NC). Blood was collected on CIP treated participants (n = 25) immediately prior to infusion (baseline), and then 7, 14, and 28 days post-infusion. Levels of specific anti-SARS-CoV-2 antibodies were measured and compared to baseline. Paired Wilcoxon rank sum P values: * < 0.02; ** < 0.01; *** < 0.001; **** < 0.0001. Medians and the 25 and 75 quartiles are indicated on each violin plot.

FIG 4

Respiratory tract viral clearance. Serial respiratory tract swabs were collected at baseline and then 4, 7, 14, and 21 days post CIP transfusion. The inverse cycle thresholds for SARS-CoV-2 RNA are graphed. Participants who were ultimately transferred to the ICU are depicted in red.