How should we use convalescent plasma therapies for the management of COVID-19?

Convalescent plasma (CP) is collected from donors who have recovered from an infection and whose plasma contains antibodies against the agent of interest.^1-3  In the absence of other specific therapy, CP may be used as either prophylaxis or treatment to provide immediate passive immunity, transfused as clinical plasma, or further manufactured into polyclonal hyperimmune immunoglobulin preparations. CP has been used with variable success in a range of infectious diseases, including in recent decades for Middle East respiratory syndrome, severe acute respiratory syndrome (SARS) caused by SARS–coronavirus 1 (SARS-CoV-1), H1N1 influenza, and Ebola, although evidence supporting its efficacy remains limited, as reviewed elsewhere.^4-10  Where CP is of benefit, a major part of its effect is likely through the action of donor neutralizing antibodies (NAbs) against virus in the recipient.^3,11  In this Spotlight, we provide an overview of current knowledge regarding the efficacy and safety of CP for SARS–coronavirus 2 (SARS-CoV-2) infection, and considerations for future studies.

As the COVID-19 pandemic unfolded,¹²  use of CP was described in early case reports and case series from China, Italy, and elsewhere, and in larger nonrandomized studies, including through “compassionate access” schemes and “emergency use authorizations.”^13-21  Results of randomized controlled trials (RCTs) are now appearing^22-34  and 104 ongoing clinical trials are registered globally.

The studies reported to date have generally specified that CP is collected from donors recovered from, and transfused to patients with, confirmed laboratory diagnoses of SARS-CoV-2 infection. However, other key characteristics vary greatly between studies, including donor and product characteristics, dose (volume, and NAb titer), timing of administration and recipient characteristics (eg, severity of illness). Some of these differences are outlined in Table 1, and discussed later in text.

Eligibility criteria for donating CP, along with collection methods, product characteristics, and clinical application, also vary internationally.¹¹  All usual blood-donor eligibility and product-testing requirements apply, unless specific exemptions are permitted by regulatory authorities. CP may be collected by whole-blood donation or apheresis. Whole-blood donation is more widely available. Apheresis requires specialized equipment and longer duration of donation procedure, but permits larger volumes of plasma to be donated by a single donor at one time and, more frequently, with return of red cells to the donor.

Twelve RCTs have already been reported, although only 6 are published in the peer-reviewed literature; 4 were terminated early, mostly due to falling local case numbers^22-34  (Table 2). Only 1 small trial²³  showed benefit from CP for a range of outcomes (including time to clinical recovery, progression to severe disease, and mortality), although others reported benefits in secondary outcomes (eg, viral clearance).

Li et al from Wuhan, China reported outcomes for 103 adults with severe or life-threatening COVID-19, of whom 52 received CP in addition to standard care in an open-labeled RCT.²²  The trial was terminated early, and was underpowered for its primary outcome of time to clinical improvement within 28 days. Patients receiving CP had no improvement in the primary outcome, 28-day mortality, or time to discharge, but did have higher rates of viral clearance (87.2% vs 37.5%; odds ratio, 11.39 [95% confidence interval, 3.91-33.18]; P < .001). One nonsevere allergic reaction and 1 episode of transfusion-associated dyspnea were reported.

In a study from Iran by Rasheed et al, 21 critically ill patients received 400 mL of CP in addition to standard care.²³  Patients receiving CP had shorter time to clinical improvement, shorter duration of illness, and lower mortality (4.8% vs 28% in controls; P = .03). One mild allergic reaction was reported.

Agarwal et al from India reported on the PLACID RCT, in which 464 hospitalized adults were randomized to receive either 2 doses of 200 mL of CP (with a median NAb titer of 1:40, given 24 hours apart) or control, in addition to standard care.²⁴  Participants who received CP did not show any improvement in the study’s primary outcome (composite of progression to severe COVID-19 disease or mortality at 28 days) compared with standard care. Detectable NAbs at study entry were later detected in 80% of participants. Three possible transfusion-related severe adverse events (SAEs) were noted.

Two open-label RCTs have been reported (in preprint). Gharbharan et al in The Netherlands enrolled 86 of a planned 426 participants, but the study closed early, in part due to the observation that 79% of patients had NAb titers comparable with those of the CP donors.²⁵  There were no differences in mortality, length of hospital stay, or disease severity at day 15, but the study was underpowered. No plasma-related SAEs were reported. Avendano-Sola et al from Spain reported on an RCT that terminated after enrolling 81 of a planned 278 participants with no significant difference in their primary or secondary outcomes.²⁶  Nearly one-half of the patients enrolled were later identified as having detectable antibodies at baseline. No confirmed plasma-related SAEs were described.

These differences in requirements for a minimum CP NAb titer, NAb-measuring assays, heterogenous patient populations, and baseline NAb prevalence in recipients are likely important.^34,35  In PLACID, NAb assays were not available at study commencement and, therefore, were not used to prospectively select CP.²⁴  The median NAb in CP administered across the trial was 1:40 (interquartile range, 1:30-1:80); however, only 68% of patients allocated to CP received plasma with detectable NAbs, and only 29% received CP with NAbs >1:80. If future trials fail to show benefit, an important question will be whether this relates to insufficient antibody titer of the CP (due to low NAb titer and/or volume administered). Future analyses, including individual patient data meta-analyses, may be able to examine efficacy by antibody titer, but only if reported in a standard manner, so availability of standardized testing (performed by laboratories meeting regulatory requirements for testing of blood products) is an important practical issue and a high priority.

Many patients already have anti–SARS-CoV-2 antibodies at study entry, even in studies with a relatively short time from symptom onset to randomization; the consequence of this for whether patients are likely to benefit from CP is unknown. There may be qualitative differences in humoral response between individuals that could support the rationale for testing CP in patients with measurable NAbs. Atyeo et al reported early functional differences in humoral responses between hospitalized patients who survived and those who died of COVID-19.³⁶  Although they had similar levels of SARS-CoV-2–specific immunoglobulin G (IgG) and NAbs, there were other differences between the 2 groups, with a shift toward spike-specific humoral response in the patients who recovered and elevated nucleocapsid response in patients who died. There may also be qualitative and quantitative differences between the endogenous anti–SARS-2 antibodies circulating in a recently infected patient and those collected from donors who may be many weeks out from infection, for example, IgG-affinity maturation. Finally, there may be other considerations, for example, a recent report described neutralizing autoantibodies against type I interferons in patients contributing to severity of COVID-19, which may have implications for CP donors and transfusion recipients.³⁷ 

These results highlight a number of issues with designing and interpreting clinical trials of CP, and as a consequence of several of these trials stopping early, we still have limited evidence about the efficacy of CP. However, these reports generate important information and questions for ongoing studies, including whether we should be aiming to give CP with higher titers earlier in the course of the illness, and whether this approach will lead to better outcomes for patients. Addressing the logistical and other challenges required to identify patients with no or low titers of NAbs at study entry should be a high priority. The potential benefits of CP for patients who are unable to make their own NAbs is further discussed later in text.

In the past month, three large RCTs of CP have issued public statements announcing cessation of recruitment to CP interventions based on reaching prespecified end points of futility following analysis of available data. Interim analysis of the international REMAP-CAP trial (NCT02735707) indicated that the probability that convalescent plasma was beneficial in all critically ill patients was only 2.2%.³⁸ Preliminary analysis of data from 10 406 hospitalized patients in the RECOVERY trial (ISRCTN50189673) from the United Kingdom showed no significant difference in the primary end point of 28-day mortality (18% convalescent plasma vs 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; P = .34).³⁹ The international CONCOR-1 trial (NCT04348656) notified closing to recruitment after interim analysis of data from the first 614 patients of 973 patients randomized to CP indicated meeting the prespecific threshold for futility.⁴⁰ No safety concerns were reported. More information is anticipated soon from each of these trials, and we await full peer-reviewed publication of the results. Importantly, analysis of follow-up data from additional patients already recruited prior to closure of the entire trial or the CP intervention arm, and subgroup analyses will be important to understanding the full picture of the experience with CP in these trials. Another smaller trial (160 participants) of very early treatment (within 72 hours of symptom onset) with high-titer plasma showed potential benefit, with reduction in progression to severe disease by approximately 50%.²⁷ This, and other trial evidence has prompted the FDA to update its Emergency Use Authorization for convalescent plasma, so that only high titer plasma should be issued.³⁵ 

Plasma transfusions are associated with known hazards, including allergic reactions ranging from trivial to life-threatening anaphylaxis, along with transfusion-related acute lung injury (TRALI) and transfusion-associated volume overload (TACO).^10,11,41  CP-specific concerns include antibody-dependent enhancement of infection,^10,41  and potential transmissibility by transfusion. SARS-CoV-2 RNA has been detected in blood donations, but there is no evidence it is transmitted by transfusion.^42,43  Treatment of CP with pathogen reduction technologies may further minimize this risk.^1,41 

Joyner et al in the United States have reported 7-day mortality and other safety data on 20 000 adults receiving 200 to 500 mL of CP through a multicenter expanded-access program (EAP).²¹  They described 141 transfusion-related SAEs and 63 deaths occurring within 4 hours of CP infusion. These events, representing <1% of all transfusions, included 36 reported TACO, 21 TRALI, and 21 severe allergic reactions, of which 10 were considered possibly transfusion-related and none were probably or definitely related. Furthermore, 1247 other SAEs were reported within 7 days of receiving CP, including 113 thromboembolic or thrombotic events, 457 sustained hypotensive events requiring IV pressor support, and 677 cardiac events. Of these, 75 thromboembolic/thrombotic SAEs and 597 cardiac events were considered unrelated to receiving CP. The authors report an overall mortality rate of 13.1% for patients in the EAP. It is not possible to determine efficacy from these studies, and it is noted that characteristics of patients in the study have changed over time (for example, to earlier use in less unwell patients). Salazar et al¹⁶  from the United States and Abolghasemi et al¹⁷  from Iran reported no plasma-related adverse events in 25 patients receiving 300 mL of CP and 115 patients receiving 500 mL of CP, respectively.

Published preliminary safety data have not identified any new early plasma-related SAEs or worsening of COVID-19 illness following receipt of CP, although comparative data are lacking. This is reassuring, but more information is certainly required. Other unforeseen hazards may exist. The most important way to prevent complications of plasma transfusions is to avoid unnecessary exposure: unless the benefits clearly outweigh the risks, the transfusion should not be given at all. All usual requirements for blood administration, including informed consent and product traceability, should be followed for CP transfusions.^18,44 

Reported studies to date have mostly focused on hospitalized adults, including the critically ill. If the main mechanism of CP action is through viral neutralization, earlier administration, including prehospital or as prophylaxis, may be of benefit, and several trials are under way (eg, NCT04323800, NCT04438057).

There may also be specific patient groups who are more likely to benefit, including patients with inherited or acquired immunodeficiencies. Higher SARS-CoV-2 viral load in patients with hematological malignancies compared with noncancer patients, and delayed clearance of SARS-CoV-2 in immunosuppressed patients, has been reported.^45,46  In a French case series, 17 patients who had received anti-CD20 therapies and were profoundly lymphopenic with persistent COVID-19 symptoms and SARS-CoV-2 viremia without detectable antibody received 800 to 880 mL of CP at a median of 56 days (range, 7-83 days) from the onset of symptoms.⁴⁷  Sixteen recovered with rapid abatement of symptoms. SARS-CoV-2 virus became undetectable in all 9 patients who were retested using sensitive methods. No transfusion-related SAEs were observed. Finally, results from trials in adult populations may not be generalizable to pediatric patients. Although SARS-CoV-2 generally appears to cause milder disease in children,⁴⁸  some do develop severe disease (including those with comorbidities and/or immunosuppression) and may benefit from CP if shown to be effective.⁴⁹ 

Blood-component alternatives to CP include hyperimmune globulin, which has potential advantages over CP such as a more standardized product (antibody titer), pathogen inactivation, lower volume, and easier storage. However, due to the necessity to pool large volumes of plasma and manufacture the product, there are inherent delays in its availability. Hyperimmune globulin preparations for COVID-19 are being manufactured globally, with trials under way.⁵⁰  Monoclonal antibodies targeting SARS-CoV-2 are entering clinical trials, although data are not yet available on efficacy or safety.^51,52  Polyclonal immunoglobulins for IV (IVIG) or subcutaneous use likely already do, or soon will, contain anti–SARS-CoV-2 antibodies given rising rates of antibody positivity among blood donors.^39,40,53,54  IVIG is already being used in the treatment of COVID-19, although evidence of benefit is limited.^50,54  There is preclinical evidence that platelet-derived IgG may be more potent at viral neutralization than plasma IgG, raising the question of whether platelets could be a novel method of delivering passive immune therapy.⁵⁵ 

Therapeutic plasma exchange (TPE) is being studied in trials in critically ill COVID-19 patients; however, the rationale for this treatment is not related to passive immunity but rather removal of potentially harmful circulating cytokines and other molecules, and replacement of protective plasma proteins to maintain microcirculatory flow and prevent vascular leak.⁵⁶  However, unless CP is used, TPE may lead to reduction in circulating antibodies directed at SARS-CoV-2.⁵⁷ 

Recent achievements in COVID-19 clinical practice and research present opportunities to learn and improve. A high priority for the future should be opening and completing high-quality trials faster.^41,57-59  Examples of the success of large, simple, pragmatic studies for COVID-19 are RECOVERY and SOLIDARITY (ISRCTN8397115),⁶⁰ which combined have randomized >45 000 patients to date. The opportunity to add CP “domains” to established multi-interventional platform trials was taken with RECOVERY and REMAP-CAP. International collaboration on trial design (such as agreement on universal end points measured in standardized ways) and management (such as common protocols) will permit comparability of results.^59,61  By working through these networks, duplication of effort and cost can be avoided when setting up independent studies in each country. Additionally, there can be flexibility in completing trials that are started: new sites can join quickly as a pandemic spreads, and recruitment can be stopped if cases decline locally (without compromising trial completion as other locations take over recruitment) or seamlessly reactivated if there are “second (or later) waves.”

Standardized protocols for CP collection, characterization, and use (developed by blood establishments and hospitals in SARS-CoV-2 and other recent epidemics and enabled through international blood supplier networks, research collaborations, and the World Health Organization) can be further harmonized and activated quickly when needed in the future.^{11,19,20,41,61-63} 

Data sharing of meta-analyses of individual patient data from completed trials as well as reports on the experiences of blood establishments that collect CP is becoming more widespread, even prior to study completion and analysis.^64,65  International hemovigilance definitions can facilitate comparison of adverse event reporting, and hemovigilance systems established in many countries can support vigilance for potential emerging adverse reactions related to CP, during and after completion of clinical trials.

Availability of patient, product, and blood-donor samples in biorepositories will enable important correlative studies to better understand the mechanism(s) of action of CP and other therapies, and support laboratory quality-assurance activities.

While considering the potential role for CP in helping patients, we should not forget our responsibility for the welfare of blood donors, who are community volunteers and have themselves recently recovered from illness. Blood establishments have implemented a range of public health measures to protect donors and staff, and to enable safe donation and preparation of CP. This can be very challenging at times when measures to contain an infectious outbreak substantially affect blood center operations and efforts to maintain sufficiency in other blood products.^66-69  Logistical issues such as delays in access to CP for clinical trials have been reported.^68,69 

CP may be of benefit for patients with COVID-19, but more information on both efficacy and safety is needed.^41,58,70  Results from randomized trials are essential, and are starting to appear in the peer-reviewed literature. Harmonization of approaches in elements of study design (eg, use of standardized end points) and management (eg, use of common protocols for characterization of CP) will greatly assist interpretation of results. National and international collaborative studies are under way and will provide detailed product characterizations as well as clinical outcome and cost data. Available information is continuously being summarized and continually updated, including through a series of living Cochrane reviews and coordinated data-sharing activities.^34,64  Professional guidance to date has largely been based on first principles (including, importantly to “first do no harm”) and experience with CP in other settings, and will transition to evidence-based guidelines as data become available.^58,71,72  In the future, availability of established trial platforms will help us open and complete high-quality trials sooner and at lower cost, and obtain better answers faster.

E.M.W. was supported by an Investigator Grant (#1177784) from the National Health and Medical Research Council, Australia. Z.K.M. was supported by a Clinical Research Fellowship from the Victorian Cancer Agency.

The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the UK National Institute for Health Research (NIHR), National Health Service (NHS), NHS Blood and Transplant, or the Department of Health.

Contribution: E.M.W., L.J.E., and Z.K.M. conceived and wrote the paper.

Conflict-of-interest disclosure: E.M.W. and Z.K.M. have received funding from Australia’s Medical Research Future fund for a trial of convalescent plasma; and, through Monash University’s Transfusion Research Unit, have received research funding for research outside of the scope of this work from AbbVie, Alexion, Amgen, AstraZeneca, the Australian and New Zealand Society for Blood Transfusion, the Australian Red Cross Blood Service, Bristol-Myers Squibb, Celgene, CSL Behring, Dova Pharmaceuticals, Janssen-Cilag, Maddie Riewoldt’s Vision Foundation, National Blood Authority Australia, the New Zealand Blood Service, Novartis, Roche, Sanofi, and Takeda. E.M.W. is president of the International Society of Blood Transfusion. L.J.E. has received funding from the NIHR for convalescent plasma trials (RECOVERY and REMAP-CAP) and funding from a Horizon 2020 European Union (EU) grant as part of the SUPPORT-E programme; and is employed by NHS Blood and Transplant. Z.K.M. is a member of the Scientific Advisory Committee of the Australasian Leukaemia and Lymphoma Group.

Correspondence: Erica M. Wood, Monash University, 553 St Kilda Rd, Melbourne, 3004 Australia; e-mail: erica.wood@monash.edu.