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COVID-19 and Convalescent Plasma and Antibody Therapies: Frequently Asked Questions

(Version 7.0; last updated March 23, 2021)

Input from Beth Shaz, MD; Cindy Dunbar, MD; Chris Hillyer, MD; Parameswaran Hari, MD; Terry Gernsheimer, MD; Richard Davey, MD; and Evan Bloch, MD.

Note: Please review ASH's disclaimer regarding the use of the following information.

What is the evidence that convalescent plasma might be beneficial in COVID-19?

The use of convalescent plasma (CP) collected from previously infected individuals to passively transfer antibodies in order to protect or treat humans dates back almost 100 years. Results from small case series during the prior MERS and SARS coronavirus outbreaks suggested that CP is safe and may confer clinical benefits, including faster viral clearance, particularly when administered early in the disease course.1 The vast majority of patients who recover from COVID-19 illness develop circulating antibodies to various SARS-CoV-2 proteins two to three weeks following infection, which are detectable by ELISA or other quantitative assays and often correlate with the presence of neutralizing antibodies. Immunity appears to be protective, based on primate studies showing that animals could not be experimentally re-infected with SARS-CoV-2 weeks to months later, detection of memory B cells able to produce neutralizing antibodies in patients following infection, and the very infrequent occurrence of recurrent COVID-19 in recovered patients.

Multiple studies have now reported the use of COVID-19 convalescent plasma (CCP) to treat COVID-19 patients, without unexpected or serious adverse events (see below). Many of the early studies were observational and nonrandomized, in patients with severe or critical disease, complicated by evolution of additional treatment interventions over time such as steroids, antivirals, and other drugs; patient heterogeneity; and a lack of detailed analyses of neutralizing antibody content of infused units. More than 100,000 patients were enrolled in a U.S. Food and Drug Administration (FDA) –sponsored expanded access program coordinated by Mayo Clinic. While many patients improved clinically, the specific role of CCP was unclear given treatment with other therapies including antivirals and/or corticosteroids. In a retrospective study of a subset of these patients (n=3,082) with data available on titer of neutralizing antibodies in the administered CPP, the relative risk of mortality was lower in hospitalized but non-ventilated patients receiving high-titer versus low-titer CPP.2

Data are accumulating from randomized controlled trials (RCTs) carried out around the world, differing with respect to target population, disease severity, outcome measures, and characterization of antibody status and titers in donors and recipients. Several of the early trials failed to demonstrate significance (e.g., China, Netherlands, Spain), in part given their inability to meet their enrollment goals. Many trials have focused on severely ill hospitalized patients, despite consistent findings and theoretical considerations that support administration of CCP early relative to symptom onset. An RCT in Argentina showed no benefit for CCP in severely ill patients, and an Indian RCT did not find a significant difference in outcome in moderately ill patients with COVID-19.3,4 The large Recovery trial in the United Kingdom comparing CCP to usual care also closed early due to futility. Another trial in Argentina enrolled elderly patients with mild COVID-19 within three days of symptom onset and administered only high-titer CCP. This trial reported less progression to severe respiratory disease in the CCP arm, with the most benefit conferred by CCP units with the highest titers.5 The National Institutes of Health (NIH) recently halted accrual to the C3PO trial for futility after enrolling 511 of 900 planned participants. This trial administered CPP (or placebo) to patients presenting to the emergency department with mild to moderate symptoms within one week of onset. The endpoints included hospitalization, return to the emergency department, or death within 15 days of study onset. Further analysis of the data is necessary to understand if the three- versus seven- day window was critical. Current NIH treatment guidelines do not recommend for or against use of CCP.

What are the potential risks of convalescent plasma for COVID-19?

More than 100,000 people have received CCP in the United States, and many more worldwide; in the United States, safety data were published for 20,000 patients who received CCP via the expanded access program.6 CCP was observed to confer comparable risk to that of non-immune plasma. The incidence of severe adverse events was less than 1 percent, most of which were deemed to be unrelated to CCP. Known general risks of plasma transfusion more generally include allergic reactions, transfusion-associated circulatory overload , and transfusion-associated acute lung injury . Specific additional concerns were raised regarding CCP prior to deployment, including worsening of immune-mediated tissue damage via antibody-dependent enhancement , blunting of endogenous immunity, and transfusion transmission of SARS-CoV-2. These specific events have not been demonstrated with CCP.

What mechanisms exist for providers to access CCP therapy clinical trials or other mechanisms to deliver this treatment to patients? What is emergency use authorization?

On August 23, 2020, the US FDA first granted emergency use authorization (EUA) of CCP in hospitalized individuals with COVID-19, and updated the EUA recently to reflect new information. The EUA continues to be limited to hospitalized patients, but now suggests treatment “early” in the hospital course and the use of “high titer” CCP units as measured by specific anti-viral Ig testing and titer threshold criteria given in the EUA.

In addition, ongoing clinical trials continue, including for indications not covered by the EUA. These include RCTs for prophylaxis following high-risk exposure, early treatment prior to hospitalization, and trials specifically in pediatric patients. Early administration of any passive antibody therapy to non-hospitalized patients, including CCP, hyperimmune globulin, and monoclonal antibodies, makes sense given the potential to mitigate viral replication and tissue damage, thus preventing progression to severe disease. Since many patients improve on their own, large numbers of subjects will be required to show a benefit for CCP. To date, accrual to these RCTs has been a major challenge.

How is CCP collected?

CCP is procured from recovered patients (e.g., prospective donors), who donate at blood centers or other collection centers. These blood collection organizations then test the plasma for SARS-CoV-2 antibody levels and standard infectious disease markers before releasing the plasma for clinical use. Some centers use availability of screening for SARS-CoV-2 antibody levels to incentivize donors. Plasmapheresis is desirable as a means to collect large volumes of plasma. Clinical assays that measure the level of antibodies reacting against various SARS-CoV-2 proteins are widely available and may correlate, albeit imperfectly, with neutralizing antibody titers, and thus might be used to predict the potency of CCP units ( data on this relationship continue to evolve). It is important to consider the assay platform as well as the specificity (e.g., reactive with spike protein vs. nucleocapsid) and the class of antibody (IgG vs. total) when evaluating results, given major differences reported for available commercial serologic assays regarding correlations with neutralizing antibody activity.

How do recovered individuals volunteer to donate CP?

Potential donors must have had documented SARS-CoV-2 infection (either nasopharyngeal swab positivity or serologic positivity), be symptom-free for at least 14 days, and meet standard blood donor eligibility requirements. Currently, individuals who themselves were treated with CP for their own COVID-19 illness are not allowed to donate blood products, including CP, for three months. Individuals who received COVID-19 vaccines are not eligible to donate CCP. Donations can occur as frequently as weekly for several months before antibody titers begin decreasing. Allowed donation frequency varies between blood centers. Listed below are some sites for referral of potential donors:

  • AABB: Information about convalescent plasma donation and a feature that helps potential donors locate AABB-accredited donation sites. Donors then contact these centers for more information on eligibility.
  • FDA Donate COVID-19 Plasma: Lists places to donate convalescent plasma for transfusion or for manufacturing of hyperimmune globulin.
  • National COVID-19 Convalescent Plasma Project

What other passive immunity therapies are available or under development for COVID-19?

More targeted or purified passive antibody therapies are becoming available for COVID-19, including hyperimmune globulin (concentrating neutralizing antibody activity up to tenfold) and monoclonal antibodies. In November 2020, two engineered monoclonal SARS-CoV-2 neutralizing antibody preparations received EUAs in the United States for the treatment of mild to moderate COVID-19 in non-hospitalized patients who are at high risk for progressing to severe disease, based on interim analyses of early-phase clinical trials7 (and unpublished), reporting decreased viral shedding, symptoms and hospitalizations with antibody treatment. One preparation, bamlanivimab, consists of a single antibody, and the second preparation is a combination of two antibodies, casirivimab and imdevimab, all directed against the SARS-CoV2 spike protein. Most recently, a combination of bamlanivimab and etesevimab also received an EUA. However, clinical trials enrolling hospitalized patients have been placed on hold or stopped due to safety events and/or lack of efficacy on interim analyses for both antibody preparations. Additional clinical trials of these and other purified or engineered antibody therapies are ongoing, with most focusing on treatment of very high-risk exposed but not yet PCR-positive individuals, immunocompromised patients, or high-risk patients early following confirmed infection — settings more likely to be beneficial for any passive antibody therapy.

The NIH COVID-19 Treatment Guidelines panel has stated that the data are insufficient to recommend either for or against the use of monoclonal antibodies for the treatment of outpatients with mild to moderate COVID-19. They also indicated that these antibodies should not be used in hospitalized patients outside of a clinical trial. Given distribution and difficulty in administering these intravenous antibodies to SARS-CoV-2–infected outpatients, these drugs are not being widely utilized, despite the EUA, even in very high-risk patients, at the time of diagnosis or first symptoms. Immunocompromised patients less likely to be protected by vaccination and at higher risk for progression to severe disease would in theory be a target population for early administration of passive antibody therapies or CCP.

Recent concern has arisen due to evidence for resistance of several increasingly prevalent SARS-CoV-2 viral variants to the available monoclonal antibodies.8 The EUAs for these antibodies have been amended to reflect this new information. Polyclonal antibodies contained in CCP or generated by vaccine are less effective against variants carrying the E484K spike mutation but still show some activity. There is concern that variants are arising and being selected for in immunocompromised patients being treated with CCP or antibody therapies.


  1. Casadevall A, Pirofski L. The convalescent sera option for containing COVID-19. J Clin Invest, 10.1172/JCI138003.
  2. Joyner MJ et al. Convalescent plasma antibody levels and the risk of death from COVID-19, New Eng J Med, 2021. 10.1056/NEJMoa2031893.
  3. Agarwal A, et al. Convalescent plasma in the management of moderate COVID-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID trial), Brit Med J, 2020 371:m3939 http://dx.doi.org/10.1136/bmj.m3939.
  4. Simonovich VA et al. A randomized trial of convalescent plasma in severe COVID-19 pneumonia. New Eng J Med, 2020. 10.1056/NEJMoa2031304.
  5. Libster R, et al. Early high titer plasma therapy to prevent severe COVID-19 in older adults. New Eng J Med, 2021. 10.1056/NEJMoa2033700.
  6. Joyner MJ, et al. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest, 10.1172/JCI140200.
  7. Chen et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med, 2020: 10.1056/NEJMoa2029849.
  8. Wang P et al. Antibody resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature, 2021. https://doi.org/10.1038/s41586-021-03398-2

For additional information, see:

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ASH Comment on EUA for Convalescent Plasma

In response to the EUA, ASH has published additional commentary and recommendations regarding convalescent plasma.

Read the comment

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