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COVID-19 and Convalescent Plasma: Frequently Asked Questions

(Version 6.0; last updated November 30, 2020)

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

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 course1. The vast majority of patients who recover from COVID-19 illness develop circulating antibodies to various SARS-CoV-2 proteins 2-3 weeks following infection, which are detectable by ELISA or other quantitative assays and often correlate with the presence of neutralizing antibodies. These antibodies appear to be protective, based on several primate studies showing animals could not be re-infected with SARS-CoV-2 weeks to months later.

Multiple studies have now reported the use of COVID-19 convalescent plasma (CCP) to treat severely or critically ill COVID-19 patients, without unexpected or serious adverse events (see below). Many of the early studies were observational and non-randomized, 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. Preliminary efficacy results from 35,000 patients enrolled in a US FDA-sponsored expanded access program coordinated by Mayo Clinic were made available on a preprint server. While many patients improved clinically, the specific role of CCP is unclear, because all patients received at least one additional therapy, including antivirals, antibiotics or antifungals, and/or corticosteroids. Mortality was lower in patients who received CCP within 3 days of diagnosis of COVID-19, and in those who received units of CCP with higher specific IgG levels, however, uniform testing for neutralizing antibodies was not performed.

Published and preprint data is accumulating from randomized controlled trials (RCT) carried out around the world, differing with respect to target population, disease severity, outcome measures, an characterization of antibody status in donors and recipients. Several of the early trials failed to demonstrate significance (e.g. China, Netherlands, Spain) but were stopped early due to inability to meet enrollment goals. Most trials have focused on moderate to severely ill hospitalized patients, despite consistent findings and theoretical considerations that support early CCP use relative to symptom onset. One large trial in India (PLACID) did not find a significant difference in outcome in moderately ill patients with COVID-192. However, a high proportion of recipients had low or absent antibodies. A randomized, double-blinded, placebo-controlled Argentinian multicenter trial enrolled hospitalized patients with COVID-19 pneumonia a median of 8 days from symptom onset and failed to show clinical or mortality benefit for CCP, despite use of high titer units. Another trial in Argentina preliminarily reported favorable outcomes in elderly subjects following use of CCP within three days of symptom onset. Current NIH treatment guidelines do not recommend for or against use of CCP.

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

Over 100,000 people have received CCP in the US and many more worldwide: in the US safety data were published for 20,000 patients who received CCP via the expanded access program3. Convalescent plasma was observed to be relatively safe, with comparable risk to that of non-immune plasma. The incidence of severe adverse events was less than 1%, 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 (TACO), and transfusion-associated acute lung injury (TRALI). Specific additional concerns were raised regarding CCP prior to deployment, including worsening of immune-mediated tissue damage via antibody-dependent enhancement (ADE), 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 COVID-19 convalescent plasma therapy clinical trials or other mechanisms to deliver this treatment to patients? What is Emergency Use Authorization?

On August 23, 2020, the US FDA granted emergency use authorization (EUA) of CCP in hospitalized individuals with COVID-19. The EUA language suggests treatment early in disease course, and the use of “high titer” CCP units as measured by specific anti-viral Ig testing and titer threshold criteria. Those CCP units (including those collected prior to the EUA) that have not undergone such testing, or do not meet the titer threshold, will be considered “low titer”, but can still be administered under the EUA per the judgement of the treating clinician.

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. Similar efforts are ongoing around the world. Early administration of any passive antibody therapy to non-hospitalized patients, including CPP, 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 convalescent plasma collected?

The logistics of CCP procurement are complex, requiring cooperation between multiple stakeholders including recovered patients (e.g. prospective donors), blood centers or other plasma collection centers, treating physicians and their patients, and health care administrators and regulators overseeing the safety of each step. 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 protein are widely available and may correlate —albeit imperfectly— with neutralizing antibody titers, and thus might be used to predict the potency of CCP units, although data on this relationship continues 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.

How do recovered individuals volunteer to donate convalescent plasma?

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 convalescent plasma, for 3 months. Donations can occur as frequently as weekly for several months following clearance of infection 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 being developed for COVID-19?

The use of CCP is an interim approach until there is approval and wide availability of alternative treatments such as hyperimmune globulin (concentrating neutralizing antibody activity up to ten-fold), engineered monoclonal antibodies, and/or antiviral drugs, and availability of effective vaccines, although many immunosuppressed hematology patients may not respond optimally to vaccination and may continue to need passive immunity interventions. 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 patients who are at high risk for progressing to severe disease, based on interim analyses of early phase clinical trials4 (and unpublished), reporting decreased viral shedding, symptoms and hospitalizations with antibody treatment. (See here and here.) One preparation, bamlanivimab consists of a single antibody, and the second preparation is a combination of two, casirivimab and imdevimab, all directed against the SARS-CoV2 spike protein. 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, most focusing on treatment of very high risk exposed but not yet PCR test positive individuals or high-risk patients very 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 there is insufficient data 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 the drug should not be used in hospitalized patients outside of a clinical trial. Given major manufacturing, distribution and administration hurdles, these antibodies are unlikely to be available in the near term to more than a tiny fraction of patients covered by the EUAs as eligible, ie those at high risk for complications due to age, obesity, diabetes, cardiovascular disease, COPD, kidney disease, smoking, pregnancy, an immunocompromised state, or sickle cell anemia. States and hospital systems are in the process of designing allocation plans.


  1. Casadevall A, Pirofski L. The convalescent sera option for containing COVID-19. J Clin Invest, 10.1172/JCI138003.
  2. Bloch EM, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19, J Clin Invest, 10.1172/JCI138745.
  3. Li L, et al.  Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA, 2020. doi: 10.1001/jama.2020.10044.
  4. Joyner MJ, et al. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest, 10.1172/JCI140200.
  5. Chen et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med, 2020 Oct 28; NEJMoa2029849. doi: 10.1056/NEJMoa2029849

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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