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COVID-19 and Convalescent Plasma: Frequently Asked Questions

(Version 5; last updated August 25, 2020)

Input from Drs. Beth Shaz, Cindy Dunbar, Chris Hillyer, Parameswaran Hari, Terry Gernsheimer, 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. CP has been used both as post-exposure prophylaxis as well as treatment for diverse infectious diseases, notably in times of outbreaks (e.g. polio) and pandemics (e.g. Spanish flu and now COVID-19). Other examples of CP use include rabies, hepatitis B, measles, influenza, Ebola and hemorrhagic fevers1, 2. 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.

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). Most of these studies have been 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. Most recently, 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, unform testing for neutralizing antibodies was not performed.

There is only incomplete and very limited randomized controlled trial (RCT) data available to date. In a Chinese RCT, patients with severe disease, but not intubated patients with critical disease, showed more frequent and faster clinical improvement with CCP infusion compared to controls, however the trial was terminated early with accrual of only half of the planned patients, due to lack of eligible patients at the study sites with waning of the pandemic3. An RCT from the Netherlands, available in preprint, was halted early due to the discovery that the vast majority of participants already had anti-SARS CoV-2 antibodies in their own plasma at baseline, similar in titer to donor units. This is consistent with other studies which demonstrate the presence of antibodies within days of COVID-19 diagnosis. There were no differences in mortality, disease severity or length of hospitalization. A preliminary report of a very small RCT performed in Iraq with limited statistical power reported improved survival with CCP containing high IgG and IgM titers.

In total, these studies provide some encouraging but thus far inconclusive evidence for CCP efficacy. All suggest that CCP, preferably with high antibody titer, should be given early, prior to intubation and development of life-threatening inflammatory end organ failure, in order to expedite viral clearance and prevent further tissue damage.

Multiple ongoing clinical trials are investigating the use of CCP in patients with less severe disease earlier following infection, or prophylactically in individuals with a high-risk exposure (e.g. household contacts of those diagnosed with COVID-19). situations predicted both theoretically and from prior CP experience in other infectious diseases to more likely benefit from passive antibody transfer. 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.

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

Over 72,000 people have received CCP in the US and many more worldwide: initial safety data has been published for the first 5,000 patients in the US receiving CCP via the expanded access program4. Convalescent plasma appears to be a relatively safe intervention. 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 to date 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 announced emergency use authorization (EUA) of CCP in hospitalized people with COVID-19. Prior to this announcement, patients in the US gained access to CCP through three mechanisms. The vast majority were transfused via the FDA/Mayo Clinic expanded access program or via an emergency access eIND, with smaller numbers enrolled in a variety of FDA-approved clinical trials. The trials that are underway focus on a variety of indications, including some not covered by the EUA. These include RCTs focused on prophylaxis following high-risk exposure, early treatment prior to hospitalization or prior to progression to severe disease, and safety and efficacy earlier phase trials in pediatric patients. Similar efforts are ongoing around the world.

The Mayo/FDA expanded access program required local IRB approval for CCP administration, and mandated submission of clinical data, serving as barriers to participation for patients at some hospitals, particularly in the midst of intense local pandemic activity. This program is discontinued as of 08/27/2020, given the approval of the Emergency Use Authorization (EUA). An EUA is issued when a treatment is deemed safe and showing sufficient potential benefit to justify urgent access to a potentially-lifesaving treatment outside of a clinical trial. The current EUA applies only to hospitalized patients 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.

The use of CCP is an interim approach until there is approval and wide availability of alternative treatments such as hyperimmune globulin, engineered monoclonal antibodies, and/or antiviral drugs, and the development of effective vaccines. 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 becoming widely available and have been shown to correlate with neutralizing antibody titers, and thus might be used to predict the potency of CCP units. There are multiple ELISA-based assays for antibody detection: 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 titers.

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:

What other passive immunity therapies are being developed for COVID-19?

Companies are working to purify concentrated neutralizing antibodies from high titer CCP (hyperimmune globulins) and to engineer designer monoclonal antibodies active against specific SARS-CoV-2 targets. Clinical trials are ongoing.


  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.

For additional information, see:

View All COVID-19 FAQs

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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