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COVID-19 Resources

COVID-19 and Convalescent Plasma: Frequently Asked Questions

(Version 4.1; last updated June 8, 2020)

Input from Drs. Beth Shaz, Cindy Dunbar, and Chris Hillyer

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 collected from previously infected individuals to passively-transfer antibodies in order to protect or treat humans dates back almost 100 years, with some evidence for benefit against rabies, hepatitis B, polio, measles, influenza, Ebola and other  pathogens.1,2 Results from small case series during the prior MERS and SARS coronavirus outbreaks documented safety and faster viral clearance following convalescent plasma administration, particularly when given early in the disease course.

The vast majority of patients who recover from COVID-19 illness develop some level of circulating neutralizing antibodies to various SARS-CoV-2 proteins 2-3 weeks following infection, detectable by ELISA or other quantitative assays. This has been demonstrated in at least two cohorts of rhesus macaques infected with SARS-CoV-2 who generated antibody responses and could not be re-infected with the virus weeks to months later.

Multiple published and unpublished studies have now reported on the use of convalescent plasma to treat severely or critically ill COVID-19 patients, without unexpected or serious adverse events. Many patients improved clinically and cleared the virus, however the role of the convalescent plasma treatment in these patients is unclear, because all patients received at least one additional therapy, including antivirals, antibiotics or antifungals, and corticosteroids. In the sole randomized controlled trial reported to date, patients with severe disease, but not intubated patients with critical disease, receiving convalescent plasma showed more frequent and faster clinical improvement compared to controls, however the trials was terminated early due to lack of eligible patients at the study sites in China, with waning of the pandemic there3. The results from this RCT support the concept that convalescent plasma should be used prior to life-threatening disease in order to more rapidly clear virus and avoid further tissue damage, rather than using this approach to treat patients with inflammatory end organ failure.

Multiple ongoing clinical trials are investigating the use of convalescent plasma in patients with less severe infection, or prophylactically in highly susceptible individuals, such as exposed health care workers or family caregivers of COVID-19 patients, situations predicted to result in more potential benefit from passive antibody transfer. 

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

Convalescent plasma transfusion appears safe as over 7000 units have been transfused to over 5000 patients to date in the US (uscovidplasma.org). Known risks of plasma transfusion include allergic reactions, transfusion-associated circulatory overload (TACO), and transfusion-associated acute lung injury (TRALI) as with any plasma or blood transfusion. Additional concerns include potential worsening of immune-mediated tissue damage via the poorly understood phenomenon of antibody-dependent enhancement (ADE), and blunting of endogenous immunity to the virus. However, ADE has not been documented to date, so likely is not a major issue for COVID-19 convalescent plasma infusions. Importantly, blood product transmission of the SARS-CoV-2 virus has not been documented and is extremely unlikely via transfusion from a recovered donor with a documented antibody response, even if viral spread to tissues outside the lung may have occurred earlier in the donor’s illness.

What mechanisms exist for providers to access COVID-19 convalescent plasma therapy clinical trials or other mechanisms to deliver this treatment to patients?

 In the US, on March 24, 2020, the FDA announced an emergency IND (eIND) process to allow individual physicians to treat patients with serious COVID-19 disease with convalescent plasma. On April 7, 2020, the FDA announced a National Expanded Access Protocol administered through the Mayo Clinic (https://www.uscovidplasma.org). The protocol enables a wider range of adults to be treated with convalescent plasma by including those at risk of severe disease as well as those already suffering from severe disease. Lastly, there are a number of FDA-approved multicenter clinical trials ongoing, focused on a variety of study subjects, including high-risk individuals for prophylaxis, patients with mild disease, those with serious but not critical disease, ICU patients, or children. Similar efforts are ongoing around the world.

The use of convalescent plasma is an interim approach to treatment until availability of hyperimmune globulin, drug therapies, and vaccines. While the concept of plasma treatment is simple, numerous steps are involved, requiring cooperation between multiple entities including recovered patients who serve as donors, blood centers or other plasma collection centers, treating physicians and their patients, and health care administrators and regulators overseeing the safety of each step2. Use of plasmapheresis to collect large volumes of plasma is desirable. Current estimates suggest a single donor collection can be used to treat 2-3 recipients. We now have antibody assays available to ensure plasma units contain antibodies. However, we have yet to correlate these antibody assays with neutralizing antibody titers, or most importantly with patient outcomes. Additional questions remain, including dosing, optimal antibody types (IgM, IgG, and/or IgA), and timing of administration during disease course.

How do recovered individuals sign-up 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. New blood center sites for plasma collection are being set up almost daily, and information is rapidly evolving. Listed below are some sites for referral of potential donors:

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

Companies are developing purification procedures to produce potent concentrated neutralizing antibodies from convalescent sera and immunizing large animals such as horses and cows with SARS-CoV-2 proteins in order to create antiserum. Biotechnology companies are racing to develop cocktails of monoclonal antibodies active against the SARS-CoV-2 virus, and clinical trials are in active development..

References

  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

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