The Promise of COVID-19 Convalescent Plasma Therapy

July 25, 2020

As the number of cases of SARS-CoV-2 in the United States continues to rise into the millions, with the death toll now topping an almost unimaginable 142,000 and no end in sight, there is rising anxiety about when, and if, a vaccine will be available. The most rosy estimates predict one or more vaccines will become available in 2021, but these estimates are optimistic because questions about the safety, efficacy, production, supply and distribution of said vaccines remain to be answered. 

It is clear that COVID-19 will be with us for the foreseeable future. Therefore, other COVID-19 treatment and prevention modalities are urgently needed. One promising treatment, the use of convalescent serum from COVID-19 patients, was advocated by Casadevall and Pirofski in a recent commentary. The guiding principle behind this therapy is that convalescent serum, collected from patients who have recovered from COVID-19, will contain antibodies against SARS-CoV-2 that can be transfused to prevent or treat infection in others. The use of antibodies to treat or prevent a variety of viral infections, such as hepatitis A, poliomyelitis, measles, mumps, rabies and influenza was first described in the 20th century. More recently, studies during the 2009 H1N1 influenza outbreak and the 2013 African Ebola epidemic, as well as a systematic review of convalescent plasma use in severe acute respiratory infections, all show survival benefit with convalescent plasma therapy. 

Understanding why this type of therapy has been so historically successful requires a deeper dive into immunity. There are 2 basic forms of immunity, active immunity and passive immunity. 

Vaccination is an example of active immunity. Injection with a foreign substance, such as viral protein, produces an active immune response from the host that results in the production of antibodies (as well as other proteins, which aid in defending the body against the viral pathogen). Upon secondary exposure to the virus, those antibodies bind to the foreign proteins (antigens) associated with that virus and prevent viral infection or reproduction in host cells.

Passive immunity results when antibodies are “passed” from one host to another. It is an essential form of immunity for the fetus developing in utero, and in breastfed infants. Antibodies that the mother has produced against a wide variety of microbial pathogens are “passed” to the child and offer protection at their most vulnerable stage of immunological development. 

The use of convalescent plasma from patients who have recovered from SARS-CoV-2 is another example of passive immunity. Antibodies from recovered patients are transfused to a new host with the goal of mediating protection by neutralizing the virus. However, all viruses behave differently. We cannot assume or expect that convalescent plasma will work for SARS-CoV-2 just because it worked for other viruses. 

So what do we know about the use of convalescent plasma to treat COVID-19 patients? Two recently published papers are worth highlighting. The first, published by Joyner et al., is a safety report from the Mayo Clinic Expanded Access Program (EAP). This EAP was developed in response to the COVID-19 outbreak in the U.S. It was a collaboration between the U.S. Food and Drug Administration (FDA), the Mayo Clinic and the national blood banking community to collect and distribute investigational convalescent plasma to patients infected with SARS-CoV-2 who progressed, or were at high risk of progressing, to severe or life-threatening disease, and were hospitalized in acute care facilities. Less than 1% of the first 5,000 hospitalized participants with severe or life-threatening COVID-19 to receive COVID-19 convalescent plasma (CCP) had serious reactions to the treatment. In a recent pre-proof print, Joyner et al. provided a safety update in 20,000 hospitalized patients that were treated with CCP under the Mayo Clinic EAP. Incidence of serious adverse events remained low, and CCP was thus judged to be safe in hospitalized patients with COVID-19.   

The second paper by Li et al. is a recently published open-label, multicenter study of CCP treatment of COVID-19 in China. This study included 103 patients with severe or life-threatening COVID-19 from 7 medical centers in Wuhan, China, who were randomized to receive either CCP + standard treatment (n = 52) or standard treatment alone (n = 51). The study was underpowered, in large part because it was terminated early due to containment of SARS-CoV-2 in China (they had planned to enroll 200 patients), but trends toward accelerated clinical improvement were observed by day 28 in patients who presented with symptoms around 2 weeks into their illness. Furthermore, in an analysis stratified by disease severity, patients with less severe disease experienced about 5 days faster recovery and overall greater likelihood of clinical improvement by day 28 days. 

Although current knowledge about COVID-19 therapies, including CCP, is increasing rapidly, there are still many challenges to be addressed. As Casadevall and Pirofski very nicely point out, there are a number of requirements that must be met before convalescent plasma can be deployed as a treatment or prevention option for COVID-19. First, there must be a population of available donors who have recovered from COVID-19 and can donate convalescent plasma. Second, we must have blood banking facilities that are equipped to initially process the donations and then later issue the correct plasma. Third, we must have the necessary SARS-CoV-2 serological, virological and neutralization assays, as well as the adequate laboratory support to perform these assays. Lastly, we need to develop prophylaxis and therapeutic protocols to assess the efficacy and measure the immune response of CCP, while still maintaining good regulatory oversight. In order to meet the above requirements, we need to first answer some critical questions.

Who is a good candidate for CCP donation? 

Growing evidence is emerging about whether SARS-CoV-2 antibodies are capable of potent neutralizing activity. In particular, Robbiani et al., as well as multiple other studies, have shown that the receptor binding domain (RBD) of SARS-CoV-2 is a major target of neutralizing antibodies. However, the quantity of SARS-CoV-2 antibodies necessary to have a therapeutic or preventative effect is currently unknown, and it is therefore crucial to define the therapeutic range of antibody titers for CCP.

Further, there are many donor variables that we currently don’t understand. The growing body of literature on SARS-CoV-2 antibodies, including an oral abstract by Markmann et al., suggests that not all CCP is the same. We suspect that only some CCP contains the right amount of the right antibodies to be an effective therapy. In short, we still need to identify who, if anyone, has developed enough protective antibodies to be clinically valuable against SARS-CoV-2.

What are the logistical barriers to collecting and processing of CCP?

Plasma is a component of whole blood. The other main components of whole blood include red blood cells, white blood cells and platelets. While a single unit of plasma can be processed after whole blood collection, most patients are currently treated with at least two units of plasma. The demand for CCP as therapy would far exceed donor supply if relying on whole blood preparation. A more efficient method to collect at least 2, and up to 3 or 4, units of plasma from a single donor collection is plasmapheresis. Plasmapheresis is the process of separating plasma from the other whole blood components. A plasmapheresis machine is used to draw blood, then separate and return blood cells and platelets to the donor. This whole process takes about 45 minutes, and what is left over for donation is the plasma. After collection, plasma must be quickly frozen until use. 

Barriers to donor recruitment need to be taken into consideration. CCP donation centers will only be effective if the public has knowledge of and easy access to the facilities. Information has to be disseminated in ways that are accessible  – both from a content perspective and a language perspective. We were fortunate to rapidly establish a COVID-19 plasma donation center at the University of North Carolina (UNC). A major challenge we faced was disseminating information in Spanish during a time when we are seeing disproportionally high infection rates in the Latinx population in North Carolina. 

Furthermore, donors need to be able to get to a plasma donation center in order for the program to be effective. For donors that live hours away, simply getting to the door can be a huge barrier, both from a time and cost perspective – something we are currently witnessing. Next, the facilities, equipment (i.e., the plasmapheresis machine, freezers to store the plasma, supplies) and staff must be available. Lastly, effective leadership and coordination of these processes is essential. 

How do we ensure the safety of CCP?

Donated blood products, including plasma, must be tested and meet certain, stringent requirements (which include absence of bloodborne pathogens) outlined by the FDA before they can be used. Furthermore, the blood type of the donated plasma must match the blood type of the recipient. Finding CCP donors who are AB blood types, the least common ABO blood type at only ~5% of the U.S. population, has been particularly challenging.  In addition, there are infrequent risks associated with receiving plasma, i.e. allergic reactions, lung damage and difficulty breathing. All recipients must therefore be monitored for these uncommon adverse reactions. 

Who should receive CCP therapy, and when should they receive it?

We, and many other researchers across the globe, are furiously in the process of trying to answer these questions. Does this therapy only work at certain stages in the disease process – i.e. earlier versus later? Does the severity of one’s illness at a given time dictate whether they will benefit from treatment? Does the pool of the recipient’s existing SARS-CoV-2 antibodies affect whether they will benefit from CCP or not? Are there certain biomarkers that can help predict whether a recipient will benefit from CCP? These are essential questions we need to address through well-designed and well-powered (large) randomized, controlled trials (RCTs).

How will we measure the efficacy of CCP therapy?

You may start to see a theme here – one critical way to assess efficacy of CCP is through RCTs comparing people who get CCP and those who do not. Another important aspect to note, as stated nicely by Bloch et al. is that the antibodies’ duration of efficacy is unknown, but is postulated to be weeks to a few months. After a patient receives CCP, how long do those antibodies remain at high enough levels to continue providing therapeutic effect? Are multiple transfusions necessary during the patient's disease course and recovery?

Because of the growing COVID-19 epidemic in the United States, I (HR) was abruptly recalled to the U.S. from South Africa where I was doing HIV/AIDS research as part of my Infectious Diseases Fellowship at UNC. Unsure of what would be required of me, I was surprised to see, on my first day of the COVID-19 infectious diseases service, that we were able to offer CCP as a potential treatment for very scared and ill patients with COVID-19.

But this leads us to our final point. One of the most compelling things about CCP, if it proves to be a beneficial therapeutic or preventative for COVID-19, is the potential availability and scalability of this treatment. In our current global pandemic, low, middle and high-income countries are all being affected by this virus. As a result, health disparities and inequities are being magnified. The race for new, experimental therapies requires significant financial investment and scientific infrastructure, which puts many of these therapies out of reach for much of the world’s population during the early stages of development and production. CCP, on the other hand, comes from patients who have recovered from SARS-CoV-2 infection. Currently, we have 2 of the 3 things that may allow this to be globally scalable; a global infrastructure for plasma transfusion, and a ready supply of potential donors. Now, if we want to make this promising therapy a global reality, we need a better understanding of the immune response both in individuals who have recovered from and those who are currently suffering from SARS-CoV-2 infection.

Author: Heather Root, M.D.

Heather Root, M.D.
Heather Root is an Infectious Diseases Fellow at the University of North Carolina-Chapel Hill (UNC).

Author: Luther Bartelt, M.D.

Luther Bartelt, M.D.
Luther is an Assistant Professor of Medicine, in the Division of Infectious Diseases at the University of North Carolina at Chapel Hill (UNC).

Author: Peter Gilligan, Ph.D., D(ABMM), F(AAM)

Peter Gilligan, Ph.D., D(ABMM), F(AAM)
Peter Gilligan is the former Director of the Clinical Microbiology-Immunology Laboratories of the University of North Carolina Hospitals.