Convalescent Plasma to Treat COVID-19 Patients: Q&A with Pavan (Tem) Bendapudi, MD

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Convalescent plasma therapy has been tested in nearly every major viral epidemic, including the Ebola virus outbreak in 2013. The therapy involves taking plasma from a recovered donor and giving it to a current patient to aid in response to a disease. During the COVID-19 pandemic, there have been cases of patients improving after experimental convalescent plasma therapy, but also instances of patients not recovering. However, there have been no quality studies to date proving it is effective.

In response to the need for a quality clinical trial, in May 2020, Mass General Brigham launched the double-blind, randomized Evaluation of the SARS-CoV-2 Antibody-containing Plasma thErapy (ESCAPE) trial. The trial is being led at Massachusetts General Hospital by Pavan (Tem) Bendapudi, MD, hematologist in the Division of Hematology at the Mass General Cancer Center and Blood Transfusion Service in the Department of Pathology at Mass General.

In this Q&A, Dr. Bendapudi explains what is currently known about convalescent plasma therapy, its potential to treat COVID-19 patients and what differentiates this trial from others.

Q: What is COVID convalescent plasma (CCP) and how does it work?

Bendapudi: When you take blood from a donor, that blood is fractionated into three different components that are used for transfusion. One is the red blood cells—that goes to people who are anemic. The second is platelets for people who are bleeding or have other problems—platelets are the cells that float through the bloodstream and help blood clot. And then the third is plasma, which is basically the liquid part of blood—the part that we call acellular because there are no cells in there. And that's where, as I like to say, is where all the goodies are—your proteins, vitamins, enzymes, antibodies and electrolytes.

If a patient is infected by COVID-19, hopefully, they'll mount an immune response. And if you take plasma from the whole blood of a recovered COVID-19 patient, it may have a significant level of antibodies against the SARS-CoV-2 virus.

CCP uses a transfusion medicine approach to collecting, processing and administering plasma to sick patients. The idea is to collect plasma from donors who have recovered from the infection and give it to actively infected people with SARS-CoV-2 to help them recover faster from the disease.

Q: What are the challenges with this therapy?

Bendapudi: We have uncertainties around this concept which we're trying to answer with the trial we're proposing. Can CCP work in a treatment setting? That is, can giving the antibodies to a patient from a recovered person really help them recover more quickly or reduce the severity of illness? I really don't know the answer to that.

I think my biggest question is whether we're going to be able to deliver enough antibodies in a couple of units. You're giving two units of CCP to a patient who has 10 to 12 units of their own plasma. Once the antibody goes in, it gets kind of sponged up by all your different tissues. One worry we have is that it's going to be too diluted to do anything.

Plasma treatment is not without risk. Of course, we all know about the chance of disease transmission from blood products and blood transfusion is very, very low these days. But it can happen. There's also transfusion-related acute lung injury (TRALI) where you can actually get an inflammatory response to plasma treatment. It's relatively rare, but it can happen and under those circumstances, people can actually get worse because the inflammatory reaction is happening in the lungs and we definitely don't want to place people at undue risk for that.

Q: What makes this clinical trial unique compared to others in the world?

Bendapudi: This study is jointly conducted between Mass General and Brigham and Women's Hospital. There is a lot of excitement around CCP right now, but we have to be cautious about over-promising on what it can do.

There's broad agreement within Mass General Brigham that we need to do this via a properly designed, well thought out and executed clinical trial because we want to gain knowledge that will help our patients—not just to give this as a one-off to a couple of patients and kind of see what happens. A lot of people have done that already and the results are mixed. But our objective here is to really help inform the future use of this treatment.

One important thing to remember about this trial is that it's a randomized, double-blind, controlled trial. A patient will come in and they won't know if they are in the control arm or the CCP arm. The treating physician will not know either. The control arm will receive standard plasma units that come from healthy donors who never had COVID. We felt it was very important to incorporate this kind of control arm so we can really tease out whether these extra antibodies in the COVID convalescent plasma are doing anything.

Where we feel that our study can add value is that we are trying to take a sophisticated approach to answer questions about CCP. We are giving a higher dose of the plasma product. We're measuring titers before and after, trying to see what kind of impact the therapy is having in the patient. We're being very careful with randomizing it, with a control arm of regular plasma. I think one of the criticisms of larger trials if they don't work, will be that not enough plasma was given. So for us to add value as a smaller trial, we are trying to answer a little bit of a different question.

Q. What do you look for in plasma donors? How is CCP treatment prepared and administered?

Bendapudi: The FDA has recently issued guidance on what would constitute legitimate CCP and we're operating within that framework. Essentially, we're looking for people who have tested positive for COVID-19 who are now negative and at least 14 days from their last symptoms to donate plasma. The plasma would be analyzed, and we make sure they have high quantities of anti-COVID antibodies—we're looking for a relatively high titer. Then we will administer two doses of the CCP to individuals who meet inclusion criteria for the study and they'll get these two doses of plasma over a 12 to 24 hour period.

For this study, we are only accepting male donors right now. And the reason for that is because women who've been pregnant before can develop anti-HLA antibodies. Anti-HLA antibodies are the reason why people get TRALI, a very dangerous complication I mentioned earlier. Because it's a lung complication on top of everything else, we don't want to risk it. Out of an abundance of caution, our protocol right now is to not recruit any female donors, regardless of whether they've been pregnant before, because it's too difficult to rule that out reliably.

Q: How is a patient selected for this study over other experimental treatments?

Bendapudi: So right now our study is focused on patients who are not critically ill. We want to treat people a little bit earlier in their disease course because our sense is that this treatment has the best chance of working by preventing people from getting sicker. We don't think it's going to do too much for the people who are very ill already. There are very legitimate concerns about giving large amounts of plasma to people who are having bad respiratory issues and are already on the ventilator because the volume load that you get from these plasma treatments is not trivial. I will say that if you give someone fluid who's on a ventilator, there's a chance of overloading their heart and lungs with all the extra fluid you're giving them, and that can make the breathing problems worse. We want to avoid that and target patients that CCP can be the most useful for.

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