Convalescent plasma as a COVID-19 treatment

Another special COVID-19 episode of The Lancet Voice looks into using the blood of recovered patients to treat serious cases. Julie Stacey speaks with Prof. Liise-Anne Pirofski of the Albert Einstein College of Medicine.

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Transcript

This transcript was automatically generated using speech recognition technology and may differ from the original audio. In citing or otherwise referring to the contents of this podcast, please ensure that you are quoting the recorded audio rather than this transcript.

Gavin: So I'm Gavin Cleaver. 

Jessamy: And I'm Jessamy Baganal. 

Gavin: So one of the reasons we're doing this podcast is there have been a few attempts to treat patients around the world during the current pandemic using convalescent plasma. This is quite an old school treatment, isn't it Jessamy? 

Jessamy: Yeah, convalescent plasma therapy has been around for a long time.

I think the sort of first definite sort of use of it is in 1891 against diphtheria by a guy who later or Who later won the nobel prize for it called emile von bearing diphtheria Obviously is not a disease which we really see now, but it was incredibly fatal and contagious disease that can affect the nose and throat and killed, tens of thousands of people.

So it's something that we know has the capacity to work, and that's because it transfers over antibodies that have been produced by someone who's had the disease to somebody who's trying to fight the disease right now. So that brings in to kind of Conversation, active, and passive immunity. So active immunity is when the person who is fighting the disease builds up the antibodies necessary to fight that and get over it.

Whereas passive immunity is when somebody has the disease and the antibodies are passed over to them. Now, normally that's in utero, so If a baby inside the mother gets immunity from something, if the mother already is, has those antibodies. But obviously this is a sort of synthetic way of doing that from one person to the other.

Gavin: Now, we're very lucky at the Lancer voice to have a team of editors working with us. One of whom is Julie Stacy, editor of the Lance Journal, e Biomedicine. 

Julie: Okay, today I'm speaking with Lisan Porowski, who is Division Chief and Professor of Infectious Diseases at Albert Einstein College of Medicine in New York City.

Lisan is leading a group of clinical researchers who are testing whether serum from people who have recently recovered from COVID 19 can help treat or prevent infection. Hi, Lisan. Hi, thanks for having me. What's the theory behind using convalescent serum for treatment? How is it thought to work? The, 

Liise-Anne: the theory behind using convalescent, in this case plasma, for treatment goes back to the early days of antimicrobial therapy.

When convalescent serum was used as a treatment for pneumococcal pneumonia and later became actually a modality of therapy that was actually produced as horse serum that contained antibodies against the agent that was the cause of pneumonia, usually pneumococcal pneumonia. More recently, convalescent serum has been used as a modality to treat people who have various infectious diseases, many viral diseases, such as SARS.

And the concept is pretty simple. It is that antibodies are really great molecules, and they have the capacity to work in two potential ways. One is that they can have a direct defect on the microbe that's causing an infectious disease. And the other is that they can exert immunomodulatory properties, which so that they fall into this category of immunotherapy so that they work by helping the patient and boosting the immunity of the patient against whatever the causative agent of an infectious disease is.

So started with history, the discovery of an antibiotic. Bodies are able to help people recover from certain infectious diseases and then moved on to really proof of different mechanisms of antibody action, and then to observations really in desperate situations, such as the one that we're in today, that the plasma of people who recover from epidemic diseases can help those who are ill get better too.

Julie: Could you tell us about any clinical trials that are underway using this treatment for COVID 19? 

Liise-Anne: When we talk clinical trials, we need to be a little bit specific and to break the use of convalescent plasma into two main categories. One is a use outside of a clinical trial and what is often thought of as a compassionate use protocol.

And the other is to use it in a clinical trial that would really be designed to determine. There are currently two protocols that have been approved by the FTA here in the United States to use convalescent plasma as a so called compassionate use agent. Recently, because of the success of what is called a single patient protocol for convalescent plasma, there was an expansion to an expanded access program where many people can be treated.

At the moment, there are many patients being treated in many centers, I don't know the exact number, on that sort of a protocol. There are now efforts afoot to launch randomized clinical trials to evaluate the efficacy of convalescent plasma for COVID 19 in three main indications. One is Prophylaxis protocol where the IND is held by Johns Hopkins and that is an effort to use convalescent plasma to evaluate the efficacy of convalescent plasma in preventing the development of COVID 19 in people who are exposed, but not ill, to patients that have COVID 19.

We at Montecure and a number of other centers are gearing up to submit a randomized controlled trial to treat moderate to early severe disease with COVID 19. The idea is to determine whether convalescent plasma can avert the development of severe respiratory failure and avoid the use of intubation.

And ventilators in patients who present with respiratory symptoms. And then the third type of protocol, which is being planned as a trial, is to evaluate the efficacy of convalescent plasma in extremely ill patients who are on ventilators and are severely ill. And it is hoped that within a couple of weeks, that all three of these trials will be approved at various states.

IRBs across the country, and there will be INDs issued for each of them. 

Julie: And maybe related to this, since it seems like they're being tested in all phases how will it be determined which COVID patients should receive treatment?

Liise-Anne: Historically, going back to those early observations about convalescent or antibodies being effective, particularly in respiratory diseases like pneumonia, the available evidence suggests that convalescent plasma works, or that antibodies work early in the course of this type of infectious disease.

One of that is there could be a number of reasons there may be less evidence. virus presence early in disease, and so the antibodies may have less work to do, or there may be other factors that govern the ability of the antibody to work early. It may synergize with the natural immune response of the patient better, or something that we don't know.

The data from the use of convalescent plasma in SARS, Suggested that it worked better on well, if it was given earlier, that was within the first 14 days of illness and there were good outcomes in terms of patients improving clinically and being able to be discharged from the hospital earlier. As far as the use of convalescent plasma in the trials that I described, available data would suggest that it could work extremely well in prophylaxis.

It may work in early disease. But I really have to underscore that We don't know. And that's why we're doing this. It makes a lot of sense. There's certainly a lot of evidence to support trying this. And we're going to learn. And that's why it's just so important to do trials. Because if we don't do trials and we don't figure this out, even in patients in whom We think we're not really sure whether it's going to work there.

Once we do know, we'll just be in so much better shape. And I do want to point out, related to this, that we in New York are in the absolute epicenter. And we're working under extremely dire conditions in terms of how sick our patients are and how overwhelmed our hospital system is. We truly hope that being able to intervene with this type of a therapy at this point may really help inform the development of future trials that would be more focused on more specific questions and that could really improve potentially upon the trials that are used if other parts of the country experience surges in COVID 19 as we have here in New York.

Julie: Is this treatment thought to be safe and what are the risks? 

Liise-Anne: The treatment is thought to be extremely safe. The risk of receiving convalescent plasma is similar to the risk of receiving a blood transfusion, or what's called fresh frozen plasma which is a standard form of plasma that is used every day in regular medical care, in control of bleeding and also in In surgery major surgery or trauma where one needs to control coagulation and bleeding.

So that is the main risk. There may, there is an additional risk that could be associated with the presence of this type of antibody in the plasma. And that would be related to the theoretical possibility that antibodies to this coronavirus may enhance infection, something called antibody dependent enhancement, which is a phenomenon that has been described for other viruses and is a theoretical possibility when you have a kind of genetically related virus.

There have been no reports of antibody dependent enhancement in the trials of convalescent plasma that have now been peer reviewed and published from China. And there were no reports of antibody dependent enhancement when convalescent plasma was used for SARS. It is a possibility and it is a risk that a patient needs to know is possible.

There are also risks of triggering inflammatory processes. And there are risks of transfusion ABO incompatibility, which in modern blood banking really is not a possibility. I would say that these are risks that are far outweighed by the potential benefit of convalescent plasma. This plasma is.

Very different than a drug, for instance, where a person's renal function may prohibit its use, or a person's cardiac function may prohibit its use, and you're hearing a lot about that, about hydroxychloroquine. It's different that way, although it is volume, so patients that have circulatory overload, or what?

failure, plasma needs to be administered to them very carefully. And it's possible that depending upon a person's circulatory status, they may receive less plasma as part of plasma therapy than somebody who has a normal volume status. 

Julie: Okay. Can anyone who has had an infection donate sera? 

Liise-Anne: Yes, I hedge a little because the rules for donation have been a bit of a moving target, but the way it stands right now is that a person who has had a documented infection with COVID 19, so they have a positive test Or they have an isolation order, because early on, for example, in New York City, we had isolation orders that were issued to, for example, the New Rochelle community.

And they have been recovered, meaning absolutely no symptom of COVID for 14 days. They are eligible to be a donor if their plasma contains antibodies to the virus. So there's a pre screening of people that have had illness that are 14 days out from illness to establish that they have the antibody. If people have been recovered for 28 days or more, they are eligible to donate on the basis of having had COVID 19.

This is actually very important because as you can imagine, this product is very valuable and limited and it is the bottleneck in our ability to treat. Many people. It's different than taking our drug off the shelf and the manufacturer kindly makes us millions of the pill or of the drug. So we have to manufacture this.

The blood banks need to and I have to say that they have really risen to the occasion and in New York here, the New York Blood Center has opened up many other areas where people can donate. But there, it is a bit of a heavy lift, and we need to assure that there are antibodies in those units, and that has also required a very fast tracking antibody detection method.

We at Montefiore have a really great assay going that's actually being vetted to become a licensed clinic. test in our laboratory where we've been able to look at our donors and our experience is very similar to many other places that have begun donation programs. And we're very reassured at the levels of the antibody that we are seeing in the plasma of our donors.

Julie: What would need to be done to scale up this sort of therapy if it looks effective? 

Liise-Anne: This specific therapy could be scaled up by more blood donation. Basically, getting people to donate. A person who has a high titer who's healthy can donate every couple of weeks. But the next step, clearly, is To be able to get at the antibodies themselves and to potentially develop a immune globulin, a specific immune globulin preparation, sometimes called hyperimmune globulin, or to develop monoclonal antibodies.

This is intended to be a stopgap measure in an emergency situation where we really do not have any proven therapies and where there is at least a track record for a convalescent plasma being effective and early reports suggest that it is promising. However, the labor that is involved and The heterogeneity of the product clearly suggests that the development of more homogeneous agents that may be reproducible and able to be scaled up in larger amounts would be the next steps in the development of this kind of therapy.

Julie: What do you feel are the most important outstanding questions about this virus and the pathophysiology of COVID-19? 

Liise-Anne: Wow, great question. Almost everything. So it is a very intriguing disease. It's hard to use the word intriguing for something that's been so devastating, but it's clear that there are a couple of different disease manifestations, ranging from extremely mild Had a cold, didn't even know I had it, to a more protracted disease, which can be very debilitating, but that doesn't involve the lungs, doesn't really appear to involve any organs, but that causes this profound influenza like illness that can lay people up anywhere from two weeks to three weeks or longer that is really just marked by this profound fatigue and recurrent fevers.

And then there is the respiratory decompensation, which occurs in some people who can be fine or appear to be minimally ill and then really take a turn for the worse. And so it is clearly an outstanding question. What makes these different manifestations occur? And how much of it is the virus and how much of it is The patient.

And so this to me really fits into a construct called the Damage Response Framework that my colleague, Arturo Casadevall, who you may have also interviewed and I have worked on, where one can begin to think about an infectious disease as an outcome, that the disease is an outcome of an interaction of Viral factors, in this case, and what we would call host factors, and so the people who appear to be very well would be in this parabola that we use to kind of depict damage in the patient would be below the danger line and have some sort of either compensated immune response that doesn't really lead to any sort of manifestation of disease that we can see, whereas Those who develop this very severe respiratory decompensation may be people who have eliminated the virus or dealt with it fairly well, but who are now experiencing this overly exuberant inflammatory response and that the damage that they're really experiencing that's translating into this terrible disease, need for intubation, cytokine storm, may really be due to a dysregulated inflammatory response.

There is precedent for this in influenza that occurs in young people, including in 1918, as well as H1N1 and in SARS, there were many indications that actually some younger people who had very robust immune responses were the ones who were infected. Manifesting that sort of illness, and oftentimes without evidence of the virus being present.

I would say that the main unanswered question is these varying clinical manifestations and how they tie into viral factors, and host factors, and then where those two come together. Thanks so much, Lisan. 

Gavin: Fascinating interview then, Jessamy. And an interesting an interesting avenue towards treatment.

But, as we keep emphasizing, so little, so far, is known. But this is definitely a very interesting, if slightly archaic way of treating this disease. 

Jessamy: Yeah, it's funny, isn't it? Because we're in a situation where, we don't have a treatment for this disease. We're desperately trying to create a vaccine.

We're looking at repurposing lots of other old drugs, and with that comes this sort of, as you say, archaic concept of transferring someone's immunity to another person. And obviously, that's an interim measure. In between, while we don't have a treatment and while we don't have a vaccine, it, has the potential to help people.

Gavin: Yes, it's something, at least, isn't it? And there was an early study that seemed to show promising results, but obviously that comes with a lot of conditions and rejoinders and other things affecting it, for example, all the patients, obviously, that received convalescent plasma were receiving other treatments as well.

It's difficult to isolate so far. 

Jessamy: But I was just going to say, that it is difficult, because physicians are treating patients who are extremely ill, and when you're doing that, there's a sort of humanitarian drive to try anything, any medication, and that often means that patients end up being on lots of different medications, and that's certainly You know the info and data that we've been getting from china where you know, 80 percent might be on antibiotics 90 might be also on steroids and then they're adding in other drugs other Immunotherapies as well and it's very difficult to see Therefore which ones are being a benefit and when you then add on the fact that you know Obviously lots of people do get is very sick with covid19.

But for the most part this is a self resolving disease. So people get better on their own. So the fact that you might give convalescent therapy and then people get better, doesn't mean that convalescent therapy work, plasma therapy works because people would have got better anyway. So there's so many different things to consider and difficult things to, to untangle when we're looking at different therapies for COVID 19.

Gavin: Yeah, absolutely. Very important points to make. So thanks so much for listening to this special episode of The Lancet Voice about COVID 19. We've got many other special episodes up on our podcast pages, so you can search The Lancet Voice on any platform to find the rest of our episodes. Thank you so much for listening to this episode and hopefully we'll see you again very soon.