Plasma therapy for COVID-19: Updates from Prof. Arturo Casadevall

Back in May, Medical News Today spoke to Prof. Arturo Casadevall, from Johns Hopkins, about the potential of using convalescent plasma therapy in the treatment of COVID-19. Now, we follow up with Prof. Casadevall on the latest findings.

In May, we spoke to Prof. Arturo Casadevall — chair of the Molecular Microbiology & Immunology Department at the Johns Hopkins Bloomberg School of Public Health in Baltimore, MD — about the possibility of using convalescent plasma to treat cases of COVID-19.

This procedure requires the use of donated plasma, a component of blood, from people who have had and recovered from COVID-19 to treat or prevent the disease in those most at risk of developing it.

That is because convalescent plasma from people who have recovered from COVID-19 usually contains antibodies against SARS-CoV-2. This is the virus that causes the disease.

On August 23, 2020, the Food and Drug Administration (FDA) granted emergency use authorization (EUA) for convalescent plasma in the treatment of COVID-19.

However, some scientists have called this move controversial due to a lack of conclusive evidence regarding this therapy’s effectiveness.

Now, MNT have caught up with Prof. Casadevall, who was the co-senior author on one of the trials that informed the FDA’s decision. We asked Prof. Casadevall what he thinks of the EUA and what has changed in convalescent plasma research since the last time we spoke.

We have lightly edited the interview transcript for clarity.

The EUA and research since May

MNT: The FDA granted EUA for plasma therapy on August 23, but this decision sparked some controversy. What is your take on the matter?

Prof. Casadevall: The first thing I would say is that all the issues of controversy have been [based on] newspaper reports. The truth is that I don’t even know if there is any real controversy. I think that it’s been reported to be a controversy. But let’s just assume that what they reported is correct.

I [and Prof. Nigel Paneth] wrote an op-ed in The Wall Street Journal a couple of weeks ago, arguing that the issue seems to be [based on] differences on the degree of certainty. That is, the FDA made this decision based on its regulatory power for the laws of the land that say that once […] the information is there that [a treatment] may be effective and that it is reasonably safe, that they can issue an EUA. That’s what it says.

Everyone, including myself, feels that just because an EUA has been issued doesn’t necessarily mean that one has proven beyond reasonable doubt the efficacy of plasma.

[Given] the regulatory landscape [of] the FDA, this was, in our mind, the correct decision. It is also the correct decision to continue to do randomized clinical trials. So these two are not in conflict with one another.

Because in many places, there is no randomized clinical trial. So if you get sick in a place and you go to a hospital where there is no randomized clinical trial, you can’t even join to be able to be randomized to the plasma group.

So, what this decision says is [that] the available data suggest[s] that this [therapy] may be effective if given early with a sufficient amount of antibodies.

That’s the decision. In the meantime, it is very important to continue to do all we can to establish efficacy.

MNT: Some have expressed a worry that, like vaccines, plasma therapy may be pushed out too soon.

Prof. Casadevall: You know, I’m not worried about that. I will tell you that I worked with the government scientists, the FDA, [and] the people who made this decision for months before it was [taken], and I can assure you — and I can assure [your readers] — that these government scientists are very devoted and dedicated people, and I’m not worried about that myself, based on what I know.

I think that when the regulatory agencies give the go-ahead, it will be based on science. And I would say to you, look at hydroxychloroquine: Based on the initial results, [the FDA] issued an EUA, [but] when the data was not there [to support the initial findings], they pulled it.

And that’s very important to keep in mind — that these agencies are responding to the available knowledge. And we’re in the middle of a pandemic, and we’ve got to try to make the best decisions with the available information.

MNT: The last time we spoke, in May, there was less research and less evidence around the safety and efficacy of plasma therapy for COVID-19. How has the research around plasma therapy developed since?

Prof. Casadevall: There has been a lot of new evidence. The evidence comes in four categories. The first one is — we now have reports [from] five randomized control trials.

Three had to be stopped prematurely because they ran out of [participants]. That’s in China, in Spain, and in the Netherlands.

And then there are two [more]. One was completed in India, and it did not show an effect [on] mortality, but there were problems in the study because over a third of the units did not have antibodies.

So that is a problem in the study itself. And then there is another small study from Iraq, [a] randomized control trial, showing that [plasma therapy] reduced mortality.

So the data that you have out there in the randomized control trials is suggestive that this is doing some benefit, but it’s not conclusive for a variety of issues, ranging from the changing epidemic to the problems with trials.

Then, you have the observational studies, and those are suggesting that, if given early, [convalescent plasma] is associated with a great reduction in mortality. [By] great, I mean about half.

And the two studies that I would point people to look at [are] the Houston Methodist [Hospital] study, published in the American Journal of Pathology, and then there’s one from [Mount] Sinai [Icahn School of Medicine], published in Nature Medicine.

The third piece of data — it comes from the FDA themselves, where they looked at a large number of people in a cohort that didn’t have a control [group].

But it didn’t matter, [because] when you looked at it, you saw that if you gave [convalescent plasma] early and if you gave a significant amount, there was less mortality than if you gave it late or if you gave less.

In that study, there is a really important piece of data. There is a dose response. And whenever [we] see a dose response in science, we tend to consider that [to be] very important because it’s part of what we use for assigning causality — that is, causality that [the] antibody is the active agent.

And then the fourth piece of data is coming from experiments of nature. These are people who don’t have antibodies because of congenital disease. When they get COVID-19, it becomes intractable.

And then [for] the administration of plasma — even though these are case reports, they are powerful evidence that when you give the plasma, you shut down viral replication and you clear it.

So what I would say to you is, do we have the definitive data today? No, definitive data is coming. Numerous randomized control trials have been done in the United States, in England, and [in] other parts of the world, and we will know more in the next few months, but it’s October 9 [at the date of this interview]. As you look at the data that we have today, it is suggesting that the early administration of plasma with sufficient titer is beneficial.

‘What have we learned?’

MNT: Based on the information that has emerged from the studies conducted since May and until now, have your views about plasma therapy changed in any way?

Prof. Casadevall: Certainly there is a massive amount of data available in October that was not available in May, and most of it is positive.

So [some important things that] we learned is that this is a therapy that is going to take a while to figure out how to make work well, that this is not a simple therapy, that you need to have a set amount of antibodies in the plasma, that you need to give it early, [and] that it works best in non-intubated patients.

We did not know any of this in May. In fact, I would argue that if we had designed a randomized control trial then, it would have become obsolete by now, because the information used to design the trial would have been superseded by what we have learned since then.

So I think that we have learned a lot since then.

MNT: With the research that you were involved in, what were the main challenges, and how do you think you might overcome them in future trials?

Prof. Casadevall: So [one of the trials] I’ve been involved with [is] the Mayo study, [where] Michael Joyner was the [principal investigator]. So the challenge there is to try to understand efficacy in a situation where you don’t have a control group. And that is a big challenge. It hasn’t been done before, and yet, I think that we learned a lot from that.

At Hopkins, we have two randomized control trials. They’re headed by David Sullivan and Shmuel Shoham, and these are in the outpatient space. And when we talked in May, they were theoretical.

Since then, they have been put in place, and they are rapidly accruing [participants]. The most important thing that we learned is how hard it is to set up randomized control trials in the middle of a pandemic and to keep them going when the [number of] cases switch from one part to another.

For example, one of the things that have become very apparent is that these trials are very difficult to do in any one location.

So the trials now in the U.S. [take place] in many states because the epidemic changes, you know. You had [a high number of cases in] New York City in March and April, and then you had [the same in] Arizona in the summer, and now it is moving to the Midwest.

So that is the big lesson, but the good thing is that they’re in place, they’re recruiting, [and] they’re very clean studies, because they’re happening in the outpatient space.

These [participants] are not [taking] corticosteroids. They’re not on remdesivir. They are at home, and if they’re sick, you give them a unit of plasma and you ask the question: “Do [they] progress?”

Or, the other trial looks at prophylaxis. [The participants] are at home. They’re exposed [to SARS-CoV-2] because a family member may have [COVID-19]. If you give them human plasma, do you prevent disease?

So these [studies] are happening, and I guess what you asked me [was], if we had to do everything over again, what have we learned? I think the most important thing to have learned is that […] we need to think about flexible trial design, because even if you had been able to get all the resources and get going in March and April, the information that we have learned on a weekly basis often makes the assumption that you start with obsolete.

And one of the great challenges in getting really good information in the middle of a pandemic, where science is generating information by the week, is the ability to do flexible clinical trial design that would allow some of these things to happen. And this falls into the science of clinical trials, and I think “trial” is an issue on how to go forward.

MNT: Earlier, you also mentioned a lack of resources. What resources did you feel you were missing?

Prof. Casadevall: Early on, there were very [few] resources. The only resources that we had was … the Bloomberg Philanthropies gave us some money, and the state gave us some money. We used that money to set up the clinical trials, which, months later, the government funded very well. We are funded now by the Department of Defense.

So I think the early lesson is that [receiving] money upfront can make a big difference. Because the early days are critical. The other thing that we have learned is … think about it, if you were designing a clinical trial in March or April, you didn’t have the assays.

They had not been validated. How would you have decided what plasma to use when the antibody assays and the neutralization assays and all that [were] being validated very rapidly? It’s another example of the need for flexibility, and we need to think [about] how to do this thing and how to do it better, because humanity is going to be confronting other pandemics.

And the question is, you know, how are we going to do it when bird flu comes, or when another pox virus or something [comes], or coronavirus number seven?

Out of this experience, one of the things that I hope people focus on is that the line of defense — humanity’s line of defense — is science.

You know, the military budget doesn’t help you against coronavirus.

And […] the line of defense, science‚ was actually pretty stressed before this began, you know, with funding cuts in most places, problems […] with employment and all that. Yet it is amazing when you think over 100 vaccines are in development.

We can always do things better, but we also have to celebrate the tremendous amount of work that has gone on and the options that are available in October as a result of having a vibrant worldwide scientific enterprise.

More conclusive data may be available ‘in the next 2 months’

MNT: It is sometimes easier to judge than it is to celebrate, especially when the world is in this atmosphere of anxiety, where people do not always understand what is going on, and they may start to lose trust in science. So, on a related note, what will it take to conclusively prove or disprove the efficacy of plasma therapy for COVID-19?

Prof. Casadevall: I think that certainly having a large, well-designed randomized control trial, where the plasma is given early, in high amounts … if you got [confirmation of] efficacy [in such a trial], then it would be very convincing.

If you do not get efficacy, then I am the first person to say to you: “We read all the trials, bias has crept in.”

Because we need to retain equipoise — as a scientist, one always has to basically say what will convince you that it didn’t work. And to me, it would have to be a confirmation from those [new] trials.

Trials in which this is done in patients who are intubated, or [where] there are problems with the plasma, are inconclusive. One of the most frustrating things is that a lot of the information that is coming out is simply inconclusive.

[This is] not because people aren’t working really hard to [find conclusive evidence], but because the trials [were] often designed without all the information that was needed.

The best example of that appears to be the Indian trial — a massive amount of effort … [I have] great admiration for my Indian colleagues, but when this decision was made to seek plasma, a lot of their donors had mild disease. Mild disease does not result in high antibody titers. They didn’t know that when [the trial] was set up.

But I will tell you, plasma has already given humanity a tremendous piece of information. It is safe. It cleared the way for monoclonals. It cleared the way for a lot of things.

Back in May, when we were talking, there was still a lot of discussion of an antibody-dependent enhancement. Are you going to give anti-antibodies to a patient? Are you going to trigger a cytokine storm [by doing that]?

None of that happened. So the great use of plasma […] [in] over 100,000 patients established the safety of giving antibodies to somebody who’s sick.

That is a huge contribution, because we heard, for example, that monoclonal antibodies … they are now trying to push them forward with a fraction of the experience, but that experience is resting on the plasma experience.

That is a big, big, big contribution.

And the other thing is that we — certainly [if we are based] in well-resourced areas — we have a tremendous responsibility to figure out what’s going on with plasma, because in regions that don’t have a lot of resources, this is going to have to be the therapy for the next few months, even years, because monoclonal antibodies are going to be unaffordable. We don’t have, in the immediate future, any new antiviral[s].

So plasma may be — in the U.S., in well-resourced areas — plasma may be a stopgap between a time in which you have nothing to a time when you have monoclonals and you have other reagents. [M]uch of the world may still need plasma, and we need to figure out when and how and if to use it, because that information can be life saving in those circumstances.

MNT: One last question: How long until we know when, how, and if to use plasma therapy for COVID-19?

Prof. Casadevall: Since we talked in May, we have learned that [plasma therapy] is safe, we have learned that [it has to have] high titer, and we have learned that you have to use it before people get ventilated.

So I think that there is a very high probability that, in the next 2 months, some of these trials will provide additional information. My hope is that they are conclusive.

However, if you publish a trial with 1,000 people where the average day when the plasma was given was day 8, day 10, that’s not conclusive. But I would say that if you go to PubMed and if you go to the archives and if you look [for] “convalescent plasma,” you would see an enormous amount of information that has been generated since May.

And the information is already telling you that [it] is [safe], and if you’re going to use it, use it early and make sure that the plasma has sufficient antibody content.

So I think that those are tremendous advances in relatively few months, when you consider what the situation is.

MNT: Thank you so much for your time and for all of the updates. Do you have any final remarks for our readers?

Prof. Casadevall: I would say that papers are coming out by the week, and […] I urge the [readers] and I urge anyone who’s interested to approach the data carefully […] [and] ask the question: Did they give [convalescent plasma] early, did they give enough, and what were the conditions of the [trial]?

And you can often find that information [in the studies]. And certainly, even when [convalescent plasma] is given late, we’re not getting [conclusive] results or side effects. But [in terms of establishing] the efficacy — it’s early [days].

And for those of you who are planning clinical trials, please incorporate this information into [the study papers], because it’s very important to have conclusions.

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Convalescent plasma therapy for COVID-19: Why is it promising?

Some researchers and doctors have started using plasma from people recovering from COVID-19 to treat others who have developed the disease. Medical News Today spoke to Dr. Arturo Casadevall, from Johns Hopkins University, to learn more about this approach.

In the search for an effective treatment for COVID-19, an old method of fighting infectious diseases has recently resurfaced: transfusions with convalescent plasma. Plasma is a component of blood.

This method has a simple premise. The blood of people who have recovered from an infection contains antibodies. Antibodies are molecules that have learned to recognize and fight the pathogens, such as viruses, that have caused disease.

Doctors can separate plasma, one of the blood components that contain such antibodies, and administer it to people whose bodies are currently fighting an infectious disease. This can help their immune systems reject the pathogen more efficiently.

Stay informed with live updates on the current COVID-19 outbreak and visit our coronavirus hub for more advice on prevention and treatment.

Recently, researchers and healthcare professionals have been looking into the possibility of using this method to treat people with COVID-19, the respiratory disease caused by the SARS-CoV-2 virus.

In the United States, a group of researchers and doctors from 57 institutions, including Johns Hopkins University, the Albert Einstein College of Medicine, and the Icahn School of Medicine at Mount Sinai, are investigating and applying convalescent plasma therapy for COVID-19.

This is a concerted initiative — called the “National COVID-19 Convalescent Plasma Project” — born after the publication of a viewpoint paper in The Journal of Clinical Investigation in March, 2020.

The paper argued for the potential merits of passive antibody therapy in the treatment of COVID-19. It was authored by immunologists Dr. Arturo Casadevall, chair of the Molecular Microbiology & Immunology Department at Johns Hopkins Bloomberg School of Public Health, and Dr. Liise-anne Pirofski, professor of Infectious Diseases in the Department of Medicine at the Albert Einstein College of Medicine.

To understand more about convalescent plasma therapy, its merits, its risks, and its current use in COVID-19 treatments, Medical News Today recently spoke to Dr. Casadevall.

Here is what he told us, alongside more information on the current state of convalescent plasma therapy.

A therapy ‘used for over 100 years’

So, where did the idea of using convalescent plasma, or passive antibody therapy, come from?

This notion was first introduced in the late 19th century when physiologist Emil von Behring and bacteriologist Kitasato Shibasaburou discovered that they could use antibodies present in serum — another blood component — to fight the bacterial infection diptheria.

Since then, doctors have used passive antibody therapy, on and off, at least since the 1930s to treat or prevent both bacterial and viral infections, including forms of pneumonia, meningitis, and measles.

When we asked him how the idea of using convalescent plasma therapy to treat COVID-19 came about, Dr. Casadevall told us: “I have worked on antibodies my entire life professional life […], and I knew that convalescent plasma — or sera […] — was being used for over 100 years.”

“In fact, the first Nobel Prize was given [to Behring] for the use of serum to treat diphtheria, so I knew the history.” This long history of successfully using this method against different infectious diseases suggested that it might also be effective against the disease caused by SARS-CoV-2.

“I knew that in epidemics when you don’t have a lot of things, […] the blood of those who recover can have antibodies that can be used [as treatment],” Dr. Casadevall explained.

“So it’s an old idea, it’s been around for a long time, and I think that my contribution was, in fact, to alert my friends, authorities, that this [therapy] could be used in this epidemic.”

Recent research has already shown that people who have contracted SARS-CoV-2 have developed antibodies that can react to the coronavirus.

“There [are] now multiple studies that have shown that when people recover from the virus, they have in their blood neutralizing antibodies that are able to kill the virus,” Dr. Casadevall also told MNT.

Although “[p]eople differ greatly in the amount of antibodies that they make — some make large amounts, some make small amounts — […] the good news is that most have [them],” he added.

Given the willingness of people who have recovered from COVID-19 to donate blood, the method seems feasible right now. In fact, some doctors are already using convalescent plasma therapy in some cases.

Settling the matter of safety

In the U.S., the National COVID-19 Convalescent Plasma Project have already been trailing this method as widely as possible.

Dr. Casadevall told MNT that “in the United States, we have close to 12,000” people who have received the convalescent plasma treatment for COVID-19.

Based on the data obtained from a little less than half of this cohort, Dr. Casadevall and his colleagues have concluded that this approach is safe for the patients receiving treatment — the first step necessary before ascertaining the method’s effectiveness.

The team has reported these findings in a preprint that they have made available online.

“[On May 14], we put out a paper on the first 5,000 [patients] showing that [this therapy] was relatively safe. That’s the first step,” Dr. Casadevall explained.

“You want to show safety. And then the question of efficacy will be coming in the next few weeks. Right now, the data [is] being analyzed. We are hopeful,” he also told MNT.

“And,” he added, “especially since [the] Italians are reporting already that the use of convalescent plasma was associated with a drop in mortality [due to COVID-19]. We are hopeful that similar insights [will] come from the analysis of the data in the United States.”

In Europe, the European Blood Alliance — a non-profit association — report that 20 countries have initiated the use of convalescent plasma in the treatment of COVID-19 or are considering it for the near future. These include Italy, Spain, and the United Kingdom, some of the European countries most aggressively hit by SARS-CoV-2.

Demonstrating this procedure’s safety is essential because of the risks inherent to the transfusion of blood or blood components.

“[One] of the issues that we were worried about 2 months ago [when the initiative started] was whether the administration of antibodies would make things worse. Even though there’s very little precedent about that, you have to always worry that your intervention can do harm. Fortunately, we did not see any of that, so we are now focusing on efficacy.”

– Dr. Arturo Casadevall

There is also the issue that adding more liquid volume into a person’s vascular system could lead to a risky overload, Dr. Casadevall explained.

“The concerns when you give plasma [include the fact that] rarely, you can get a transfusion reaction, [and] rarely, you could have a volume overload. What do I mean by that? I mean that […] you’re putting volume into blood, and if it goes in too rapidly, it could [lead to an] overload [of the] cardiac system,” he said.

“So when we looked at the experience of the first 5,000 [patients], we were very reassured that we did not see any major problems.”

Worries and hopes going forward

While different centers in the U.S. are already using convalescent plasma in the treatment of COVID-19, Dr. Casadevall expressed a worry that the therapy is not as effective as it might be because most patients receive it too late in the course of the disease.

Aside from its use in clinical trials, the Food And Drug Administration (FDA) have approved the administration of this form of therapy only in emergency situations to patients in a severe stage of the disease, which may not be soon enough.

“Often, physicians are using the plasma on patients that are very ill, and we don’t really know whether that’s going to be as effective as if you gave it early in the course of the disease,” Dr. Casadevall pointed out.

“Here in the United States, patients have been treated when they’re intubated, but we think that is relatively late. Many physicians are trying to move it earlier, that is, when people begin to decompensate,” he added.

But even where there is a will, getting this treatment to the patients who need it sooner rather than later is not always straightforward. “Some of the problem […] is that it takes time,” Dr. Casadevall explained.

“Because let’s say the doctor orders plasma and people are getting worse. It sometimes takes a while for the plasma to arrive. Some hospitals have it on site, others have to get it from blood banking centers.”

Despite these obstacles, the use of convalescent plasma therapy is so attractive to healthcare practitioners because they can access it and use it now.

Unlike with vaccines, whose development takes time, or experimental medication, which needs to go through several different stages of testing before it can obtain formal approval, this approach allows doctors to use what is already there — the blood of those who have recovered from the illness — to treat hospitalized patients.

“People often get confused [about the difference between convalescent plasma therapy and some vaccines] because they both involve antibodies,” Dr. Casadevall told MNT.

But while vaccines also operate on the premise of stimulating a person’s immune system to block or kill the virus, they do not use “ready made” antibodies, and testing them for safety and efficacy could take a year or more.

“When you get plasma, someone else is giving you the antibodies, and you get them immediately,” Dr. Casadevall explains.

Going forward, he thinks that doctors could use this therapy alongside other options as they gradually become available.

“This [therapy] will provide something that is immediately available. I think what you [will] see in the United States [will be its] continuous use. I hope that there will be better options down the line. For example, [I and my colleagues] are trying to make antibodies from convalescent plasma that may become available in a few months. There is also a hope for monoclonal antibodies in the future and various antivirals.”

– Dr. Arturo Casadevall

“[C]onvalescent plasma provides something that can be used today with standard knowledge and standard procedures […] But we do hope that better options will be available in the future,” he reiterated.

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