David Perlin, PhD, Chief Scientific Officer, Chief Scientific Officer at Hackensack Meridian Center of Discovery and Innovation at Hackensack Meridian Health talks about convalescent plasma therapy in treating COVID-19.
Can you explain what convalescent plasma therapy is and how it works in the system?
PERLIN: Convalescent plasma therapy uses blood plasma from patients who have recovered from COVID-19 and have mounted a strong antibody response that neutralizes virus to treat newly-infected COVID-19 patients. It is a fairly simple process. Blood is removed and identified for the presence of high levels of neutralizing antibody. Then the red blood cells are separated, and you are left with a yellowish gold liquid, which is plasma, and that contains the antibodies. Those antibodies are called neutralizing because they can kill the virus or block its replication. We can then use the neutralizing antibodies to either treat patients who have disease and are not able to mount an effective response or prevent the disease in high risk individuals.
How is it administered into a patient?
PERLIN: So, with the plasmapheresis process the blood cells are separated, the plasma is produced, and then it slowly gets infused into patients.
How do the antibodies start working in the system?
PERLIN: When a person is infected with a viral or other infectious agent there are two components to the immune system that help keep us healthy. There is the innate immune system where our bodies lymphocytes and macrophages scavenge and protect us from pathogen assaults, which we have all the time. In the case of COVID-19, you get a prolonged infection that can overwhelm the innate immune system resulting in tissue damage. This leads to a strong inflammatory response that can impact breathing. The infection also activates the adaptive immune system which involves the production of antibodies. Although, this may take 9 or 10 days. The antibodies are extremely effective at neutralizing the virus and clearing the infection. So, for patients who recover on their own, they have mounted an immune response. Typically, they have antibody responses that neutralize and block virus replication, and they get better. What is left in the individuals who recover are these antibodies which are very, very potent agents to fight the virus.
What is your lab’s role right now in this therapy?
PERLIN: Currently my laboratory’s role is to support our convalescent plasma therapy program. We have been trying to identify potential donors who have produced high levels of neutralizing antibodies that could be used for therapy.
What has your research associate Mila been doing?
PERLIN: Mila is engaged in a process called antibody titering where we are trying to quantify the level of antibodies in potential donors. We have looked at about 1,000 donors right now, and all the individuals had the coronavirus infection and have recovered. They are at least 14 days out from the resolution of their clinical symptoms, so they have mounted an antibody response. For these patients, we need to look at their level of antibody. Mila is taking the blood serum from those patients and diluting it multiple times to determine the amount of antibody present. We have a specialized procedure which allows us to look for the potential of the binding of the antibodies to a portion of the virus protein that is critical for its uptake by cells. This provides a measure of what we call virus neutralization. We identify that a donor has high neutralizing activity of their antibodies, and we confirm that by performing a viral cytopathic assay in our biosafety level three facility in which we directly examine virus neutralization. In short, we take the virus and mix it with recipient cells that are easily infected by virus and allow virus replication. Then we add antibodies at various levels to show that we can block the behavior of the virus to destroy those cells and reproduce.
How effective is this for people who are extremely sick and do not have any other options?
PERLIN: So, this is where the convalescent plasma therapy is somewhat controversial because it varies depending on when the therapy is applied, and the amount of antibody that is used. There are multiple programs for convalescent plasma therapy and within Hackensack Meridian Health, we have two main programs. We run the national program, which was developed by the Mayo Clinic called the national expanded use program, where there are more than 100,000 patients who have been on the protocol. Then we run a separate protocol, which is much smaller with 47 patients enrolled. It is a high dose, high titer antibody program. In this program, if you were hospitalized but not on a ventilator and received convalescent plasma therapy, then 88% of those patients went home. So, they recovered and did quite well.
However, if you were seriously ill on a ventilator, then we had a mortality rate of somewhere around 47% compared with a mortality of close to 70% without convalescent plasma therapy. Where things get dicey is that this was not a randomized control trial since the high mortality encountered at the time called for intervention. Rather, we used a large number of patients with closely mimicked disease who were not treated with convalescent plasma therapy and could serve as a comparator.
In both groups, there was a clear-cut benefit. In the course of this trial, there were some spectacular examples of success including a patient who was in the ICU on a ventilator, given plasma therapy and was home within three days. So, I think many of us have seen these anecdotal situations where patients respond incredibly quickly and effectively to the therapy. Plasma therapy appears safe, so, there does not seem to be much downside to it.
As I mentioned, for patients especially early in the infectious process, they respond extremely well. I think this highlights the need for us to think carefully about diagnosing patients who have been infected and treating them early on in the infectious process. If it takes two weeks for us to diagnose an infection and we are waiting for a patient to go to the hospital because they have respiratory problems, now they’re pretty advanced in their disease process, so rescuing them is difficult. In terms of the national agenda, FDA emergency use authorization for convalescent plasma allows us to use this approach at an earlier stage in the disease process.
The FDA approved this for emergency use. So, this is when you are sick and at a certain stage. But it could be used as soon as you are identified with COVID-19?
PERLIN: I think the appropriate way for it to be used would be for a patient who is newly infected presenting with symptoms. At that stage, it would be appropriate to receive plasma therapy. I think that is where it is being used in many places. For us, that is the next phase of our trial which is to be able to use it at the early, early stage. In our study, we were only able to look at hospitalized critically ill patients, and severely ill patients who were ventilated. We did not have the luxury of looking at patients who were mildly ill and that is where this will have an enormous benefit. But even for hospitalized patients who were not ventilated, we had strong success with it. Now, our program uses high dose, high titer antibodies. What we found in our donor population was that about 15 or 20% of our donors produce extremely high titer antibodies. The way we are defining this is these individuals have antibodies that are 10 to 50 times in excess of the antibodies that the average person would mount in a robust response to infection, so the average response is good enough to clear the infection, but these individuals are producing massive amounts of antibodies. So that is what we use. We also infuse a higher volume of plasma into our patients for high therapy. So, it is nuanced, and it is a bit different than the national program. But in our hands, we have had exceptionally good success with it.
So, your super-producers are the ones that are producing lots of the antibodies?
PERLIN: Yes, they are super-donors and supra-producers; they are producing large amounts of antibodies. For our patients who received convalescent plasma therapy and did not mount their own immune response, they mounted a very profound and strong antibody response. Across the board, all our recipients mounted an incredibly strong antibody response. We watch most for 30 days and in some cases 60 days, and we see a strong and stable antibody response. So, the plasma therapy does not interfere with the ability for the individual to produce their own antibody and this is not the antibody that is lingering from what we infused in them.
What are the implications for having this plasma therapy?
PERLIN: Right now, we are essentially dealing with two diseases with COVID-19. We have the early phase where it is driven by the virus itself and if you can control the virus, then people will get better quickly. But in short order, the virus attacks the lung, other parts of the body, and you start seeing tissue destruction and massive inflammatory responses, especially in the lung. We see pneumonias and patients rapidly progressing toward death. Unfortunately, the inflammatory response is no longer just a viral response, so controlling the virus is not enough. When I say we have two diseases, we have the viral component and then we have the inflammatory component. In some cases, you must be able to manage both because patients are rapidly progressing. You must control virus and you must control the inflammatory response. In some patients, it is no longer the viral response, it is the inflammatory response which is dominant for their disease, and that is what needs to be controlled. But what we want to do is push it back to the earlier stage of infection, be able to treat individuals for virus only, and have a therapy that we know is safe, efficacious and has a high probability of leading to success, and that’s where the emergency use authorization comes in. It is not an approval; it is an emergency use authorization for these patients, and it is helpful because it allows us to expand the number of people who receive the product. In my view, it will save lives.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Seth Augenstein
908-447-3705
seth.augenstein@hackensackmeridian.org
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