Is Convalescent Plasma a Magic Pill for COVID-19?

We’ve discussed the hope of antibody treatment for SARS-CoV-2 treatment, either through RNA or the antibodies themselves. There is another antibody-rich option that is technologically simpler, has a long history, and is already being tried across thousands of patients: convalescent plasma. Let’s take a closer look to understand what convalescent plasma is, and how it could help treat COVID-19 patients.

What is convalescent plasma?

Plasma is the yellowy, goopy portion of blood that has been depleted of blood cells, including circulating immune cells and red blood cells. The liquid plasma retains soluble proteins, including antibodies, and is thus a source of real human antibodies from donors. Starting in the 1950s, scientists developed methods for separating plasma from whole blood and transferring the antibody-rich concoction into other patients. This technique was first used successfully to treat patients with hyperviscosity, a blood disorder in which blood becomes thick and viscous, and by 1959 it was being used to treat thrombotic thrombocytopenic purpura, an immune disorder. Through the 60s the technique was further refined and improved by scientists at the National Cancer Institute, and now we have several decades of experience using plasma transfer to successfully treat a number of blood, neurological, and immune disorders (often in conjunction with other medications), including Guillain-Barre syndrom and Rhabdomyolysis.

Plasma is the yellow goopy part of blood that contains antibodies and proteins.

Given this long history, modern plasma transfer, called plasmapheresis, is a fairly robust process: blood is drawn from the donor by a machine, the plasma portion is extracted by the same system, and the blood cells flow back into the donor without ever being directly handled. This looping reduces the chance of infection or contamination, and also allows a single donor to give more plasma, as the rate-limiting factor in blood donation is often the blood cell portion of the blood. The plasma can then be checked for common transmissible diseases like HIV and Hepatitis C before being transfused into the recipient. This does not erase all risks of transfusion, but plasmapheresis is considered a relatively safe procedure in a trained hospital setting.

Blood goes out and is separated in situ, allowing unneeded portions to flow back into the donor.

The benefit of the plasma is several-fold: in some cases like hyperviscosity, the liquid and contained nutrients are themselves valuable. With autoimmune disorders, the presence of non-self antibodies is thought to help reset the immune system. For infectious diseases, the goal is antibody transfer: plasma from a patient that has recovered from the illness often contains antibodies that could help an unexposed or unrecovered patient mount a faster and stronger immune response to the infectious agent. (Note that “convalescent” means “in recovery”; hence, “convalescent plasma” is plasma derived from already recovered patients.)

Convalescent plasma for COVID-19

The goal, then, of convalescent plasma is similar to lab-designed antibodies or RNA transfection of antibody sequences: the target recipient gets a bonus set of antiviral antibodies to add to their arsenal. In recent years, convalescent plasma was found to be useful in treating SARS (2003 version), MERS, Ebola, and H1N1. For SARS, for example, a study of 80 patients in Hong Kong found that 58% of plasma-treated patients were discharged by day 22, versus 16% of control patients. Notably, for each of these viral pandemics, the urgent nature of the pandemic, the many unknowns that result from treating a patient with unanalyzed liquid from another patient, and the variability in control patient outcomes makes a conclusive evaluation of the efficiency of convalescent plasma difficult. Still, the studies that were conducted during each of those outbreaks indicated that convalescent plasma led to faster recovery times and reduced viral load with minimal safety risk, especially when administered early.

As a result, the attitude of many scientists and doctors toward the use of convalescent plasma during the COVID-19 pandemic seems to be, “May as well; if it helps, great, and it’s unlikely to hurt.” The FDA has issued an emergency allowance for using convalescent plasma to treat COVID-19 patients, and a number of large-scale clinical trials are underway. Tens of thousands of patients have already been treated, and though controlled comparisons are not available, the treatment seems to be safe, with fewer than 1% of patients experiencing adverse events.

There is, however, a big caveat with the ongoing trials in the US: the FDA authorization is for patients with severe COVID-19 or who are at risk of severe COVID-19. The theory behind antibody treatment along with the previously published results for other infectious diseases would imply that the best time to treat with convalescent plasma is early, when the immune system is trying to mount an effective antiviral response, rather than later in the disease when the patient is likely already producing antibodies of their own. In a study in the Netherlands, COVID-19-positive patients were enrolled in a trial of convalescent plasma, but the study was halted early because the vast majority of enrolled patients were already making anti-SARS-CoV-2 antibodies, even by day 10 after symptoms appeared. Thus, though outcomes results are not yet available for the US trials, it is likely the effect of the treatment will be hampered by the fact that it is given so late in the course of the disease.

So, why not just give everyone convalescent plasma earlier in the course of disease? Or as a vaccine? The first problem is supply; convalescent plasma comes from willing, complication-free COVID-19 survivors who mounted a sufficient antibody response and are blood-type matched with recipients, and so far that set of people is vastly outnumbered by the theoretical donees. But even assuming a ready supply of convalescent plasma, the variability of the effectiveness of the plasma is likely very high; some patients produce a large number of neutralizing antibodies, and some produce none, and you don’t know what mix or nature of antibodies you get in a given patient’s plasma. Thus, if we assume supply is equal, lab-developed antibodies are preferable to convalescent plasma, as we could better control the types and amounts of antibodies given to patients. In other words, convalescent plasma is a great stopgap while we have it, and we should do our best to source and transfuse convalescent plasma for COVID-19, but it is unlikely to be a silver bullet.

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