An Update on Convalescent Plasma for COVID-19

INTERVIEW BY JOSHUA SHARFSTEIN

In the early days of the pandemic, clinicians began to treat COVID-19 patients with the plasma of people who have recovered from COVID-19. The idea was that protective antibodies in the plasma would help prevent severe illness and death. Nearly two years later, more evidence is in and it’s being hotly debated.

In this Q&A, adapted from the January 12 episode of Public Health On Call, Arturo Casadevall, MD, PhD, chair of Molecular Microbiology and Immunology, talks with Josh Sharfstein, MD, about the results of the COVID-19 Plasma Project and his take on divergent recommendations about using plasma as a therapy.

WHAT IS CONVALESCENT PLASMA?

People who recover from COVID-19 have antibodies in their blood; those patients can then donate plasma to other individuals for treatment of the disease.

CAN YOU EXPLAIN WHAT HIGH-TITER PLASMA AND LOW-TITER PLASMA ARE?

“Titer” is a word for the number of antibodies a person may have. After recovering from COVID-19, someone might have a lot of antibodies, and others might have fewer antibodies. The best plasma comes from donors who have a lot of antibodies. We call that high-titer. You can figure out which plasma is high-titer by testing it in the lab.

THE WORD ‘ANTIBODY’ BRINGS TO MIND MONOCLONAL ANTIBODIES, WHICH HAVE BEEN WIDELY USED AND PROVED TO BE EFFECTIVE FOR MANY PATIENTS. HOW DOES CONVALESCENT PLASMA COMPARE TO MONOCLONAL ANTIBODIES?

Antibodies are proteins that are normally produced during infection. They can also be made in the laboratory, and [those are] known as monoclonal antibodies. Both plasma and monoclonal antibodies have the same active ingredient. Therefore, if one works, the other one should work, and that’s something very important to discuss.

WHEN THE PANDEMIC FIRST STARTED, THERE WASN’T A VACCINE ON THE IMMEDIATE HORIZON. WHAT WERE YOUR THOUGHTS ON PROPOSING CONVALESCENT PLASMA THERAPY?

Antibody therapy in the form of convalescent plasma, also known as serum therapy, goes back 130 years. We have a lot of experience transferring antibodies to treat diseases. Whenever there is a pandemic or an epidemic, physicians often resort to it, because it’s available as soon as a person has recovered.

WHAT IS HAPPENING INSIDE SOMEONE’S BODY WHO IS GETTING ANTIBODY THERAPY, BE IT MONOCLONAL ANTIBODY THERAPY OR CONVALESCENT PLASMA?

If you haven’t been immunized and you become infected with COVID-19, you’ll go through this initial viral phase where the virus replicates. The virus replicates in tissues in the nose, sometimes in the lungs. It takes around seven to 12 days for the immune system to begin making antibodies. For most people, the immune system will catch up and check the virus, allowing them to recover, but some don’t. Those are the ones who then get massive inflammation and end up in the emergency room.

What can be done is to administer antibodies early in the process to neutralize the virus and stop the progression of the disease. This is the premise behind plasma and monoclonal antibodies to prevent hospitalization.

A LOT OF STUDIES HAVE BEEN DONE ON CONVALESCENT PLASMA. SOME OF THEM HAD POSITIVE RESULTS, AND SOME OF THEM HAD NEGATIVE RESULTS. CAN YOU CHARACTERIZE THE DATA THAT’S EMERGED?

To put everything in perspective, in the 130 years before COVID, we had one randomized control trial from plasma that was done in Argentina in the late 1970s. The reason there’s only one is that they’re very hard to do in the middle of a pandemic. But in the last two years, we have completed about 25. So we have a lot of very high-quality data. What I can say to you is that antibody therapies are most effective if used early, and with sufficient antibodies.

If you take all these 20-plus trials and put them in a row, you’ll see the patients that were treated late show no efficacy.

WHY WOULD IT BE THAT THIS TREATMENT WOULD WORK EARLIER BUT NOT LATER WHEN PEOPLE ARE REALLY SICK?

Late in the disease process, people already have their own antibodies. So, giving them an antibody on top of something that they already have might only benefit them a little.

What is causing deaths when it comes to COVID is inflammation. Inflammation in the lungs prevents gas exchange, and you cannot expect the antibody to reverse inflammation. All you can expect is the antibody to neutralize the virus. If you can neutralize the virus, you prevent further inflammation. The earlier you treat, the more likely you are to affect the process.

THE NATIONAL INSTITUTES OF HEALTH DID A STUDY IN 2020 AND 2021 CALLED THE C3PO STUDY AND CONCLUDED THAT EARLY USE OF CONVALESCENT PLASMA DIDN’T WORK.

We had great hopes for the C3PO study when it was first designed. The word early here is relative, because the people involved in this study are already sick enough to be walking into the emergency room. This study involved patients in the ER with COVID to randomly receive convalescent plasma or an infusion with some sort of vitamin water. If you follow the rules of the study, you don’t see a difference. Those who got plasma and those who got vitamin water ended up roughly about the same. But the study was designed so that people who showed up on that index visit [first visit to the ER] only counted if they got admitted.

If you’re sick enough to go to the emergency room and get admitted, I don’t think you can expect plasma to work right away. So, if you look at the same data and remove those patients who were admitted on the index visit, C3PO has an efficacy of over 30%. That is, those who were discharged home were less likely to come back if they received plasma. It makes sense: The ones who were discharged were probably less sick than the ones who got admitted.

IN A WAY, YOUR CRITIQUE OF THAT STUDY IS THAT THEY INCLUDED IN THEIR PRIMARY ANALYSIS PEOPLE WHO WERE ACTUALLY PRETTY SICK.

Exactly. We have posted a critique of that study on our website. Those who are interested can go and look at it. Those of us in the field are considering this a positive study, while the NIH is considering a negative study.

I’M SURE YOU’RE AWARE THAT THE WORLD HEALTH ORGANIZATION LOOKED AT THIS QUESTION OF EARLY USE OF CONVALESCENT PLASMA AND DECIDED NOT TO RECOMMEND IT ON THE BASIS OF ALL THE STUDIES THAT WERE DONE IN EARLY DECEMBER. THAT WAS A BIG MOMENT IN THIS FIELD. WHY DID THEY DECIDE THAT? AND HOW DID YOU RESPOND?

We were very disappointed with the WHO’s position and we don’t agree with it. They took all the randomized controlled trials and did a meta-analysis. Basically, they concluded that there wasn’t a lot of efficacy. Some of these randomized controlled trials were huge. If you do a meta-analysis, a huge trial that is negative totally wipes out the effect of the other trials that are positive.

WOULD IT BE FAIR TO SAY THAT SOME OF THOSE STUDIES MAY NOT HAVE USED THE HIGH-TITER PLASMA? 

Absolutely. Some of these studies used plasma very late; other studies used insufficient plasma. The WHO did not have access to the Hopkins data. We are hopeful that since they are physician-scientists and rigorous people, they will issue new recommendations in the future.

https://publichealth.jhu.edu/2022/an-update-on-convalescent-plasma-for-covid-19?fbclid=IwAR2BeynvGqzu7ZGtoOlxfTZOfLAQuPUDX0L40lrF6Q_ynTa7fJFtL4RUlwE

Créditos: Comité científico Covid