A recent study co-authored by a Warren Alpert Medical School professor showed the effectiveness of convalescent plasma therapies for treating COVID-19 early in its disease course and preventing hospitalization.
The study in the journal Clinical Infectious Diseases, co-authored by Adam Levine, professor of emergency medicine and health services at the Med School, was a collaboration with a group of researchers based in Argentina, the Netherlands, Spain and the United States. The paper consists of a meta-analysis of five clinical trials across these four countries.
‘We had tested in the wrong population’: Prior usage of convalescent plasma
Convalescent plasma is a blood product that individuals can donate as they would during a regular blood or plasma donation. Since “it is the part of the blood that includes all of the antibodies we have against different diseases,” it was one of the earliest treatments considered at the start of the pandemic before the development of vaccines, Levine said.
Anyone who had COVID-19 and recovered has antibodies in their plasma, “and the idea was that if you gave (antibodies) to people who were sick with COVID-19, those antibodies could neutralize the virus and reduce complications such as severe illness, hospitalization or death in those patients,” he said.
This led convalescent plasma to be approved as a “blanket treatment for COVID-19 under an emergency use authorization, and then people started giving it to everyone,” Levine explained. Many patients who were hospitalized and “on their deathbed” were given convalescent plasma treatment. This population is where the first studies on administering the therapy for COVID-19 took place, according to Levine.
But these initial studies found that convalescent plasma did not work to treat COVID-19 and did not reduce mortality in these patients.
“Unfortunately, like with so many things at the beginning of the pandemic, we were rushing so much that we didn't really take the time to stop and think about how best to study” convalescent plasma therapies, Levine said. “The problem was we had tested in the wrong population.”
While convalescent plasma has antibodies that neutralize the virus, “by the time you're hospitalized with COVID-19, the virus isn't the problem anymore — it's the body's immune response to the virus, the inflammatory phase and the inflammation against the virus that actually kills people with COVID-19,” Levine said. “So it's not surprising that convalescent plasma wasn't useful in that population.”
With this in mind, researchers at Johns Hopkins University, with a grant from the United States Department of Defense, led a study beginning in 2020 on convalescent plasma treatments — specifically in patients at early points in their disease course or before hospitalization. This study involved other collaborators across the country, including Brown and Rhode Island Hospital, and Levine served as the primary investigator in Rhode Island.
The study’s findings, published in the New England Journal of Medicine, showed that hospitalizations were reduced by approximately 50% in patients who received the COVID-19 convalescent plasma therapy compared to control patients.
“But the problem was that there were a lot of other studies that showed contradictory results and so … it wasn't clear where and how to use convalescent plasma,” Levine said.
Convalescent plasma versus alternatives
Convalescent plasma has a number of advantages over alternative treatments, according to Levine and Yuriko Fukuta, assistant professor of medicine-infectious disease at Baylor College of Medicine.
Monoclonal antibodies — which only have one type of antibody specific to one receptor on the virus — lose their effectiveness when a virus mutates and that receptor changes, which is what happened with COVID-19 variants, according to Levine.
The other main methods for treating COVID-19, including Remdesivir and Paxlovid antiviral therapies, also have limitations, according to Fukuta.
The intravenous administration of Remdesdivir requires patients to come to the infusion center once a day for three days. This is “a lot of work … and why not many hospitals have set up Remdesivir for outpatient (settings),” Fukuta said.
While convalescent plasma is also administered through infusion, it only needs to be done once, she added.
Paxlovid is a pill taken in an outpatient setting, and the “appeal” of this medication is that doctors can see patients virtually and call in a prescription to a pharmacy, so there is “much less risk from an infection control standpoint and it’s easier for patients,” Fukuta said. However, she also noted that Paxlovid can have drug interactions with other medications, especially for immunocompromised patients, which is “why we think plasma can be the alternative for them.”
“Convalescent plasma is beneficial because it keeps up to date with the virus and as people get infected, they produce antibodies to the newer phases of the virus, so if you get convalescent plasma from someone who's recently been infected then you know you have a treatment that works with the current phase of the virus,” Levine said.
The alternative treatments to convalescent plasma are also patented and more expensive, meaning they are not available to many lower-income countries despite a push for pharmaceutical companies to share their intellectual property, according to Levine.
“As of right now, the only treatment for COVID-19 that doesn't have a patent is convalescent plasma because it comes from the human body — you can't patent it,” Levine said.
Knowing that convalescent plasma treatment was effective from the initial 2020 trial while also remaining aware of the conflicting data surrounding this therapy led the researchers to do “a meta-analysis to provide strong evidence on whether (convalescent plasma) really is effective,” Fukuta said.
Results of meta-analysis
The researchers’ meta-analysis focused on convalescent plasma therapy studies in the outpatient setting because earlier studies found that convalescent plasma is not as effective once patients are already hospitalized, according to Levine.
“We wanted to bring together all of the studies that looked at outpatients and so we did a big literature search, searching through thousands of articles, and found only five (studies) that had been published in the world that looked specifically at outpatients,” Levine said.
They then reached out to the authors of the five trials asking them to share their original data — some of which had not been published in the studies — to have a more comprehensive picture for their meta-analysis. The authors of these five trials were also listed as co-authors in the meta-analysis study.
Through this meta-analysis, the researchers found that convalescent plasma is effective at reducing hospitalization by about 30% and works best when administered during the first five days of symptoms.
They also discovered that the therapy is more effective when patients receive high-titer convalescent plasma, or plasma with more antibodies against COVID-19. Convalescent plasma in the top 50% titer reduced hospitalization by over 50%.
Combining all five studies also allowed researchers to look at a “very representative sample of the human adult population,” Levine said. The studied population ranged in ages, risk level and treatment setting, suggesting that the findings “are very generalizable to the wider population.”
Convalescent plasma’s comeback: On the ‘slope of enlightenment’
In an editorial commentary responding to the study, Shmuel Shoham, professor of medicine at Johns Hopkins University School of Medicine, wrote about how COVID-19 convalescent plasma therapy has reached the “slope of enlightenment” stage in the Gartner Hype Cycle, a model that describes the introduction of new technologies via their five life cycle stages.
The five stages of the cycle include an innovation trigger, peak of inflated expectations, trough of disillusionment, slope of enlightenment and plateau of productivity. “That's definitely been the story with convalescent plasma,” Levine said of the commentary.
In this scenario, the COVID-19 pandemic served as the trigger, creating a “huge amount of hype, a lot of inflated expectations, thinking that (convalescent plasma therapy) was a panacea or silver bullet,” Levine said. “But there are no magic bullets in the real world.”
People then started to think the therapy would not work, but in reality, “it just works in certain populations and certain ways,” Levine said. “That's the phase that we're finally getting to now with this particular innovation.”
“We're learning how to use (convalescent plasma), but we're not quite there in the plateau of productivity yet,” Shoham said. “We now know what we need (and) who we need to give it to … but we have problems with logistics.”
‘We do not have to repeat the same mistakes we made early in this pandemic’: Looking ahead
Shoham said he is optimistic about the promise of COVID-19 convalescent plasma therapy. But he also said that the therapy is still not accessible for many patients around the world and many healthcare systems do not have the infrastructure set up for this treatment. There is also “a lot of misinformation out there” about the therapy, he added.
Another challenge with convalescent plasma — and blood products in general — is the variability in the antibody level between donations, according to Shoham. There is also uncertainty regarding whether the antibodies in a particular bag of plasma used to treat a patient will be effective against the specific variant of virus the patient has.
Shoham added that the current data on convalescent plasma suggests that the therapy “should be effective, but it's not the same as if I had a higher level of precision that you often have with actual pharmaceuticals.”
Finding solutions to these logistical issues is “going to be necessary to get to the plateau of productivity,” he said.
The researchers are also continuing to publish secondary analyses of the data collected in the meta-analysis, according to Levine. One question they have: “What are the effects of convalescent plasma on long COVID-19?”
They hope this study will influence the National Institute of Health, World Health Organization and FDA to make convalescent plasma a recommended treatment for COVID-19, especially for parts of the world that have limited access to pharmaceutical treatments.
The findings from this meta-analysis are “very important for the next pandemic because when it happens, there will be a huge desire for treatments really early and the only treatment we will have available at that time will be convalescent plasma,” Levine said. “But now we know how to give it, who to give it to and what type of plasma to give, so that we do not have to repeat the same mistakes we made early in this pandemic.”
Editor's Note: This story has been updated to add more information about expectations surrounding convalescent plasma therapy.
Gabriella is the Senior Science & Research Editor of The Brown Daily Herald. She is a junior from San Francisco studying neuroscience on the premedical track.
