Convalescent Plasma Therapy for COVID-19 – Another Missed Opportunity

With thousands dying daily, Convalescent Plasma Therapy (CPT) has in recent weeks gotten some renewed and overdue attention to treat COVID-19 – especially when used early and targeted at individuals most vulnerable to severe disease or death. Sadly, it has been another tragic missed opportunity to bring antibodies into the battle with meaningful impact on the epidemic.

Convalescent Plasma Therapy gives the antibodies from people that have successfully beaten COVID-19 to those most vulnerable who are lacking natural immunity

CPT Got Lots of Attention Early On

CPT received a great deal of attention, focus and resources early on in the epidemic. By May, the FDA had issued Guidance for Investigational Use of COVID-19 Convalescent Plasma and BARDA started working to coordinate across the U.S. government for a unified effort to collect convalescent plasma for use as a treatment for COVID-19 patients under an expanded access protocol and in clinical trials. This was accompanied by efforts coming out of the private healthcare sector, such as Johns Hopkins National Convalescent Plasma Project, the  American Red Cross Plasma Donations Center and CoVIg-19 Plasma Alliance.

At the time, with almost no other treatment options available, desperate medical staffs embraced this initiative and it was used widely across the country, with blaring headlines about “liquid gold” and hopes for breakthrough. Volunteers all across the country came into donate blood plasma, and an ongoing partnership of government and industry drove large scale production.

The Early Results Were Disappointing, and Good Data Was Sparse

Sadly, early results from the use of CPT were disappointing. Several different issues arose.

  1. Clinical trial data did not show significant positive effects for CPT in treatment of hospitalized patients;
  2. What data was collected was not very good. Because of the urgency of using them, in most cases there were no double-blind trials, and CPT was used in combination with many other drugs. In those circumstances, it is very difficult to determine and prove that a drug or treatment is effective – or not.

Given this, not surprisingly, the media spotlight shifted – and with it focus and priority – to vaccines and drug therapeutics such as Remdesiver.

But History and Comparables Indicate that When Antibodies Are Used is Critical to Efficacy

The key question that remains unanswered is due to both the incompleteness of the data from trials, but also the focus of how and when CPT was used during this period. Based on the fundamental principles of how antibodies work, either prophylactical use prior to exposure or rapid treatment after exposure is where we would expect them to be most effective. Yet – partly because CPT is normally only administered in a hospital setting, and partly because of the urgency of the medical crisis at that time – the vast majority of patients that received it were hospitalized with severe symptoms of COVID-19. This is how the American Society of Hematology puts it:

The use of convalescent plasma (CP) collected from previously infected individuals to passively transfer antibodies in order to protect or treat humans dates back almost 100 years. Results from small case series during the prior MERS and SARS coronavirus outbreaks suggested that CP is safe and may confer clinical benefits, including faster viral clearance, particularly when administered early in the disease course1. The vast majority of patients who recover from COVID-19 illness develop circulating antibodies to various SARS-CoV-2 proteins 2-3 weeks following infection, which are detectable by ELISA or other quantitative assays and often correlate with the presence of neutralizing antibodies. These antibodies appear to be protective, based on several primate studies showing animals could not be re-infected with SARS-CoV-2 weeks to months later.

Multiple studies have now reported the use of COVID-19 convalescent plasma (CCP) to treat severely or critically ill COVID-19 patients, without unexpected or serious adverse events (see below). Many of the early studies were observational and non-randomized, complicated by evolution of additional treatment interventions over time, such as steroids, antivirals and other drugs; patient heterogeneity; and a lack of detailed analyses of neutralizing antibody content of infused units. Preliminary efficacy results from 35,000 patients enrolled in a US FDA-sponsored expanded access program coordinated by Mayo Clinic were made available on a preprint server. While many patients improved clinically, the specific role of CCP is unclear, because all patients received at least one additional therapy, including antivirals, antibiotics or antifungals, and/or corticosteroids. Mortality was lower in patients who received CCP within 3 days of diagnosis of COVID-19, and in those who received units of CCP with higher specific IgG levels, however, uniform testing for neutralizing antibodies was not performed.

Published and preprint data is accumulating from randomized controlled trials (RCT) carried out around the world, differing with respect to target population, disease severity, outcome measures, an characterization of antibody status in donors and recipients. Several of the early trials failed to demonstrate significance (e.g. China, Netherlands, Spain) but were stopped early due to inability to meet enrollment goals. Most trials have focused on moderate to severely ill hospitalized patients, despite consistent findings and theoretical considerations that support early CCP use relative to symptom onset.

American Society of Hematology: COVID-19 and Convalescent Plasma: Frequently Asked Questions

Studies and EUAs Have Continued – Focused On Early Treatment and Prevention Use Cases

The good news is that investigations and studies of CPT have continued, with a focus on the early treatment and prevention use cases where they are most likely to be effective. On September 8th, for example, the NIH announced a major clinical trial to explore the use of convalescent plasma in at-risk outpatients with early COVID-19.


The C3PO trial will determine whether transfusions with the COVID-19 convalescent plasma can prevent the relatively mild to moderate symptoms in this vulnerable group from developing into advanced illness that can lead to organ failure and may require life-saving mechanical ventilation. It also will assess the safety of the plasma transfusion itself. “We think from preliminary information that COVID-19 convalescent plasma may have the best chance of being effective if used when patients are just starting to show symptoms,” said Simone Glynn, M.D., M.P.H., chief of the NHLBI’s Blood Epidemiology and Clinical Therapeutics branch, who is coordinating the trial. “What we want to find out is whether this plasma is effective enough to keep these at-risk patients from progressing to a point where they need hospitalization.” 

NIH clinical trial explores use of convalescent plasma in at-risk outpatients with early COVID-19

Over the course of 2020, there were a number of updates and steps by the FDA to authorize and provide guidance for its use. While all of these continue to emphasize that insufficient data has been collected, and the need for continuing trials, they also are consistent in recommending early use.

FDA Letter of Authorization for Emergency Use, August 23, 2020
  • Current data suggest the largest clinical benefit is associated with high-titer units administered early in the course of disease.
FDA Updated Evidence to Support the Emergency Use of COVID-19 Convalescent Plasma – as of September 30, 2020

In summary, taking the totality of evidence into account, including prior experience with convalescent plasma in other outbreak settings, data from animal studies, data in the published literature from clinical studies performed during the current outbreak, and the results obtained from the hospitalized patients evaluated in the EAP, FDA continues to find that COVID-19 Convalescent Plasma has met the “may be effective” standard for an EUA. However, because the efficacy analysis of the EAP did not include an untreated group of patients for comparison who did not receive convalescent plasma, FDA strongly encourages the continuation of randomized controlled clinical trials to more definitively evaluate the potential benefits of this therapy.

FDA Recommendations for Investigational COVID-19 Convalescent Plasma, November 30, 2020
  • Provide updated guidance on pathways for use of investigational convalescent plasma, collection of convalescent plasma, record keeping, compliance and enforcement policy regarding investigational new drug requirements for use of convalescent plasma
FDA Fact Sheet for Health Care Providers
  • Risk-Benefit Assessment: Based on the totality of scientific evidence available at this time, the known and potential benefits of COVID-19 convalescent plasma outweigh the known and potential risks.

With the Deaths Soaring, Is This Source of Antibodies Being Leveraged Aggressively?

We don’t know, of course. With hospitals under siege from the surge of patients, we can only hope that this information and understanding has broken through the noise. But we do know the following things:

  1. there was a nationwide effort to collect, process and stockpile convalescent plasma for COVID-19 since May of 2020;
  2. the only silver lining of the 3rd wave is that there is also now an ample supply ‘out in the wild’;  and
  3. while not as effective as monoclonal antibodies, this the oldest and original technique of transferring immunity / protection from “convalescents” (people who were infected, recovered and have high levels of antibodies) to vulnerable population groups.

Due to a lack of recognition of the importance of antibodies, the opportunity to scale up production of monoclonal antibodies and hyper immune globulins for COVID-19 during the course of 2020 was sadly missed. It is not too late to start now – antibodies are an important tool that is likely to play an important role long term. But right here and now, we are facing an epic surge in hospitalization and deaths, and ramping up production takes time. But CPT, when applied early, is likely to make a difference, with good risk vs. benefit ratio for the vulnerable individuals that are now dying by their thousands.

So we ask: are we doing enough with CPT?

Further Reading and Materials:
Convalescent Plasma Therapy for COVID-19 – Another Missed Opportunity
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