By Marie Rosenthal, MS
The FDA issued an emergency use authorization (EUA) for the investigational use of convalescent plasma for treatment of COVID-19 in hospitalized patients.

Despite encouraging early results, however, infectious disease specialists said more study in controlled trials is needed to ensure its effectiveness and to determine when this treatment should be given, which patients should receive it, the amount of antibodies the plasma should contain, and how long the immune response lasts. 

Convalescent plasma remains an unapproved therapy, according to the FDA, but said it reviewed the data generated over several months stemming from efforts to facilitate emergency access to convalescent plasma for patients.

“We’re encouraged by the early promising data that we’ve seen about convalescent plasma. The data from studies conducted this year show that plasma from patients who’ve recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus,” said Stephen M. Hahn, MD, the FDA commissioner. 

The FDA’s Biomedical Advanced Research and Development Authority (BARDA) determined that the statutory criteria for issuing an EUA were met based in part on data from a program by the FDA, BARDA and Mayo Clinic. In a preprint of their study, the researchers at Mayo Clinic reported on a cohort of 35,322 adult participants enrolled in the U.S. Convalescent Plasma Expanded Access Program (EAP) between April 4 and July 4, who were hospitalized with (or at risk for) severe or life-threatening acute COVID-19 respiratory syndrome. The cohort included a high proportion of critically ill patients, with 52.3% in the ICU and 27.5% receiving mechanical ventilation at the time of plasma transfusion. There was a diverse group of participants by age, sex, race and ethnicity, and body weight. Study participants consisted of approximately 40% women, 38% Hispanic/Latino, 19% Black and 4% Asian. 

In a subset of the cohort (3,082 patients), the investigators found lower mortality associated with plasma transfusions that contained higher levels of antibodies against the virus that causes COVID-19. Deaths occurred in both the high- and low-titer groups, but were fewer in the high-titer group (8.9% vs. 13.7%). Physicians treating hospitalized patients with COVID-19 at any U.S. institution can register their patients into the Mayo trial here. 

In addition, the investigators found:

  • The seven-day mortality rate was reduced in patients transfused within three days of COVID-19 diagnosis compared with patients transfused four or more days after diagnosis. A similar trend was seen for the 30-day mortality rate.
  • The use of convalescent plasma with higher antibody levels was associated with reduced seven- and 30-day mortality.

It is important to note that the researchers said the program was not intended to be a clinical trial to determine the efficacy of convalescent plasma. The program was established to increase access to plasma to help severely ill patients at the height of the pandemic and to determine the safety of plasma transfusions. 

“The current observations might indicate factors that may impact the effect of treatment and help direct the randomized clinical trials that are needed to establish efficacy. The intent was to offer a procedure that had a history of use at a time when there was no known treatment for this deadly condition,” they said, while citing several limitations:

  • No data existed on what dose might be appropriate.
  • Inclusion criteria were broad and exclusions were minimal.
  • There was no standardized treatment protocol.
  • Enrollment sites were very diverse, from university hospitals to community hospitals.
  • Personnel training was minimal as was the fine detail of data reported.

“While the data to date show some positive signals that convalescent plasma can be helpful in treating individuals with COVID-19, especially if given early in the trajectory of disease, we lack the randomized controlled trial data we need to better understand its utility in COVID-19 treatment,” said Thomas L. File, MD, the president of the Infectious Diseases Society of America (IDSA). 

Convalescent Plasma’s Action
Convalescent plasma is a passive immunization method whereby antibodies derived from the blood of people who have recovered from an infectious disease—in this case, COVID-19—are collected and prepared. Convalescent plasma is a known commodity and has been used for diseases such as hepatitis B, respiratory syncytial virus and rabies, explained Shmuel Shoham, MD, FIDSA, an associate professor of medicine at the John Hopkins University School of Medicine, in Baltimore, at a press briefing sponsored by the IDSA. 

“Passive immunization gives the body an immediate supply of potentially protective antibodies,” said Dr. Shoham, who was not directly involved in the Mayo study, but sits on the scientific advisory board for the EAP and is helping people at Hopkins who want to get plasma by this pathway. Dr. Shoham is also involved in two studies looking at convalescent plasma for COVID-19 at Hopkins and several facilities across the United States and the Navajo Nation. He is the principal investigator for the post-exposure prophylaxis study and the coinvestigator for an early treatment study.  

He said timing might be important for the success of this therapy, and the efficacy probably will be higher if given early when the viral load of SARS-CoV-2 is low. “But we need to find answers as to how effective it is, and the sooner we get the answers to these questions, the better,” Dr. Shoham said.

“I cannot think of an infectious disease that doesn’t require early therapy,” added Liise-anne Pirofski, MD, FIDSA, the Selma and Dr. Jacques Mitrani chair in Biomedical Research and chief of the Department of Medicine, Division of Infectious Diseases at Albert Einstein College of Medicine and Montefiore Medical Center, in New York. “It appears from the data that was presented in the preprint that earlier treatment is better.”

Another important issue that still needs to be determined is the level of antibody that is needed to be effective, Dr. Pirofski added. Although not part of the Mayo study, Dr. Pirofski began looking at convalescent plasma early in the pandemic when COVID-19 hit New York. 

“There appears to be a dose-response [relationship] of the plasma that was given in the Mayo paper,” Dr. Pirofski said. “Units of plasma that had more antibody appear to be more effective. This is something that we look for in the development of any sort of drug or therapeutic intervention—the dose response,” she said.

“As an absolute general principle if you’re going to treat people, then it seems like using ‘high-octane stuff’ is better than using plasma that has lower antibodies,” Dr. Shoham said. That is not to say a low-titer convalescent plasma would be ineffective, but it is just one of many questions that need answering.

The Hopkins studies are using plasma with titers of 1:320 determined by enzyme-linked immunosorbent assay. Other studies are using different cutoffs. 

The good news is the early data give the product high marks for safety. “There are data from tens of thousands of hospitalized patients that have received plasma that make it appear to be exceedingly safe,” said Dr. Shoham, who is also the associate director of the Transplant and Oncology Infectious Diseases Center at Johns Hopkins.

Dr. Pirofski agreed: “I cannot think of one shred of data that I have seen that would suggest harm.” However, she reiterated that all of the data are anecdotal, and controlled trials are needed to confirm the anecdotal reports.

Both doctors said more resources are sorely needed: better funding, more plasma and more study patients. They pleaded with clinicians to enroll their patients in clinical trials and urged people who have recovered from COVID-19 to consider donating plasma. For clinicians interested in enrolling patients in the Hopkins plasma trials, click here.  For information about donating plasma, click here; in New York, click here.

“The EUA is not intended to replace randomized clinical trials, and facilitating the enrollment of patients into any of the ongoing randomized clinical trials is critically important for the definitive demonstration of safety and efficacy of COVID-19 convalescent plasma,” the FDA said, adding that it is being regulated as an investigational, not an approved, product for COVID-19. 

The EUA authorizes the distribution of COVID-19 convalescent plasma in the United States and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19. The EUA requires that fact sheets providing important information about using COVID-19 convalescent plasma in treating COVID-19 be made available to health care providers and patients, including dosing instructions and potential side effects, which include allergic reactions, transfusion-associated circulatory overload and transfusion-associated lung injury, as well as the potential for transfusion-transmitted infections.

Historically, Dr. Shoham said, passive immunization is more efficacious when combined with vaccination—something that is not yet available for COVID-19, although many companies and experts are working on a vaccine.