Convalescent plasma shows renewed promise for COVID-19 in outpatient trial | Science

Among the possible treatments for people just developing COVID-19 symptoms, antibody-rich plasma donated by recovered patients has taken a backseat to options such as monoclonal antibodies and antiviral pills. But a new clinical trial suggests it may deserve a bigger role. The trial results, posted today as a preprint, showed a transfusion of convalescent plasma cut rates of hospitalization roughly in half—from 6.3% to 2.9%—in people treated early in the course of their infection with SARS-CoV-2.

The treatment is currently authorized in the United States only for emergency use in certain hospitalized patients, but the researchers behind the study now say its use should be expanded. And they hope convalescent plasma will take a more prominent role in the fight against COVID-19 as the Omicron variant, shown to reduce the effectiveness of some monoclonal antibodies, becomes dominant. They argue it may be particularly useful in lower income countries that can’t afford or don’t have access to other treatments.

Convalescent plasma “was pretty much done for” after disappointing results from previous clinical trials, says Frederick Korley, an emergency physician at the University of Michigan Medical School who was not involved in the new trial. Earlier this month, for example, the World Health Organization (WHO) recommended against its use in SARS-CoV-2–infected people with “nonsevere” illness. This study “brings it back on the table,” Korley says—but leaves unanswered questions about which subset of newly diagnosed patients will benefit from the treatment.

In August 2020, the U.S. Food and Drug Administration (FDA) under then-President Donald Trump issued an emergency use authorization for convalescent plasma to treat severe COVID-19, a move that was criticized as politically motivated and unsupported by science. The agency revised that authorization in February, requiring that the plasma administered have high levels of SARS-CoV-2 antibodies, and limiting its use to hospitalized patients who are early in the course of disease or who are unable to make sufficient antibodies to the virus.

Meanwhile, evidence from clinical trials has been mixed. A study of 160 older patients in Argentina found convalescent plasma led to a 48% reduction in severe disease. However, a larger trial sponsored by the U.S. National Institutes of Health was halted early after investigators found the treatment did not prevent disease progression—as measured by emergency room or urgent care visits, hospitalizations, or deaths—in high-risk patients. That finding in turn drew pushback from a group led by Arturo Casadevall of Johns Hopkins University (JHU), who has championed the potential of convalescent plasma since early in the pandemic. Among their critiques of the trial, the researchers pointed out that some patients hospitalized the same day as their recruitment into the study did not have time to benefit from the treatment.

The new study, posted as a preprint on medRxiv and led by a JHU team that includes Casadevall, suggests infected people, treated early enough, can benefit after all. The outpatient trial, which predated the emergence of the Omicron variant, randomized 1181 people in the United States who were within 8 days of the onset of their COVID-19 symptoms to receive either a transfusion of convalescent plasma with high levels of anti–SARS-CoV-2 antibodies or a placebo solution. Within 28 days of the intervention, 17 of the 592 people in the treated group had been hospitalized, versus 37 of 589 in the placebo group.

“We have a clear difference,” the study’s principal investigator, JHU immunologist David Sullivan, said in a press conference today. He added the JHU team had shared its results with WHO and FDA, and that plasma was “already under review by the FDA for expansion to the outpatient setting.”

Because convalescent plasma comes from recently recovered patients, it can keep up with ever-changing viral variants, JHU epidemiologist and co-author Kelly Gebo added. And collecting, banking, and transfusing plasma is feasible in low- and middle-income countries where SARS-CoV-2-targeting monoclonal antibodies are not widely accessible, she said.

Korley agrees that “one of the biggest appeals of convalescent plasma” is its wide availability. But big questions remain about who the best candidates for plasma treatment are: anyone infected with SARS-CoV-2, or only those with certain risk factors? Although the treatment is relatively safe and well-studied, it does carry a risk of transfusion-related reactions that can require hospitalization and treatment with steroids, he notes.

The negative NIH trial, on which Korley was an investigator, included COVID-19 patients who were older and already sicker, on average, than those in the new trial. “Perhaps treating people who are less sick may be the way to go,” he says, “but then you have to ask yourself: If I dont treat them, what happens?” In this study, nearly 94% of patients who didn’t get plasma recovered without hospitalization anyway. Meanwhile, unvaccinated people made up 81% of the study participants, and nearly all (53 of 54) of those hospitalized.

“We have to understand which subset of COVID patients will derive the most benefit from these treatments,” Korley says, “and if it turns out to be only the unvaccinated people, maybe the solution is just to improve our effort at vaccination.”