Convalescent Plasma: ‘Flavor of the Month’ or Valid COVID-19 Treatment?


On March 31, soon after the US Food and Drug Administration (FDA) authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, New Jersey.

It may have worked. Eleven days after receiving the plasma, Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the US Department of Health and Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma — both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University School of Medicine, told Medscape Medical News.

Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health (NIH) recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, in Baltimore, Maryland, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine in New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they write, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East Respiratory Syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.

Aiming to Prevent Infection

So far, the FDA has approved 12 plasma trials — including Shoham’s — and the NIH’s lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Casadevall and Pirofski write.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in emergency department patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins and at Hopkins-affiliated hospitals in Maryland, Shoham said. He hopes it will eventually expand nationwide, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.  

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a PCR-positive test; participants will be tracked for 90 days. Hospitals and healthcare workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen — a short-term boost of immunity rather than a long-term therapeutic.

What Can We Learn From Expanded Access?

Meanwhile, some 2200 hospitals are participating in the expanded access program being led by the Mayo Clinic; more than 9000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the US COVID epicentre: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital — if it’s not being offered there, can you have them transferred?” she told Medscape Medical News.

When Northwell — through the New York Blood Bank — opened up donor registration, 800 people signed up in the first 24 hours, Brennan said. As of mid-May, 527 patients had received a transfusion.

Who’s the Best Donor and When Should Donation Occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom-free for 14 days, have a negative follow-up molecular test, and be virus-free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Casadevall writes in the Journal of Clinical Investigation article. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, from Pisa University Hospital in Italy, and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they write, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Shoham told Medscape Medical News. A reassuring point: even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Casadevall and Porofski have disclosed no relevant financial relationships.

Shoham has disclosed no relevant financial relationships.

Journal of Clinical Investigation. Published Published online March 13, 2020. Full text

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