The Peculiar 100-Plus-Year History of Convalescent Plasma

In March of this year, as the COVID-19 outbreak raged in New York and after several National Basketball Association players tested positive for the disease, at least four players offered to donate their blood to science. More specifically, after recovering from COVID-19 they offered to provide their blood, and the antibodies in it, for an experimental treatment called convalescent plasma. Media outlets from ABC to Yahoo picked up the news, often with complimentary coverage. At the time, a convalescent plasma program spearheaded by the Mayo Clinic was just getting underway, and the athletes donated to it.

By August, the Mayo Clinic program had provided tens of thousands of Covid-19 patients with access to the therapy. In a preprint study posted August 12, scientists who analyzed more than 35,000 patients said the treatment appeared to show some benefits for early treatment of people with severe cases of the disease. “Transfusion of convalescent plasma with higher antibody levels to hospitalized COVID-19 patients significantly reduced mortality compared to transfusions with low antibody levels,” scientists wrote in the paper. “Transfusions within three days of COVID-19 diagnosis yielded greater reductions in mortality.”

Critics, however, pointed out the research was done without establishing a placebo group. “The lack of high-quality trials in making clinical decisions about how to treat patients with coronavirus infection is a national embarrassment,” Steven Nissen a clinical trialist at Cleveland Clinic told STAT. “Here we have another non-randomized study, NIH-funded, and uninterpretable.” Researchers said that the study enrolled participants that otherwise might have participated in randomized controlled trials, which are necessary to know if the therapy truly improves outcomes for severely ill COVID-19 patients. Many patients did not want to take the risk of being placed in the placebo group of such a study, opting for the Mayo Clinic’s program instead.

Then, in late August, the Food and Drug Administration (FDA) gave emergency use authorization for convalescent plasma as a treatment for Covid-19, after stating just a few days earlier that the agency did not have enough data to issue such a declaration. The commissioner of the FDA, Stephen Hahn, appeared with President Trump at a press conference and said the treatment could save 35 out of every 100 people who contract the disease, apparently based on analysis of that same Mayo Clinic study. After widespread criticism that Hahn misrepresented the data by overestimating the benefits of the treatment—he communicated the numbers as an absolute survival benefit, rather than as a relative difference between two groups in the study—the commissioner walked back his statement. “I have been criticized for remarks I made Sunday night about the benefits of convalescent plasma," he wrote on Twitter. "The criticism is entirely justified.”

While convalescent plasma is the latest treatment to dominate the Covid-19 news cycle, the therapy has a long history going back more than 100 years. In the late 19th and early 20th century, convalescent blood was used to treat measles, Spanish influenza, and many other diseases. After World War II, plasma became a hugely valuable part of the pharmaceutical industry, which used it for products to successfully treat everything from bleeding disorders to immune deficiencies to shock. Past experience suggests convalescent plasma may not be a cure-all for Covid-19, however, as its use was eventually phased out for most diseases. Still, every time the world faces a novel disease threat, the treatment seems to experience another 15 minutes of fame.

“So, it’s not surprising that it keeps coming up,” says Scott Podolsky, a primary care physician at Massachusetts General Hospital and a medical historian at Harvard Medical School. “It seems to currently be coming up as something that’s promising… but it’s still logistically difficult to administer.”

The history of plasma’s use as a treatment began in the 1890s when the German scientist Emil von Behring purposefully exposed horses to the toxic bacteria that causes diphtheria. After the animals had recovered, Behring used their antibody-rich blood to successfully immunize humans against the deadly disease. It was a major breakthrough, among the first demonstrated uses for ‘serum therapy’—the use of blood from an animal or human who had recovered from a disease to treat that disease in another animal or human. Serum therapy, as it was often called at the time, uses the same principle as convalescent plasma today, although scientists could not yet separate plasma from whole blood. In 1901 Behring won the first Nobel Prize in Physiology or Medicine for his achievement.

The same year Behring won the Nobel Prize, Francesco Cenci, an Italian physician, retrieved blood from a man who had recovered from measles and used it to inoculate four children. Those children did not end up contracting measles during an ongoing outbreak unlike their siblings, according to a finding published recently by Piero Marson, a physician at the University Hospital of Padova, Italy. Five years later during another local measles epidemic, Cenci tried injecting severely ill children with convalescent blood once again and found the therapy helped them recover more quickly. Cenci’s work may mark the earliest known use of convalescent serum as a therapeutic, rather than preventative, treatment, Marson writes.

Serum therapy was more widely adopted after the 1918 influenza pandemic, when it was tested as a treatment for severely ill flu patients. At the time, studies conducted across the United States suggested this treatment led to reduced mortality for humans with the flu who had also developed pneumonia, according to a 2006 meta-analysis of old research. Early 20th century researchers did not conduct randomized, blinded clinical trials, however, so these studies wouldn’t meet today’s publishing standards.

In the 1920s and 30s, cities and towns across the country built “serum depots,” says Susan Lederer, a medical historian at the University of Wisconsin-Madison. These hyperlocal blood banks collected and helped distribute blood from disease survivors. While not much is known about these sites, Lederer posits they may have functioned similar to milk depots, responsible for the safe collection and distribution of milk in municipalities. Convalescent serum therapy was used to treat many feared diseases during this period, including pneumonia, measles, meningitis, plague, and scarlet fever. Serum therapy also formed the basis for state-led pneumonia control programs in the late 1930s, adds Podolsky.

“Before vaccines, if you had a measles epidemic, convalescent blood seemed to be an effective therapy,” says Lederer. “Now when I said ‘seemed,’ [it’s] because of course there’s no randomized controlled trials of these…. But it was something people could do.”

At the time, people made careers out of being a blood donor, says Lederer. Donors even organized a labor union recognized by the American Federation of Labor, although they had to promise not to strike because they rendered a life-saving service, she says.

People who donated their blood for free were often celebrated in the press, Lederer says. In the mid-1930s, a woman named Rose McMullen allowed herself to be purposefully infected with streptococcus bacteria so that she would generate antibodies and her blood could save her niece from a life-threatening infection. She went on to give her antibody-infused blood to many others as well, her heroic acts written up in laudatory articles. Newspapers referred to her as the “lady with the golden blood.” McMullen’s fame soured in later years—she may have ended up scamming some patients’ families by offering transfusions for illnesses her antibodies could not treat, according to Lederer.

Separating plasma from whole blood became possible for the first time during World War II, when biochemist Edwin Cohn figured out how to split blood into its component parts. A prototype of the fractionation machine he used is now stored in the Smithsonian’s National Museum of American History. Plasma on its own is much more shelf-stable than whole blood, making it possible to ship blood overseas to provide life-saving transfusions to soldiers.

When war broke out in Western Europe, the United States set up the Blood for Britain program to provide the British military with much-needed plasma for blood transfusions. The program was run by Charles Drew, a physician, transfusion pioneer, and the first African American to earn a medical degree at Columbia University. After the war, Drew was recruited to develop a blood bank program for the Red Cross, but he soon resigned over racist policies that insisted on the segregation of blood by donor race.

After the war, medical advancements lessened the need for convalescent blood as a treatment for infectious diseases. For the most part, it was supplanted by other treatments, says Podolsky. In the post-war period, production of penicillin and other antibiotics took off, and eventually scientists invented antiviral medications. Scientists also created preventative vaccines to protect against old threats, like measles and influenza.

But the growing pharmaceutical industry found uses for plasma elsewhere. Plasma was a crucial component in a revolutionary treatment for hemophilia, a rare blood disorder where patients lack the clotting factors, normally found in plasma, needed to prevent bleeding. By taking the plasma of healthy donors, researchers could create a medication full of these missing factors that patients could administer themselves with a quick injection for a temporary fix. Making the medication at a commercial scale required pooling the plasma from thousands of individual donors to create a highly-concentrated product, says Stephen Pemberton, medical historian at the New Jersey Institute of Technology. Insufficient safety measures made the blood supply susceptible to hepatitis and HIV, decimating hemophiliac communities before the supply was cleaned up in the 1990s.

Over time, plasma became a big business for the United States. As science journalist Douglas Starr details in his book Blood and a recent article for Elemental, the demand for plasma led to decades of shady business tactics. Plasma collectors set up shoddy centers in poor communities and later in Haiti and Central America to try to extract enough blood plasma to feed the demand for hemophilia treatments. These centers were eventually replaced with better, cleaner outfits, writes Starr, but they set a precedent of exploiting the poor and vulnerable. The United States is still one of the few countries that allows plasma donors to be paid, and a recent ProPublica investigation revealed dozens of donation centers located at the U.S.-Mexico border. Selling plasma is banned in Mexico but in the United States, donors can give plasma up to 104 times a year; donating too often can be bad for the immune system, ProPublica reports.

Today, the U.S. is the top producer of plasma products in the world, says Pemberton, with blood accounting for 2 percent of the country’s exports in 2017. Convalescent serum therapy is still used as a treatment today for a few illnesses, like Argentine Hemorrhagic Fever, says Podolsky. Primarily, however, plasma is used to treat certain types of shock as well as to create treatments for bleeding disorders and antibody deficiencies—which can negatively impact the immune system, multiple sclerosis, and other conditions.

“Plasma’s liquid gold, and ounce per ounce it’s one of the most precious commodities on the market,” says Stephen Pemberton, echoing a phrase Starr also used to describe the substance.

In recent years, convalescent plasma has also reemerged as a possible therapy during outbreaks of novel diseases. In 2006, concern about a widespread outbreak of H5N1 prompted the meta-analysis of serum therapy during the 1918 pandemic. Around the same time, plasma was used to treat SARS patients, with a small study indicating the substance helped reduce hospital stays for patients who received it. An experimental treatment for Ebola in the 2010s that dramatically improved the condition of two Americans with the illness also had its roots in serum therapy, wrote Podolsky in a 2014 article in Annals of Internal Medicine.

As the debate around Covid-19 treatments rages on, the discussion of convalescent plasma largely mirrors the past. On social media and the news, many outlets celebrate plasma donors like newspapers celebrated Rose McMullen in the early 20th century, says Lederer. While physicians and patients embrace the treatment, trying whatever they can to save patients, there is still limited research proving its effectiveness. And if it does prove effective, plasma will be harder to scale up than other treatments because it is so dependent on limited donations, says Pemberton. Scientists are also intensely focused on the vaccines and medications that could eventually replace plasma as a first line treatment.

Perhaps this old therapy will prove to be a game-changing treatment for COVID-19. Or perhaps it will eventually be shelved in favor of other therapies, before being brought out again to confront the next infectious disease crisis.