How a century-old blood therapy turned into a new way to fight COVID-19
Last week the US Food and Drug Administration (FDA) approved the experimental use of blood from recovered COVID-19 subjects as a treatment for newly infected patients. Known as convalescent plasma therapy, the treatment harks back to the late 19th century, and doctors today are suggesting it may be the stop-gap we need to hold the virus at bay while more complex treatments and vaccines are developed.
A very special juice
In the 1890s German scientist Emil Behring pioneered a novel treatment for diphtheria. Behring, along with a Japanese physician named Kitasato Shibasaburō, discovered that blood serum from animals infected with certain toxins could be infused into humans providing treatments for various illnesses.
Behring described these protective molecules at the time as "antitoxins," and spent the rest of the decade optimizing the process. He ultimately found horses to be the most efficient animal for producing large volumes of serum antitoxins. In 1901 Behring won the very first Nobel Prize in Physiology or Medicine for his work developing these diphtheria serum therapies.
Today we understand how this kind of treatment theoretically works, as we understand how an organism’s immune system generates antibodies to fight off certain infectious agents. However, over a century ago, the field of immunology was still young, and scientists didn’t understand exactly how serum therapy could be working. Behring himself referred to blood as, “a very special juice” and used terms such as disinfectant to describe how his serum therapy healed patients.
Across the first few decades of the 20th century the treatment became known as convalescent plasma therapy, and was frequently utilized in times of infectious disease outbreak. Blood products from recovered patients were common treatments for everything from measles and mumps to polio.
The treatment was widely deployed during the Spanish flu pandemic in 1918. A 2006 meta-analysis examining eight studies published between 1918 and 1925 suggested convalescent plasma therapy significantly reduced mortality rates in cohorts receiving the treatment.
The 2006 study of course cites significant limitations in interpreting these results, as recorded case studies from the early 20th century do not have the methodological rigor of modern research practices. These were not blinded, randomized, or placebo-controlled trials. Control groups were calculated by simply counting untreated patients in the same hospital or ward.
Bearing all this in mind, the meta-analysis suggested the overall case-fatality rate among patients treated with convalescent plasma was 16 percent. The case fatality rate in the untreated control group was 37 percent.
This treatment method ultimately fell out of common use by the mid-20th century. From the discovery of antibiotics to the development of sophisticated vaccines, scientists eventually produced more effective modes of medical treatment.
But … new treatments take time to develop, trial and deploy. And when a new virus starts spreading through the population we don't really have the luxury of time.
It worked then, it may work now
In the early 2000s a new respiratory coronavirus appeared in China. The virus was named SARS and the world suddenly faced a pandemic unlike anything it had seen in decades. Ultimately, SARS was contained with less than 10,000 cases recorded between 2002 and 2004.
Facing an entirely new virus, with a high fatality rate and no treatment options, doctors in Hong Kong conducted an impromptu convalescent plasma study, inspired by similar recent case studies out of Africa demonstrating potential efficacy treating the ebola virus. Eighty patients were administered convalescent plasma across a two month period during the 2003 peak of the SARS outbreak in Hong Kong.
The overall fatality rate among the treated cohort in the study was 12.5 percent. The general fatality rate in Hong Kong across the same period of time was 17 percent. However, perhaps more importantly, the study found the timing of the convalescent plasma therapy significantly affected its success. Those patients receiving the treatment early (in this case less than 14 days after the onset of symptoms) displayed much better outcomes than those given the treatment later.
A more recent metastudy exploring the effect of convalescent plasma therapy, which incorporates clinical reports spanning the Spanish flu to SARS, concluded a striking 75 percent reduction in overall mortality among patients treated with the therapy. That 2015 study also confirmed early initiation of the therapy seems to be critical in whether it works or not.
The COVID-19 stop-gap
Early in the COVID-19 outbreak Johns Hopkins immunologist Arturo Casadevall rekindled the idea of convalescent plasma, following reports the treatment was being trialled in China. Casadevall not only proposed the century-old therapy as a potentially useful early treatment in patients recently diagnosed with the virus, but he suggested it could be a useful prophylactic for health care workers in frequent contact with confirmed cases.
“It is anticipated that convalescent serum will prevent SARS-CoV-2 infection in those to whom it is administered,” writes Casadevall and colleague Liise-anne Pirofski, in a recently published viewpoint. “If this is established, individuals who receive convalescent sera may be able to avoid a period of quarantine. This could allow them to continue their critical function as health care providers. Convalescent sera could also be used to prevent disease among family members caring for COVID-19 patients at home.”
Casadevall and his Johns Hopkins team quickly began establishing the infrastructure to investigate this treatment, and the FDA promptly responded a few days later, not only fast-tracking clinical trial approvals for convalescent plasma testing, but also allowing immediate compassionate use provisions. This offers doctors the ability to administer the treatment to patients outside of the limitations of a clinical trial, provided certain conditions are met.
The FDA requires a number of eligibility considerations, including a rule stipulating blood donors have been free of symptoms for at least 14 days before giving blood. Individual uses of convalescent plasma must still be approved by the FDA on a case by case basis.
In association with Casadevall and his Johns Hopkins team, other scientists from around the United States are joining forces to rapidly kick off trials investigating the optimal way to deploy this treatment. Michael Joyner, from the Mayo Clinic, and Jeffrey Henderson, from Washington University School of Medicine in St Louis, are both supplying institutional resources to get these clinical trials moving.
“This is something that can be done very quickly, much faster than drug development, because it basically involves donating and transfusing plasma,” explains Henderson. “As soon as we have individuals who have recovered from COVID-19 walking around, we have potential donors, and we can use the blood bank system to obtain plasma and distribute it to the patients who need it.”
There are still plenty of questions that need answering before the treatment can be broadly deployed. How much antibody needs to be detected in the blood of recovered patients to make for an effective serum treatment? How much convalescent plasma needs to be administered to treat the disease? When is the optimal time to administer the treatment? Does the treatment offer any reliable immunity in subjects who haven’t contracted the virus?
Casadevall is confident answers to these questions can be found quickly, but he stresses it will take resources to move fast.
"It's all doable—but to get it done it requires effort organization, resources … and people who have recovered from the disease who can donate the blood," says Casadevall.
No one is suggesting this kind of treatment is the panacea for COVID-19, but instead Casadevall and his colleagues reiterate how useful this may be as a stopgap measure. More sophisticated new treatments and vaccines are likely to take 12 to 18 months to produce, at a minimum, so developing methods in the short-term to improve patient outcomes and help prevent further spread could profoundly lighten the load on our ever fragile health care networks, and save lives.
On top of that, producing and deploying convalescent plasma treatments only require pre-existing blood bank networks. The current blood collection and supply system in the United States could be swiftly redeployed to begin gathering donations from recovered COVID-19 patients. Once Casadevall and his colleagues can verify best practice for COVID-19 treatment, convalescent plasma could be rolled out to a huge volume of patients within months, flattening the transmission curve and buying more time for scientists to work on an effective vaccine.
“Clearly, the use of convalescent serum would be a stopgap measure that could be used in the midst of the current epidemic,” Casadevall and Pirofski write in The Journal of Clinical Investigation. “However, even local deployment will entail considerable coordination between different entities, such as infectious disease specialists, hematologists, blood banking specialists, and hospital administrators. Hence, as we are in the midst of a worldwide pandemic, we recommend that institutions consider the emergency use of convalescent sera and begin preparations as soon as possible. Time is of the essence.”