Convalescent plasma. It’s an old term that’s recently resurfaced as we face a virus with no vaccine. Just this week, a study of 20,000 hospitalized COVID-19 patients who received convalescent plasma was published in Mayo Clinic Proceedings.
While convalescent plasma therapy might be promising for treating COVID-19 patients, it actually has a long history of success with many infectious diseases over the last century.
What is convalescent plasma?
To understand what convalescent plasma is, we first need to look at plasma. It’s the part of blood that remains after red blood cells, white blood cells, and platelets have been removed. Plasma is ~90% water but also contains coagulants, salts, enzymes, antibodies, and proteins.
Convalescent plasma is plasma extracted from animals or humans who have recovered from the infection. This plasma is then infused into those currently with the disease. There, the antibodies bind to the infectious agents and the immune system triggers an immune response. However, protection doesn’t last a lifetime though it helps reduce recovery time.
Convalescent therapy uses the same plasma separation technology used in blood banks, meaning that it could be up and running fast: within a couple weeks. Patients who recover could donate blood where the serum would be isolated and screened. Then the convalescent plasma is injected into sick patients.
The history of convalescent plasma begins with diptheria
Over 100 years ago, Emil Behring was awarded the first Nobel prize for physiology and medicine for using plasma to treat diphtheria. This therapy was based on the observation that people who survived diphtheria infection never became infected again. Behring suspected that the body continually produced an antitoxin which prevents survivors from being infected again. He began by immunizing guinea pigs, rats, and rabbits with weakened forms of the pathogens behind diphtheria and tetanus to produce serum.
But these animals didn’t produce enough serum to protect humans. He had to use larger animals and turned to horses. In 1891, convalescent plasma was first successfully used against diphtheria.
Convalescent plasma subsequently became solutions against tetanus, rabies, and snake venom. In the 1940s and 1950s, antibiotics and vaccines began to replace convalescent plasma as treatment options. However, it’s still useful in cases where there isn’t a vaccine, like COVID-19.
Over the last century, doctors have experimented with convalescent therapy for measles, mumps, polio, and influenza.
Measles
In 1934, a student at Pennsylvania boarding school became sick with measles and had exposed 62 others. The student recovered and convalescent plasma was harvested from the student and given to the other students. Only three developed mild infections.
1918 influenza outbreak
Fatality rates were cut in half for patients who were treated with blood plasma than those that weren’t. A meta-analysis of studies published between 1918 and 1925 showed a decreased case-fatality rate in the treated group (16%) compared to the non-treated group (37%). It was particularly effective if they received it early, before their own immune system could overreact and damage organs
Ebola
A study in Guinea evaluated 84 patients who received convalescent plasma within two days of diagnosis. When compared to 418 control treated patients in the same facility, there wasn’t an improvement in mortality rate in the treated group though those treated with convalescent plasma had decreased viral loads. Another study out of Sierra Leone showed a lower fatality rate (27.9%) for those treated with convalescent whole blood versus those that were not (44%).
Severe acute respiratory infection (SARS)
A meta-analysis of 32 studies of SARS and influenza infection showed that mortality rates drop when convalescent plasma is given early after symptom onset.
Convalescent plasma to treat COVID-19
By March 2020, convalescent plasma was already used in Shanghai to treat COVID-19 and it was being tested by many groups such as Takeda and Johns Hopkins University.
Now, over 140 clinical trials are recruiting COVID-19 patients to study effects of convalescent plasma and nearly 2,500 hospitals are participating in the U.S. COVID-19 Expanded Access Program for collecting and providing convalescent plasma to patients across the U.S. This large study led by the Mayo Clinic resulted in their conclusion that convalescent plasma treatment is safe in COVID-19 patients and that earlier administration of plasma more likely reduces mortality.
Caveats to convalescent plasma therapy
Many of the previous studies in the last century and the recent examples with COVID-19 do have some caveats. It’s important to keep in mind that many of these reports are case reports, and not randomized trials, large scale, and often without a placebo group. For the COVID-19 the patients were treated through the expanded access program and not randomized into a clinical trial with a treatment group and placebo group.
Despite these successes, there’s still concerns about convalescent plasma. Antibody-dependent enhancement (ADE) can occur where non-neutralizing antibodies bind the virus and receptors on immune cells. In ADE, the virus enters and replicates in the immune cells and ultimately spreads the infection. Another concern is that pre-formed antibodies from the plasma could block a person’s immune response.
As the medical community searches for appropriate antivirals and works towards a vaccine, convalescent therapy serves as an interim option.
Further reading:
Coronavirus: what is plasma therapy? The Conversation, 2020.
Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS, 2020.
