April 3, 2020 Johns Hopkins in Baltimore was given FDA approval to test a blood plasma therapy to treat COVID-19 patients. The trial will use blood serum (a straw colored liquid left after the clotting of plasma), collected from recovered COVID-19 patients. This trial will evaluate convalescent serum as a preventive treatment for infection in people at high risk of contracting disease, and as a potential treatment for people critically ill with COVID-19.
How does this work?
When we get better from an infection, we have made antibodies, and these tiny molecules protect us from reinfection at some point in the future. Antibodies are found in the blood serum. This therapy is therefore about harnessing the immune system of one person who has recovered from COVID-19 to help another person either prevent getting ill in the first place, or possibly recover from active infection.
Passive antibody therapy occurs with administration of antibodies against a target such as a virus, to a person who is susceptible to that virus. This is done to prevent or treat the infectious disease the virus might cause. We could contrast that to active vaccination, which occurs when for example, a protein from a virus is injected into a person to provoke an immune response to that virus. Doing that takes time, and may vary depending on the biology of the person getting the vaccination.
According to the Johns Hopkins based Health University News, Arturo Casadevall, M.D., Ph.D., Johns Hopkins Chair of Molecular Microbiology and Immunology has worked with physicians and scientists from around the United States “to establish a network of hospitals and blood banks that can collect, isolate, and process blood plasma from COVID-19 survivors.” The FDA, which is allowing emergency authorization of convalescent plasma as an investigational new drug (IND), notes “it is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic.” (footnote 1, and 2)
The history of passive immunization
The concept of using convalescent plasma is not new. Doctors have long recognized that with most illnesses there will be some people who do better than others. In the case of an infectious disease outbreak the same is true. The question is why.
Much of the answer has to do with the immune system, the body’s defense against infection. It has been shown that some people mount a more robust, or more effective immune response, than other people who might succumb to the same infection.
The therapy proposed here goes back at least to the 1890s, when it was shown that serum from rabbits previously exposed to tetanus toxin could be used to prevent tetanus in other rabbits exposed to the toxin. The technique was also shown to work with diphtheria toxin. Building on this it was shown that increasing from small to larger doses of bacterial toxins such as those in diphtheria and tetanus could induce an animal to develop immunity against larger, lethal doses. This led to mass production of serum in dairy cattle and horses for the treatment of diphtheria. It also led to the concepts of active and passive immunization, and to the field of humoral (antibody) immunity. Nobel prizes were awarded for these history-changing discoveries.
In the early part of the 20th century, physicians would often try to contain outbreaks of viral diseases such as measles, mumps, and polio by treating exposed people with convalescent serum. During the 1918 influenza pandemic, serum from recovered patients was used to treat some acutely ill influenza victims, and to treat people who had been exposed. By the 1920s it became very common to treat pneumococcal pneumonia with serum form horses. Over the next few decades clinical benefit was also seen with this technique in the treatment of Haemophilus influenza B, and meningococcus. There were multiple related therapies over the years.
An expert in the field
Dr. Casadevall discussed how doctors of the early 20th century used convalescent serum to prevent outbreaks of infectious disease on the Johns Hopkins Bloomberg School of Public Health podcast Public Health On Call. He noted that the antibodies we make with our immune system during an infection are “why people only catch measles once, and (why) they’re protected for the rest of their lives.” When an epidemic decades ago was starting, doctors “would find somebody who’s immune, somebody who’s recovered from the illness, ask him to donate blood, they would separate the blood and the serum, and then they would give small amounts of the serum to people who are vulnerable, that is, those who have been exposed, those who are likely to have caught the disease. And, it was quite effective.”
Convalescent serum was used in 1934 for example, to stop an outbreak of measles in a Pennsylvania preparatory school. In that case the serum taken from one recovered boy was used to treat 66 other boys who had been exposed. Each boy was given only 5-10 mL of serum. “When you have a disease like measles, approximately 25% of the kids will get it. It’s one of the most infectious contagious diseases that we have. And…only 3 children developed measles, even though they expected numbers would have been a quarter of the 66 children,” (17 of them). The 3 boys that had measles wound up having mild cases due to the treatment. “When vaccines came on board in the 1960s this practice was both stopped and forgotten.”
With COVID-19 many people are going to do well, and are going to make antibodies to the coronavirus. The plan is to use blood banking processes to prevent the spread of other diseases, and give small amounts of safe convalescent serum to healthcare workers, first responders, people caring for others with coronavirus at home. Convalescent serum therapy is more effective for prevention than treatment. However, it can be given after disease has already started, but there were some hard lessons learned decades back.
When antibody therapy was used to treat streptococcal pneumonia doctors found if it was given in the first few days of symptoms good results were seen, though it seemed to have much less, or no value if given later than that. One speculation as to why has to do with the amount of antibody needed. To prevent disease people need very little antibody because the number of organisms infecting a person is usually very low. Alternatively, once disease has developed in a person and cells are making copies of the infectious agent (bacterium or virus), the number of particles in the body is very high, which would require more antibodies and thus, more serum.
Conclusion
Convalescent serum sounds very promising, especially as a protective strategy for those who have likely been exposed to the virus that causes COVID-19. It seems less likely to be helpful in those with fulminant disease.
Larger doses of convalescent plasma may be helpful. Shen, et al. reported in the March 27 issue of JAMA that doctors in China treated 5 critically ill patients on ventilators with laboratory-confirmed COVID-19 by giving convalescent plasma transfusion. There were improvements in the first week, and by 37 days after infusion, 3 had been discharged from the hospital, and 2 were in stable condition. This is interesting, because the fatality rate of COVID-19 patients on a ventilator is high. It is a hopeful sign.
Given all of these points, even if convalescent serum is helpful in limiting the spread of an outbreak, it is probably a stopgap measure. There is a massive worldwide research effort aiming to give stronger therapies, such as drugs to inactivate coronavirus, monoclonal antibodies-which are usually superior to convalescent serum (think silver bullet versus shotgun), and vaccines. The problem is the time it takes to develop these interventions. Convalescent serum may be a much faster option. That is probably why this is also being tried around the world.
FOOTNOTE 1: The FDA has significant “Considerations for healthcare providers interested in obtaining COVID-19 Convalescent Plasma for Use under IND.” These include using COVID-19 convalescent plasma collected from recovered individuals if they are eligible to donate blood under the Code of Federal Regulations used by blood banks. Evidence of COVID-19 should be documented by a laboratory test either by a diagnostic test (e.g., nasopharyngeal swab) at the time of illness, a positive serologic test for SARS-CoV-2 antibodies after recovery, if prior diagnostic testing was not performed at the time COVID-19 was suspected. The donors must have either complete resolution of symptoms at least 28 days prior to donation, or complete resolution of symptoms at least 14 days prior to donation, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. In terms of recipients of the blood serum, the FDA requires laboratory confirmed COVID-19, with a severe or immediately life-threatening COVID-19 (specific criteria on the FDA website).
FOOTNOTE 2: This study in Northern China in 2003 evaluated 99 convalescent serum samples from patients 35-180 days after the onset of symptoms. Anti-SARS antibodies were detected with three lab tests in 87 of the samples. Zhang, et al., A serological survey on neutralizing antibody titer of SARS convalscent sera. J Med Virol. 2005;77(2):147-50.
