Last night, I logged onto a Zoom lecture sponsored by my great and good friends at the Secret Science Club. This was the 2020 Lasker Foundation collaboration with the SSC, and featured immunologist Dr Arturo Casadevall of Johns Hopkins University, who is chair of the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health.
Dr Casadevall's topic was the Deployment of Convalescent Plasma against COVID-19, and the good doctor began his lecture with a history of the use of serum/plasma in combatting disease. This historic overview started with an account by Thomas Hall Shastid of the use of antitoxin to combat an 1890s diphtheria outbreak. The disease often creates a 'pseudomembrane' in the patient's throat which obstructs breathing, and the treatment typically involved a tracheotomy. While accompanying a physician, Dr Shastid observed the use of an animal-derived antitoxin on a patient:
I found the boy very ill, the whole back of his throat being like white velvet. I had never used the new remedy before, but determined to try it to save the boy's life. I injected a small quantity under the skin of the stomach and watched the throat. I can only compare the marvellous result to the disappearance of snow under a hot sun. After the second dose every trace of the membrane disappeared, and the boy soon recovered.
German physiologist Emil von Behring discovered that immunity to disease can be transferred by serum and Danish physician Johannes Fibiger carried out the first randomized controlled trial in medicine in 1898 to evaluate diphtheria antitoxin. At the time, researchers didn't know that antibodies were proteins. Dr Casadevall noted that serum therapy is difficult to use, serum typing is needed to apply it. Plasma therapy, which requires blood typing, also came into use- there is no therapeutic difference between plasma and serum. Plasma, is simply obtained from blood, serum derived from coagulated blood and separated out- both contain antibodies.
Antibody therapy was used in 1918 to treat influenza-related pneumonia, and in 1934 to combat a measles outbreak in a private school. Recovery tends to be rapid with antibody treatment. The antibodies were sourced from animals or from human convalescents. From 1940-1950, with the introduction of antimicrobial drugs such as tetracycline and pennicillin, antibody therapies to treat infectious diseases fell off- with improper screening, other pathogens can be introduced to patients. Hepatitis was discovered through the use of plasma treatment, an outbreak led to a backlash against plasma use. Antibody therapy was still used to treat certain cancers.
There are three principles involved in antibody therapy:
1. Specificity- antibody use must target specific pathogens.
2. Quantitative- a sufficient amount of antibodies must be used.
3. Temporal- early treament is necessary for efficancy.
These three principles are necessary for successful therapeutic use. During the recent Ebola outbreak, an antibody therapy trial was not very effective because the amount of antibodies in the serum was insufficient. A recent flu therapy trial was unsuccesful because it started too late.
Dr Casadevall then shifted to the topic of the COVID-19 pandemic, beginning with a brief timeline, beginning in January, when there were increasing concerns that the outbreak was not containable. He noted that the history of antibody-based therapies was not well known. Accounts of the public response didn't mention plasma therapy. He realized that he needed to get the word out about antibody therapy, and shopped an article around to various media outlets. Eventually WSJ publihed op-ed and the dissemination of information followed. Even non-immunologists who used plasma in surgery spread the information.
Initial contacts created the leadership of the plasma project- not necessarily composed of immunologists. A National COVID-19 Plasma Project website was built by Amazon in March. In March 2020, things were moving fast as Michael Bloomberg and Maryland governor Larry Hogan allocated money to the project. On March 27, the first patient was treated with plasma therapy. The FDA exteded ab Extended Access Protocol and contracts with the Mayo Clinic to allow access to these therapies.
Dr Casadevall noticed that there was an imminent science crisis- the literature contains papers suggesting that antibodies can enhance symptoms. He looked at the literature and noted that the dangers were overblown, most therapies were successful. He turned to the wisdom of antiquity, but got conflicting messages: "fortune favors the bold" but "boldness is the beginning of action but fortune determines the end".
The first plasma therapy for COVID-19 took place at Houston Methodist Hospital. Thousands of COVID-19 patients were treated in the US, most occurring outside randomized clinical societies. Members of New York's Orthodox Jewish communities, hit hard and early by the outbreak, were mobilized to donate plasma. Is antibody therapy safe? It's as safe as typical plasma therapies. Most of the plasma in hospitals is used for bleeding problems. Safety in therapeutic use clears the way for other therapies, including vaccines. Is antibody therapy working?
There are many encouraging reports of good patient outcomes. In an Extended Access Protocol Data Analysis, 35,000 patients were analyzed. One study showed that, if plasma is given in first three days, mortality is 27% lower than if given after day for. The dose must be specific to SARS-Cov-2, and the dose must be sufficient. Increasing numbers of anecdotal case reports show efficacy of antibody treatment in immunocompromised individuals.
Dr Casadevall noted that there are strong precedents for efficacy based on historical use. This is strong theoretical support for efficacy based on knowledge of antibody action, and there are encouraging signs from clinical trials. He told us that his opinion has become more optimistic over past few months. He drew our attention to studies of prophylaxsis protocol- typically giving plasma to family members of patients. Early administration enhances immune response, late administration can help lower viraal loads. Antibodies made during early and late convalescence are different, but they tend to lower viral load, inflammation, and respiratory effort. There are issues- poverty is a factor in receiving therapies. Controversies make the job harder but he focuses on the science. The FDA, though cautious, was ready to go ahead with plasma therapy by June. He is avoiding political statements, but has nothing but good things to say about the government scientists.
He concluded with a recap of his observations throughout the COVID-19 outbreak, hitting on the following points: Convalescent plasma is available throughout the US, plasma use in the USA is under Emergency Use Authorization, plasma supplies are plentiful as a result of recruitment campaigns, deployment of plasma is driven by physicians and scientists- this is not a money making endeavor. There are no pharmaceutical sponsors- this involves local generated therapy. All plasma units are different, defining useful units is difficult. There is a great advantage to antibody therapy- it is low tech, easily deployable, and inexpensive. Antibody therapy will continue to be used against COVID-19 and for future epidemics. The current challenge is to figure out how to use it effectively for future knowledge. Our plasma experience established the safety of antibody therapies, cleared the way to mAbs, gamma globulins, and vaccines. Currently antibody therapy remains the only therapy for COVID0-19, but is a stopgap until better treatments, such as a vaccine, are available.
The lecture was followed by a Q&A session. The best plasma seems to be from symptomatic patients who do not require hospitalization. If you have had COVID-19, please donate. How was diphtheria antitoxin available in the 19th century? They used cultures similar to bacterial cultures, but did not know what antibodies were. What about post-COVID patients? Dr Casadevall urged his friends at Methodist Hospital to follow up on COVID-19 patients on a long-haul basis. Plasma units differ- even one patient can produce two diverse units on two different days. How many units are needed? The typical does is 200cc, but units come in different sizes. It seems that the more one gets, the better the outcomes are. Dr Casadevall noted that most of the effort is grassroots, driven by scientists, doctors, and community organizers. He is optimistic- if we have a good plasma therapy, we will likely end up with a good vaccine. Humanity has never seem this virus before, but we are successfully fighting it off. Can we pool plasma units to make them more complex and more standard? There is a risk as more plasma is used- one unit could contaminated a pooled plasma supply... this happened in the 1930s with hepatitis. Zika went away before plasma study, Ebola plasma therapy was insufficient. It took a month to get plasma studies set up for COVID-19. This current model will ensure more rapid responses in the future, giving a big boost to antibody therapies, even for illnesses as the seasonal flu. Does it remove the incentive for randomized control trials? Criticism was driven by doctors in community hospitals. There are ethical concerns- randomized control trials are needed to establish efficacy of plasma, but when there a crisis, it's ethical to use a generally safe therapy. A lot has been learned and no harm has been done. Remdesivir reduces viral replication, it and other antivirals have had a great effect on treating HIV and other virals.
Some Bastard in the Zoom audience asked: What factors distinguish viral pathogens to which the body can gain some degree of immunity, such as chicken pox, and viral pathogens for which the body does not gain such immunity? every virus is different- to survive, they need hosts, so they are experts at defeating immune systems, or they will go extinct. Every virus has a different strategy, some are fast breeders. COVID-19 is new to humanity, and we are fighting it, Another question involved knowledge of virus genetics and the role of mutation- plasma use creates selection pressure, the evolution of the virus is an open-ended question. Antibodies prevent access of virus by blocking proteins, viruses can mutate to chage their proteins. Once again, the Secret Science Club and Lasker Foundation combined to present an excellent, timely lecture. Kudos to Dr Casadevall, Margaret and Dorian, and the good people of the Lasker Foundation. Socially-distant air high fives all around!
The lecture was recorded, and will be available at a future date, but in the meantime, here's a video of Dr Casadevall discussing the state of antibody use to combat COVID-19:
Now, THAT is a perfect intersection of science and current events, which is a perfect example of the Secret Science Club sweet spot.