In May this year, the Indian Council for Medical Research (ICMR) approved 38 hospitals across the country to participate in PLACID, or convalescent plasma therapy (CP) trials. Some 450 patients were reportedly recruited to study if plasma, or more specifically, the serum that is filtered from blood and shorn of blood cells could be used to treat moderate or severely sick COVID-19 patients. It is still unclear how many benefited. For something that bagged the first-ever Nobel Prize in Medicine in 1901, there is still much mystery around serum, the pale filtrate from blood that contains antibodies.
Though a disease that seems to only mildly sicken most of those infected, COVID-19 wreaks devastation in at least one out of seven afflicted. Globally, that accounts for at least two million people and many of the 700,000-odd who have succumbed to the infection. For many of the seriously afflicted, there isn’t a clear treatment course. Attempts at destroying the virus with anti-virals have largely failed and most drug-makers and research scientists are scouring their cabinets for any, even half-promising, therapy or intervention.
Elaborate defence
The trillions of viral particles that infiltrate the lungs can only be stopped, researchers reckon, if the body learns to recognise them early on. Usually, the human immune system that has evolved over 500 million years from the last common ancestry we share with sharks, has an elaborate defence that produces sophisticated proteins, or antibodies, to stymie an array of offending viruses or bacteria.
But SARS-CoV-2 is particularly insidious in that it manages to hoodwink the immune system and proliferate. Once jolted alert, the immune system acts in two ways: either it’s able to muster a regulated response or it acts in a frenzy that can often end up being worse than the disease, even resulting in death. To avoid that, it needs help. From another immune system that’s seen it all before and managed to thwart the coronavirus.
This fundamental insight, that the victorious convalescent body produced something in those who recovered from an infection, came a little over a 100 years ago from an ancient disease: the ‘plague among children’ that killed nearly two in five children in the 18th century. In 1883, Edwin Klebs identified the disease, diphtheria, as being caused by a bacterium now known as Corynebacterium diphtheriae . The disease would start out as an infection of the respiratory tract and the bacterium would secrete a toxin that injured and then destroyed cells. A thick grey substance, from the cellular waste secreted from battling the bacterium, would envelop the pharynx and stick to the tissues and obstruct breathing. The effects of this could travel as far the heart and kidneys.
Throughout various disease outbreaks in history, convalescent plasma therapy has always been a stop-gap measure until a vaccine becomes available
Active immunity
For most of the 18th and 19th centuries, the best shot at a cure — even for children — was to perform a tracheotomy to help breathing until the infection cleared out. But this too was mostly hit-and-miss. In 1890, a German scientist, Emil Adolf von Behring, and a Japanese researcher, Kitasato Shibasaburo, built on the work of several other scientists who had shown that when C.diphtheriae was cultured in a lab, it left a residual liquid which, when injected into animals, somehow protected them from infection. This was new.
Ever since Edward Jenner injected a cowpox virus into eight-year-old James Phipps in the 1790s and made him immune to the lethal smallpox, it was known that injecting parts of the right virus or parasitic life-forms could stimulate the body’s defences to protect against a future infection. This was active immunity.
But Behring found that you mostly didn’t actually need the virus or bacteria to mount a defence. ‘Sera’ or ‘serum’ contained some kind of ‘anti-toxin’ that appeared to protect guinea pigs re-exposed to lethal doses of the bacteria and toxin. It turned out that it was possible to ‘passively’ transfer the immunity in the guinea pigs to cure diphtheria in another sick animal by injecting it with that serum. Behring was conferred the first-ever Nobel Prize for Medicine “for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths.”
While not always victorious, this was certainly a weapon that opened up an entire vista that was immunology. The anti-toxins and the serum were portals to re-imagining the body as an eternal battleground between antibodies and antigens. The cliche, of a ‘magic bullet’, had its origins here, and was coined by another Nobel Prize-winning pioneer of immunology, Paul Ehrlich, to describe ‘antibodies’ that originate in the bone marrow and are constantly traversing the body in search of a target, or it’s very own custom antigen. The latter is the part of a foreign virus, bacteria or even another blood cell from another human being. Antibodies zoom in on antigens and, if they are the right match, click themselves snug like a key that’s found nirvana. Antibodies, or immunoglobulins as they are formally called, are highly specific and bind only to their own specific antigens.
Transferable asset
There are at least five kinds of immunoglobulins, and for every different disease — be it of viral or bacterial provenance — only some are helpful. The right antibody-antigen combination works well for a patient. A healthy immune system mass produces these key-like antibodies, and they prevent more antigenic viral particles from being made. They even facilitate a mass of other kinds of immune system cells — natural killer cells, macrophages, T cells — that can destroy and swallow whole residual infectious cells. To close the deal, once an infection has been thoroughly plugged, there are even ‘memory B cells’ (a class of antibodies) that are formed. They loiter around on the lookout for a recurrent infection, and if found, the blight is nipped quickly and so thoroughly that you on the outside wouldn’t even feel sick.
There are at least five kinds of immunoglobulins, and for every different disease — be it of viral or bacterial provenance — only some are helpful.
Behring and the early immunologists’ insight that immunity was a transferable asset, where a recovered patient’s antibodies extracted from their serum can be used on another patient, unfortunately works only fitfully. Satyajit Rath, an immunologist and faculty member at Indian Institute of Science Education and Research, Pune, listed out several reasons why convalescent plasma cannot always be a magic bullet.
For one, the amounts of such plasma are inevitably always very limited. This means it cannot be widely used and even proper clinical trials are difficult to do (in fact, very, very few have been done). Secondly, any such transfer from one individual to another poses the risk of transferring infections (hepatitis viruses, HIV, etc.).
Likewise, any blood/ plasma transfer has to deal with the possibilities of transfusion reactions as side-effects, making the whole process quite hard, more so when coupled with the fact that (unlike ordinary blood/ plasma transfusions) only a few people can be donors.
Then, there is the additional complication that every potential donor does not have enough of the right kind of antibodies. Antibodies bind to antigens but some can’t overwhelm them enough to prevent them from replicating. In fact, as has been observed in dengue and Zika virus infections, such antibodies end up being sabotaged by the virus and are used by them to gain entry into healthy cells in a phenomenon known as antibody dependent enhancement, aggravating disease.
What is actually useful to arrest an infection are the so-called ‘neutralising antibodies’ — those that not only bind but prevent the viral particles from replicating. Testing for neutralising antibodies in the plasma is an additional complication. “Finally, we have no idea, in most situations, just how much of neutralising antibody will be needed and therefore how much plasma to give. Given these factors, it is not surprising that it is always a therapy of last resort, and that few proper clinical trials have been done. It is likely to remain a hopeful/ wishful stop-gap measure,” says Dr. Rath in an email.
‘Serum sickness’
Early indications that plasma therapy was an untamed beast came from domesticated horses. Guinea pigs, in whom the original antibodies for diphtheria were tested, turned out to produce too little anti-toxin. So one needed bigger bodies. ‘Docile horses’ became the fall guys. However, in 1901— the same year Behring was awarded the Nobel — several children in St. Louis, U.S., died after being injected with horse-derived serum. It was traced to a horse infected by tetanus.
The cliche, of a ‘magic bullet’, had its origins here, and was coined by another Nobel Prize-winning pioneer of immunology, Paul Ehrlich
There also emerged reports of ‘serum sickness’, or an adverse reaction, among children inoculated with horse toxin. Though serum from horses is still used to produce anti-venom against snakebite, the many complications from using it for diphtheria meant that there wasn’t a substantial dip in diphtheria deaths until a combined vaccine for diphtheria, pertussis and tetanus became routine in the 1940s. “Horse antibodies can be given to people safely only once, by and large. They are different enough to generate an immune response to the horse proteins on their own, and a second injection would then trigger an allergic reaction... which is why all horse serum injections need allergy testing first,” says Rath.
Throughout various outbreaks of disease in history — polio, tetanus, to the more recent Ebola virus or the Middle Eastern Respiratory Syndrome — convalescent plasma therapy has always been an interim measure until a vaccine comes along. When the U.S. was racked by a series of polio outbreaks in the 40s and 50s, animal serum was the iffy last straw for doctors, until Jonas Salk’s polio vaccine proved successful (in what were then one of the earliest double-blind clinical trials) and then was mass-distributed.
In a 2016 edition of the journal, Blood Transfusion, a multi-author review notes: “Although many studies have reported the efficacy and safety of CP [convalescent plasma] infusion in the treatment of various infections (especially those caused by viruses), due to the lack of large-scale, randomised, well-designed clinical trials, we tend to consider CP an ‘empirical’ therapy.” “Most of the studies conducted so far... can only provide us with low-quality scientific evidence that may or may not be representative of the target populations.”
So, promising as plasma therapy may look, and several trials are indeed under way to test its potential for treating COVID-19, a century of experience allows only for sober optimism.
