Convalescent Plasma Therapy ( CPT) has been opted as an interim approach all over the world for the treatment of COVID-19 patients until the availability of drugs, vaccines and hyperimmune globulin. This is also known as passive immunotherapy because it may provide passive protective immunity to COVID-19 patients. It should be noted that this is an immediate transient treatment and doesn’t replace the long-lasting immune memory generated by a vaccine. CTP is based on a century-old idea in medicine and earlier has been used in a disease like Measles, Influenza, Flu, Hepatitis etc. It was used with success during the 1918 Spanish Flu. The World Health Organization (WHO) recommended its use against Ebola and issued protocols for its use to treat Middle East Respiratory Syndrome (MERS) caused by a virus from the same family as SARS-COV-2 that causes COVID-19. US Food and Drug Administration ( FDA) has approved CPT as an experimental therapy.
In CPT, a liquid portion of blood known as plasma from the completely recovered COVID-19 patient ( donor) containing the antibodies against the disease-causing infecting agent known as SARS-COV-2 ( Severe Acute Respiratory Syndrome Coronavirus-2) is administered to the COVID-19 patient ( recipient). The removal of plasma from recovered COVID-19 patient is usually done 14 days after recovery of the patients.
How the antibodies are produced in COVID-19 patient and how do they make the Coronavirus ineffective?
The antibodies are Y shaped proteins produced after the infection of SARS-COV-2. For this, proteins mainly the Spike proteins present on the surface of Coronavirus bind to the receptors ( which are antibodies) of B- cells of the immune system with specificity and then virus along with receptors get into the B-cells. After a long series of biochemical events, the B-cells undergo proliferation to form many cells. They are of two types—-Effector B-cells and Memory B-cells. Effector B-cells produce antibodies which bind to Coronavirus with specificity. This binding of antibodies to Coronavirus prevent it to bind to normal human cells such as lungs cells thereby preventing the spread of infection by Coronavirus. Through certain strategies the immune system involving antibodies and without them, kill the Coronavirus. Antibodies remain in the blood for months but effector B-cells undergo death in few days time. The important thing to remember here is that Receptor Binding Domain ( RBD) present in Spike proteins of Coronavirus actually binds to the receptors are known as ACE- 2( Angiotensin-converting Enzyme-2) present on the surface of normal human cells e.g. lungs cells and if antibodies are produced by B-cells against RBD, they bind to it with specificity and high affinity thereby not allowing RBD of Coronavirus to bind human cells receptor ACE- 2 resulting into very effective prevention of spreading of Coronavirus infection. The antibodies produced against the RBD of Coronavirus are known as neutralizing antibodies. If the plasma of recovered COVID-19 patient (donor) contains high levels of neutralizing antibodies, it’s considered to be very effective.
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The memory B-cells have the same receptors on their surface as the single progenitor B-cell from which they are derived on proliferation. They remain in the blood for a long time, in certain cases life long. Vaccines are actually administered to generate memory B-cells which on natural infection instantly recognize the Coronavirus through their surface receptors and give an immune response in a similar manner as described earlier.
Clinical trials to assess the safety and efficiency of Plasma Therapy in COVID-19 patients :
The top medical experts feel that Convalescent Plasma Therapy for the treatment of Coronavirus patients is at an experimental stage and only large scale randomized controlled trials can prove its safety and efficacy. A large clinical trial of 20,000 hospitalized COVID-19 patients who received plasma of recovered COVID-19 patients, was conducted in the USA and the results were published in June 2020 in Mayo Clinic Proceedings, USA. According to this study, the experimental plasma therapy was safe with less than 1% adverse outcome such as transfusion reactions. This study suggested that transfusion of plasma to the patients earlier in the disease may be beneficial and may reduce mortality. This study was made possible by the collaborative efforts of more than 2000 medical Institutions.
A small study from China showed that plasma therapy may lower the severity of the disease, improve the liver and lungs function and reduce inflammation.
In India, many states have already got approval from the Indian Council of Medical Research (ICMR) to use CPT as experimental therapy under strict conditions. ICMR cautioned that there’s no robust evidence to support it for routine therapy. In Delhi’s Max Hospital, 49 years old COVID-19 patient admitted in April 2020 was the first to receive the plasma therapy and then successfully recovered from the disease. Many states in India have started Plasma Bank to deal with COVID-19.
The ICMR has conducted a study on plasma therapy to assess its safety and efficacy when administered to COVID-19 patients. This is known as a PLACID trial which is a Phase II, open-label, randomized controlled trial with a sample size of 452 COVID-19 patients from 52 different participant Medical Institutions in India. The institutions have submitted their findings and ICMR is expected to release the results soon. According to media reports, most of the institutes found CPT to be effective in moderately ill patients.
The biochemical studies indicate that a few days after the infection of Coronavirus, a condition is known as ” Cytokines storm” sets in because of the excessive immune response. This results in heavy damage of lungs cells which manifests into difficulty in breathing. The clinical trials suggest that administration of convalescent plasma is very effective and beneficial before the onset of cytokines storm. In other words, it means that plasma therapy is effective until the time patient is moderately ill.
Since the ICMR’ s study on plasma therapy for COVID-19 patients is based on preferred research design i.e randomized controlled trials with a moderate number of patients, it can be expected that results will provide important and reliable information on safety and efficacy of CPT which may help the planners in Health Ministry to make certain decisions about its use in future for the treatment of COVID-19 patients.
The procurement of plasma from recovered COVID-19 patients has been a major problem for investigators in medical institutes involved in the ICMR study. This is because the donors ( recovered COVID-19 patients) are required to reach to the hospitals for the purpose of donating the plasma which they dislike for many reasons but mainly because of the fear that they will contract the disease again. The planners in the Health Ministry must evolve strategies to collect plasma at the donor’s residence with certain incentives.
By Dr Aqueel Khan
Professor and Head (Retd.)
Postgraduate Teaching Department of Biochemistry, RTM Nagpur University, Nagpur, Maharashtra, India.