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Clinical Experiments: Blood plasma from COVID19 survivors is being used to treat new patients

Desperate Times Call for Desperate Measures

We are passing through one such situation now. COVID19 pandemic. Thousands of people around the world are dying. Millions are suffering. Economies are going bust. Politicians are panicking. 

We hear stories of doctors gambling with possible solutions in hospital ICUs (9).

Everybody is looking upto one community now: The scientific C. 

If anybody can find a solution to this problem of gigantic proportions, it is the scientists.  Scientists are not disappointing the world. They are racing against time even though science, the study part of it, can't be rushed through.

Several companies and academic institutions are speeding up their work to create  vaccines (1). This unprecedented speed is thanks in large part to early Chinese efforts to sequence the genetic material of Sars-CoV-2, the virus that causes Covid-19. China shared that sequence in early January, allowing research groups around the world to grow the live virus and study how it invades human cells and makes people sick. All vaccines work according to the same basic principle. They present part or all of the pathogen to the human immune system, usually in the form of an injection and at a low dose (often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins), to prompt the system to produce antibodies to the pathogen. Antibodies are a kind of immune memory which, having been elicited once, can be quickly mobilised again if the person is exposed to the virus in its natural form.

As of 8 April 2020, the global COVID-19 vaccine R&D landscape includes 115 vaccine candidates (7).

But still the vaccine is several months away - seems like forever to the ones who are staring death in the face.

Then drugs(1). Several research labs around the world are testing already available drugs like  chloroquine and hydroxychloroquine as a treatment for COVID-19 although there isn't enough evidence to say that they would work well. Some antivirals drugs are also planned to be fast-tracked for testing for coronavirus. The National Medical Products Administration of China has approved the use of Favilavir, an anti-viral drug, as a treatment for coronavirus. The drug has reportedly shown efficacy in treating the disease with minimal side effects in a clinical trial involving 70 patients. The clinical trial is being conducted in Shenzhen, Guangdong province. You have a big list of who is testing what (1).

But still even these trials might take a long long time - again looks like infinity for those who are fighting death.

One promising experiment seems to be slowly inching towards its goal of keeping people safe in all this chaos till we find a solution: antibody-rich plasma treatment popularly called as convalescent* plasma therapy . The therapy, which takes antibodies from the blood of a person who has recovered from a virus and transfuses those antibodies into a person sick with that virus, has long been used as a way to help kickstart a person’s immune system.

*Convalescent, adjective,  means (of a person) recovering from an illness or medical treatment. As the plasma is taken from just recovered patient, and used in the 'treatment', it is called 'convalescent' plasma therapy.

Plasma contains 91% to 92% of water and 8% to 9% of solids. It mainly comprises (6):

  1. Coagulants, mainly fibrinogen, aid in blood clotting,
  2. Plasma proteins, such as albumin and globulin, that help maintain the colloidal osmotic pressure at about 25 mmHg,
  3. Electrolytes like sodium, potassium, bicarbonate, chloride, and calcium help maintain blood pH.
  4. Immunoglobulins help fight infection and various other small amounts of enzymes, hormones, and vitamins

Blood plasma

Image source: Google images that says the picture is from quora.com

As people fight the COVID-19 virus, they produce antibodies that attack the virus. Those antibodies, proteins that are secreted by immune cells known as B lymphocytes, are found in plasma, or the pale yellow liquid part of blood that helps the blood to clot when needed and supports immunity.

Once a person has had the virus and recovered, that person has developed antibodies that will stay in their blood waiting to fight the same virus should it return. Those antibodies, when injected into another person with the disease, recognize the virus as something to attack. In the case of the coronavirus,  antibodies attack the spikes on the outside of the virus, blocking the virus from penetrating human cells. One person’s donation of plasma can produce two doses of the material needed for transfusions. A person only needs one transfusion to get enough antibodies to fight a virus.

Hospitals in some countries like the US (4), China (3) and India (2) are gearing up to use the blood of people who have recovered from COVID-19 as a possible antidote for the disease. Researchers hope that the century-old approach of infusing patients with the antibody-laden blood of those who have survived an infection could really help.

In the initial stages of break out of this pandemic (January/February, 2020), Chinese researchers began analysing antibodies from blood taken from recovered COVID-19 patients, isolating 206 monoclonal antibodies which showed  a "strong" ability to bind with the virus' proteins.
Doctors in China treated 13 people who were critically ill with COVID-19 with convalescent plasma. Within several days, the virus no longer seemed to be circulating in the patients, indicating that antibodies had fought it off. But  their conditions continued to deteriorate, suggesting that the disease might have been too far along for this therapy to be effective. Most had been sick for more than two weeks.
They then conducted another test to see if they could actually prevent the virus from entering cells and

found among the first 20 or so antibodies tested, four were able to block viral entry and of those, two were "exceedingly good" at doing so. The team is now focused on identifying the most powerful antibodies and possibly combining them to mitigate the risk of the new coronavirus mutating. 
If all goes well, interested developers could mass produce 'possible medicines' based on this for testing, first on animals and eventually on humans.

But the convalescent plasma approach saw modest success during past severe acute respiratory syndrome (SARS) and Ebola outbreaks—but US researchers are hoping to increase the value of the treatment by selecting donor blood that is packed with antibodies and giving it to the patients who are most likely to benefit.

A key advantage to convalescent plasma is that it’s available immediately, whereas drugs and vaccines take months or years to develop. Infusing blood in this way seems to be relatively safe, provided that it is screened for viruses and other components that could cause an infection. Scientists who have led the charge to use plasma want to deploy it now as a stopgap measure, to keep serious infections at bay .Keeping the health healthcare workers 'available' is the topmost priority.

Scientists refer to this measure as ‘passive antibody therapy’ because a person receives external antibodies, rather than generating an immune response themselves, as they would following a vaccination.

This measure has its roots in  1890s. One of the largest case studies occurred during the 1918 H1N1 influenza virus pandemic. More than 1,700 patients received blood serum from survivors, but it’s difficult to draw conclusions from studies that weren’t designed to meet current standards.

During the SARS outbreak in 2002–03, an 80-person trial of convalescent serum in Hong Kong found that people treated within 2 weeks of showing symptoms had a higher chance of being discharged from the hospital than did those who weren’t treated. And survivor blood has been tested in at least two outbreaks of Ebola virus in Africa with some success. Infusions seemed to help most patients in a 1995 study in the Democratic Republic of the Congo, but the study was small and not placebo controlled. A 2015 trial in Guinea was inconclusive, but it didn’t screen plasma for high levels of antibodies. The approach might have also shown a higher efficacy had researchers enrolled only participants who were at an early stage of the deadly disease, and therefore were more likely to benefit from the treatment.

The researchers in the US now  plan (4) to test this in three ways ... 

In the first set they would   infuse patients at an early stage of the disease and see how often they advance to critical care. Another second trial would enrol severe cases. The third would explore plasma’s use as a preventative measure for people in close contact with those confirmed to have COVID-19, and would evaluate how often such people fall ill after an infusion, compared with others who were similarly exposed but not treated.

Even if it works well enough, convalescent serum might be replaced by modern therapies later. Research groups and biotechnology companies are currently identifying antibodies against the coronavirus, with plans to develop these into precise pharmaceutical formulas. 

Now we got the news (5) that India will soon begin clinical trials of a plasma treatment for critical Covid-19 patients. According to the Indian Council of Medical Research (ICMR), the country’s apex body in the field, it is in the process of finalising the protocol for the clinical trial, which will begin after final approval from the Drugs Controller General of India (DCGI). This will not be for mild patients, but (for) those who are on ventilators and under clinical trial mode, before being recommended for all patients. Kerala has already received ICMR approval to begin the trial.

Soon Telangana and Bombay city too would be conducting these experiments too (12) in India.

Other centres that want to try the therapy will need the DCGI’s approval.

However, Research on real-life immunity to SARS-CoV-2 is in its preliminary stages, and uncertainties remain (8). One study found no correlation between viral load and antibody presence, leading the authors to question the antibodies’ actual role in clearing the virus in humans. In addition, peer-reviewed research on SARS-CoV and preprint studies on SARS-CoV-2 report that some nonneutralizing coronavirus antibodies might trigger a harmful immune response upon reinfection with those pathogens or cross infection with other coronaviruses. Thus, while much of the emerging research is promising, experts caution against using antibody testing to drive policy until researchers know the proportion of COVID-19 survivors who are producing neutralizing antibodies.

Now experts have published (11) new guidelines for the convalescent plasma therapy (10). This paper details the nuts and bolts of how to deploy convalescent plasma, and this information would be very helpful to researchers and doctors worldwide who are preparing to use this therapy against COVID-19.

The guidebook outlines a range of clinical trials underway or planned at hospitals taking part in the Johns Hopkins-led network for convalescent plasma therapy.

Among the protocols outlined in the guide are criteria for eligible donors of blood plasma, how hospitals can mobilize donors and work with local and national blood centers, methods for prescreening donors, and the risks and potential benefits of the therapy.

Convalescent blood plasma therapy can be deployed in low-resource communities. There is a difference, however, in how blood plasma may be collected in communities with low versus high resources.

High-resource communities typically rely on apheresis machines to remove a donor's blood, filter the plasma from it, and return the rest of the blood, plus a replacement for the collected plasma (i.e. a protein called albumin), back to the donor. Using the apheresis method, a single donor could produce enough plasma to potentially benefit up to three other people.

In low-resource communities where apheresis machines may be unavailable, the output of plasma would be less per donor. This is because doctors have to perform a typical whole blood donation from the donor and manually separate the plasma in a laboratory by using a centrifuge machine or letting gravity separate the blood products.

Among the most common challenges to scaling up convalescent blood plasma therapy is rapidly developing in-house testing for whether the blood plasma  of donors contains key antibodies the immune system needs to recognize and help destroy the virus in the body. There are also logistical challenges associated with identifying donors and performing repeat COVID-19 nasal swab tests for the virus in them.

Updates: 

1.Indian Study Shows No Survival Benefit of Plasma in COVID-19

A randomized controlled trial on the use of convalescent plasma therapy to treat coronavirus infections—the first in the world to be completed—yields disappointing results, but some doctors are not discouraged.

A. Agarwal et al., “Convalescent plasma in the management of moderate COVID-19 in India: An open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial),” medRxiv, doi:10.1101/2020.09.03.20187252, 2020.

https://www.the-scientist.com/news-opinion/indian-study-shows-no-su...

2. Some doctors are asking the ICMR to discontinue use of plasma therapy as the therapy might produce mutants in the immuno-compromised people.  As indications have arisen of the possibility that its use in some cases could foster the emergence of more virulent strains of Sars-CoV-2. Even if this danger is in the realm of conjecture, or turns out to bear a very low likelihood, it should suffice to stop plasma infusions.

https://www.livemint.com/opinion/online-views/call-off-plasma-thera...

Citations:

1. https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-d...

2. https://theprint.in/health/india-ready-for-clinical-trial-of-plasma...

3. https://economictimes.indiatimes.com/news/international/business/ch...

4. https://www.nature.com/articles/d41586-020-00895-8

5. https://theprint.in/health/india-ready-for-clinical-trial-of-plasma...

6. https://www.ncbi.nlm.nih.gov/books/NBK531504/

7. https://www.nature.com/articles/d41573-020-00073-5?utm_source=Natur...

8. https://www.scientificamerican.com/article/what-immunity-to-covid-1...

9. https://medicalxpress.com/news/2020-04-doctor-gambles-clot-busting-...

10. https://medicalxpress.com/news/2020-04-experts-publish-guidebook-bl...

11. Evan M. Bloch et al, Deployment of convalescent plasma for the prevention and treatment of COVID-19, Journal of Clinical Investigation (2020). DOI: 10.1172/JCI138745

12. https://timesofindia.indiatimes.com/city/hyderabad/telangana-too-fo...

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