In 1918, as the Spanish flu pandemic raced around the world, a handful of hospitals turned to an experimental potential treatment for the deadly disease: the blood of survivors. Although the trials were shaky by today’s standards, they hinted at a surprising result. Patients who received blood from Spanish flu survivors had a much lower death rate than those who went without.
More than 100 years later, health authorities are turning to this experimental treatment as a possible treatment for Covid-19, the disease caused by the novel coronavirus. With a vaccine or other potential treatment still many months away, could infusions of blood plasma help us stop hospitals filling with Covid-19 patients?
The concept behind convalescent plasma therapy is that the blood of patients who have recently recovered from a viral infection will be rich in neutralising antibodies against the pathogen, which in this case is Sars-CoV-2 – the virus that causes Covid-19. Numerous reports from both infectious disease epidemics during the first half of the 20th century, and the SARS and MERS outbreaks in more recent times, suggests that infusions of this blood can boost the immune systems of patients as well as providing a form of immunisation to those who have yet to contract it.
In late January, hospitals across China began using convalescent plasma as a treatment for Covid-19, and in recent weeks other countries have followed suit after the publication of initial results from Wuhan and Shanghai. While these trials involved just a small handful of patients, they received global attention as they appeared to demonstrate that convalescent plasma could aid recovery in even the most critically ill patients.
“This is amazing because the vast majority of people thought that convalescent plasma could only be effective if administered early in the disease course,” says Daniele Focosi, a transfusion specialist at Pisa University Hospital in Italy. “But the Chinese case series has proved clinical benefit even at a late stage which is very intriguing because it could be a life saving treatment.”
As of April 6, it was reported that 19 clinical trials of convalescent plasma are already taking place in China, the US, Italy, Iran, Mexico, and Colombia, with more planned. This week Italy is launching a nationwide initiative co-ordinated by Focosi’s team at Pisa University Hospital which will use convalescent plasma in hospitals across five more of Italy's 20 regions, complementing an existing trial taking place in Lombardy, the epicentre of the Italian outbreak.
In the UK, the NHS is currently seeking donors for two trials of its own which will compare convalescent plasma against other experimental medications such as antiviral drugs. “One of these trials is to treat patients with Covid-19 pneumonia who have not reached the stage of ventilation to try to stop that happening,” says David Tappin, of the University of Glasgow School of Medicine, who is looking to obtain approval to run his own trial looking at whether convalescent plasma can help protect NHS workers. “The other is to treat severely ill patients already ventilated to try to reduce time on ventilators and to reduce death.”
But finding suitable donors is not as straightforward as it might seem. While there are more than 400,000 people around the world who have recovered from Covid-19, the rapid mutation rate of the virus as it has passed between countries means that donors have to be sourced locally. As the pandemic in Italy worsened last month, China reportedly offered to ship 90 tons of convalescent plasma to Italian hospitals for emergency use, but tests soon showed that it could not be used.
“We have evidence that the envelope protein called the spike protein is mutating,” says Focosi, who is one of the co-investigators leading the new multi-centre trial in Italy. “So convalescent plasma collected in China may not be protective for Covid-19 patients in Europe and the US. You need antibodies derived from infection to the same strain which is circulating in your area.”
Not only that but suitable donors must have no secondary conditions such as heart disease or diabetes, and be hyperimmune – meaning they have a very high concentration of antibodies in their blood. The latter makes things particularly complicated because it tends to be only patients who have suffered a severe case of the infection who produce such large amounts of antibodies, and only within a fairly short time window.
“Just being convalescent is not enough to be useful,” says Focosi. “You need to find the right patients at the right time. It’s been proven with other respiratory coronaviruses that patients experiencing mild to moderate symptoms, with no pneumonia or need for hospital stay, typically develop very low antibody responses which aren’t useful for this treatment. So you need people who have developed severe symptoms, a high fever at least, and to collect plasma very early in the recovery period. But finding suitable people is difficult because if you needed hospitalisation, you are likely to be elderly with comorbidities.”
Different countries have taken varying approaches to trying to identify the right donors. Tappin explains that the NHS trials are waiting on the verification of a suitable antibody test to help pinpoint hyperimmune individuals, while in Italy many of the initial donors helping to kickstart the new trial are young healthcare workers who have volunteered their blood after recovering from the virus.
“They’re fully aware of the trials taking place, and as soon as they can, they go to the transfusion services to donate,” says Focosi. “But this only serves to start up activities. To scale up, we have to release a massive call to action to the public and hope to identify several periodic donors who can donate every two weeks. Each donation can be used to treat three new patients so there is a big multiplying effect.”
In the US, efforts to find donors have been fuelled by a massive collaboration effort initiated by Arturo Casadevalsl, professor of molecular microbiology and immunology at John Hopkins Bloomberg School of Public Health, who was one of the first doctors outside of China to call for the use of convalescent plasma to fight Covid-19.
Casadevalsl’s efforts have seen the FDA grant approval for the compassionate use of convalescent plasma in emergency cases, with more than 100 blood banks across the country joining forces to source suitable donors. He is also coordinating a trial to see whether plasma can protect doctors and nurses who have had contact with a Covid-19 patient within the previous 96 hours.
But one of the problems with many of the studies taking place in Europe and the US is that it will be very difficult for scientists to conclusively prove that convalescent plasma has therapeutic benefit. To do so would require conducting what is known as a randomised control trial in which some Covid-19 patients were administered a placebo, but denying dying patients a potentially life-saving treatment would of course be considered unethical in the western world.
However such trials are taking place across China. While the ethics of such studies are hard to condone, the results will be illuminating. “The whole world is awaiting results from China,” says Focosi. “They will have the most robust data to show whether this is effective on a large scale.”
With Covid-19 unlikely to go away anytime soon, major drug companies have also turned to convalescent plasma as a means of manufacturing off-the-shelf products that can be rolled out within communities to provide protection against the virus, and allow lockdown measures to be eased.
These products are based on the neutralising antibodies within convalescent plasma, and are likely to be available much sooner than a vaccine, potentially within the next three months. Japanese pharmaceutical giant Takeda began work on their TAK-888 product in February, while CSL Behring in the US and other companies are looking to produce their own equivalent.
“Many companies are investing in this because everybody believes that Covid-19 is here to stay for years,” says Focosi. “When these products are available, it will be much easier for manufacturers to scale up and make them available to larger numbers of people than hospital transfusion services. I think this will be a major shift and benefit in the fight against the virus.”
Updated 21.04.20, 16:00 BST: An earlier version of this article said that blood plasma treatment was due to be trialled in all of Italy, but the trial is currently limited to six of the country's twenty regions.
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This article was originally published by WIRED UK
