Hyperimmune plasma, where are we?

We are talking about hyperimmune plasma as a possible therapy against Covid. Here is the evidence currently available on its effectiveness

(Image: Pixabay) We are trying them all. Old and new antivirals, monoclonal antibodies, off-label treatments, vaccines, with mixed success. And for some time now hyperimmune plasma has been added to the list of possible therapies against Covid-19, i.e. the liquid part of the blood taken from recovered patients and containing specific antibodies against Sars-Cov-2. In truth, trials of hyperimmune plasma therapy began almost immediately after the outbreak of the pandemic in early April, mostly as an emergency (or compassionate) treatment on patients in whom other approaches had not worked. It is good to say it immediately: to date, the evidence of the efficacy of hyperimmune plasma is extremely scarce and not very encouraging. Indeed, to tell the truth, the data collected so far seem unfortunately to point in the opposite direction.

What it is and how it should work

Plasma is the liquid part of the blood, of which it represents about 55% (the rest are red blood cells, white blood cells and platelets). It is light yellow in color and composed of approximately 91% water. The rationale behind hyperimmune plasma infusion is quite simple. As the experts of the National Blood Center at the Higher Institute of Health explain, this is a therapy that involves the collection from people healed from Covid-19 (in this case, of course, but the speech could apply to any disease that generates a response specific immune system) and its subsequent administration to patients with the same disease. Before the actual infusion, the hyperimmune plasma is subjected to a series of laboratory tests, also to quantify the level of neutralizing antibodies (the so-called titration, which is a very important concept: we will return to it shortly), and to procedures that guarantee the recipient safety. The idea is to transfer the specific antibodies developed by healed patients to those with active infection, who have not yet produced any of their own. In this case, these are immunoglobulins, proteins involved in the immune response produced by B lymphocytes in response to an infection, which bind to the pathogen and neutralize it.

Ebola, Sars, influenza

As already mentioned, Sars-Cov-2 is not the first virus against which this approach has been attempted. One of the first cases dates back to the 1918 Spanish flu epidemic; then, over the years, it has been administered (always in compassionate therapy or clinical trials) to patients affected by hepatitis B, rabies, tetanus, chicken pox, SARS (the first), ebola, flu. In all these cases, however, the results of the administrations were not deemed solid or conclusive enough with respect to the effectiveness of the treatment. For this reason, in general, the scientific community tends to consider hyperimmune plasma at most as a bridge waiting for effective therapies or a vaccine.

"Historically, the plasma of convalescents", explained to the New York Times Erin Goodhue, executive of the US Red Cross, "has been used as a prophylaxis and as a therapy especially in periods of arrival of new diseases, both viral and bacterial, when targeted and specific therapies against these pathogens are not yet available" . In the case of Covid, as happened for all other treatments, efforts and hopes have increased tenfold: "What strikes me particularly", says Goodhue, "is that up to now, hyperimmune plasma has never been used so much: it wants say that, for the first time, the scientific community will have the opportunity to conduct rigorous studies on the procedure that will be able to evaluate its effectiveness more precisely. In previous uses of the treatment it was not possible to conduct this type of study ”. Hyperimmune plasma, among other things, has also been tested on non-viral disorders, such as burns, trauma and even cancer. But the results are always the same: there is no solid evidence of its effectiveness.

What happened in the last few months

In a long article, Valigia Blu has put together and reconstructed the news on the use of hyperimmune plasma against Covid-19 since the pandemic broke out. The first use dates back to last February, when the China National Biotech Group, a Chinese private company, reported that it had performed the treatment on more than ten patients, obtaining improvements in 24 hours. A little more than a month later, the first hyperimmune plasma experimentation protocol was also launched in Italy, conducted by the Asst of Mantua and the Policlinico San Matteo of Pavia. And then the United States, where on March 25 the Food and Drug Administration gave precise recommendations in case health facilities wanted to initiate compassionate use therapy (Nature wrote that New York hospitals were preparing to use this "ancient therapy" for reduce the pressure on intensive care). Germany, the United Kingdom, Spain, Iran, South Korea and India also followed.

“No proof of effectiveness”

Here we are at the present, which we had already anticipated. The results of the experiments conducted so far seem to confirm at the moment it is not possible to establish whether plasma is an effective therapy. The authors of a Cochrane meta-analysis, for example, which examined data from 19 studies totaling nearly 40,000 participants, wrote that they "are unsure whether the plasma of people recovered from Covid-19 is an effective treatment, and also on the fact that it can have side effects ". The results of an Indian study published in the British Medical Journal and another, very recent, published in the New England Journal of Medicine, which did not find significant advantages in the administration of hyperimmune plasma, are more striking.

Everything to forget then? Yes and no. We asked some more explanations to Francesco Menichetti, professor of infectious diseases at the University of Pisa and above all coordinator of Tsunami, an Italian study that has precisely the objective of testing the effectiveness of hyperimmune plasma: "The work just published in the New England Journal of Medicine suggests hyperimmune plasma is ineffective, ”he admits. “We take note of this result: it is a serious work conducted with excellent methodological rigor. However, there is some technical flaw relating to the titration of the plasma used, which was verified only in 56% of the cases treated and which was conducted with a method that could make it appear richer in antibodies than it really is. In any case, the study attests that hyperimmune plasma does not bring benefits but neither - fortunately - side effects ".

The technical limitations of the Argentine study could soon be dispelled by the Italian results, says Menichetti:" In our study we are using a high level titrated plasma. We have enrolled over 380 patients and in these days an independent body is conducting a preliminary analysis on our data. We hope that in a few weeks we will be able to have the first results ”. Menichetti, with great honesty, acknowledges that at the moment "the utmost caution and prudence" is necessary with respect to this therapy and above all he does not recommend its use even as a compassionate therapy: "Given the current evidence, I believe that hyperimmune plasma should only be used within clinical trials, in controlled trials ". And he concludes with an appeal to continue to donate it (here the approved centers), because the bags are starting to run out. And the experiments must go on.