Study confirms safety of COVID-19 convalescent plasma therapy

Clinical trial conducted in Brazil suggests the treatment can be beneficial if administered within ten days of symptom onset.

By Karina Toledo  |  Agência FAPESP – A Brazilian clinical trial involving 104 COVID-19 patients shows convalescent blood plasma therapy to be a safe alternative that is especially beneficial if applied in the first ten days after the onset of symptoms.

The trial was supported by FAPESP and was conducted by researchers at two leading hospitals in the city of São Paulo – Hospital Israelita Albert Einstein (HIAE) and Hospital Sírio-Libanês (HSL) – in collaboration with a group at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP). The findings are published on the preprint platform medRxiv in an article that has yet to be peer-reviewed.

“From the safety standpoint, we confirmed that the risk involved in the procedure is low, equivalent to that of any blood transfusion. As for the benefits, we found that patients treated earlier responded more positively. However, because it was a single-arm trial [without a control group given placebo], our ability to evaluate efficacy is limited,” said José Mauro Kutner, a hematologist at HIAE, a professor at its Education and Research Institute (IIEP), and one of the authors of the article.

According to Kutner, the clinical trial was designed in March 2020, when little was known about COVID-19 or the safety of convalescent plasma therapy, which was developed in 1891 to treat diphtheria and used experimentally in outbreaks of respiratory disease such as H1N1 influenza (2009-10), severe acute respiratory syndrome caused by SARS-CoV-1 (2003) and Middle East respiratory syndrome caused by MERS-CoV (2012).

Convalescent plasma therapy consists of transfusing the patient with antibodies obtained from donors who have recovered from an infectious disease. The antibodies are expected to reduce viral load and prevent the patient’s condition from worsening. The treatment is authorized in Brazil only for compassionate or clinical research purposes. 

It was administered to all participants in the single-arm trial, but the quantities and disease stages varied. All were over 18 years old and had severe pneumonia. Some were being admitted to hospital, and others were already in intensive care. The subgroups were assessed during a two-week period.

“As expected, the patients who were older or obese or had comorbidities fared worse but this wasn’t due to the treatment,” Kutner said. “The volunteers who had few or no antibodies of their own against SARS-CoV-2 before they received the plasma transfusion benefited more from the treatment than those who had antibodies. This is apparently the first time such a finding has been reported in the scientific literature.”

Contrary to the scientists’ expectations, the patients who received plasma with the highest concentrations of neutralizing antibodies – a specific type that blocks infection in cells – did not necessarily progress better than the rest. For Kutner, this was probably because the doses given to all 104 patients were larger than the minimum recommended by European studies and the US Food and Drug Administration (FDA), which is a titer of 1:160, meaning that after diluting the plasma 160 times it must still be possible to find at least one neutralizing antibody.

Neutralizing antibodies bind to a specific region of the spike protein used by SARS-CoV-2 to dock with and enter human cells, where the virus replicates. This region is called the receptor-binding domain (RBD).

“The main finding was that the patients treated early, in the first ten days after the onset of symptoms, fared better than those who received the plasma after this period,” Kutner said.

The Brazilian findings are in line with the results of studies conducted in other countries, the latest of which is published in the New England Journal of Medicine by researchers at Argentina’s Infant Foundation. According to the article, if convalescent plasma therapy is to be effective it must be administered not later than 72 hours after symptom onset and the antibody titer must be high. If these conditions are met, the treatment can reduce the need for oxygen by 50%. The double-blind, placebo-controlled randomized study involved 160 patients aged 65 and older.

Virus neutralization

Before being transfused into the patients treated at HIAE and HSL, the donated plasma was analyzed at ICB-USP by Professor Edison Luiz Durigon and his team using a technique called virus neutralization testing (VNT), which entails culturing SARS-CoV-2 in a laboratory certified for Biosafety Level III (BSL-3) and staffed by highly trained professionals.

“VNT is a complex and time-consuming technique, so it’s limited to large research centers, but simpler screening techniques are now available and could facilitate the use of convalescent plasma therapy,” Durigon said (read more: agencia.fapesp.br/34788). 

The treatment is costly, however, he stressed. In addition to the standard blood donor tests, such as those designed to detect the presence of pathogens that cause transmissible diseases, the donated plasma must be analyzed to quantify the antibody titer and stored in an appropriately equipped blood bank.

“The therapy has to be administered in a hospital and accompanied by a medical team. It’s not a panacea, but it can help some high-risk patients combat the infection in its earliest stage,” Durigon said. 

The ICB-USP group is currently investigating in the laboratory whether convalescent plasma from first-wave COVID-19 patients can neutralize the UK variant (B.1.1.7), considered more contagious than the original Chinese strain. They hope to publish their findings soon.

The article “Impact of convalescent plasma transfusion (CCP) in patients with previous circulating neutralizing antibodies (nAb) to COVID-19” can be read at: www.medrxiv.org/content/10.1101/2020.12.08.20246173v1.full.pdf.