The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of persons having recovered from SARS and severe influenza to patients suffering from active disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. A large scale trial, the DAWN-Plasma trial1, took place in Belgium to investigate this potential treatment. Professor Timothy Devos is co-first author of this trial and as a haematologist is associated with the Molecular Immunology Research group at UZ Leuven.
Can you highlight the rationale for the use of convalescent plasma (CP) as a treatment for patients with COVID-19?
“CP has been considered and used in earlier epidemics, for instance during the outbreak of SARS-CoV-1 in 2003. CP has also been used in the treatment of MERS-CoV and Ebola. However, before the actual COVID-19 pandemic, there have not been any randomized prospective clinical trials regarding CP as a treatment. So there was a high need for well-designed, high-quality randomized clinical trials to prove or disprove if convalescent plasma works as a treatment and to establish the optimal settings for administering it.”
“When patients recover from an acute COVID-19 infection, they have antibodies for COVID-19 in their plasma. This plasma is collected by the Red Cross and is processed before administering it to recently hospitalized new patients with severe pneumonia due to COVID-19. This transfer of protective antibodies via a plasma transfusion is known as passive immunization.”
In Belgium, a large scale trial, the DAWN-Plasma trial, has taken place to establish the efficacy of treating COVID-19 patients with CP. Can you share with us more information about the design of this trial and about inclusion and exclusion criteria?
“The DAWN-Plasma trial (Donated Antibodies Working against NCoV) is a phase-3 prospective randomized trial, which included 489 patients within 24 hours of being hospitalized with a COVID-19 infection. They were randomized 2:1 which meant that 326 patients received a plasma treatment together with standard of care (SOC) and the other 163 patients received SOC only. We gave the patients two units of CP on the first day, and two more within 24h-36h later. Specifically, we only gave plasma that contained high titers of antibodies. So in short: what we researched was a treatment based on early hospitalization, high dosage and high antibody titers. These three things are the most important characteristics of the trial.”
Being treated with anti-CD20 monoclonal antibodies was an important exclusion criterion, can you elaborate on this?
“It is quite important to mention the exclusion criteria. Pregnant women and patients under 18 were not included, as well as patients who had a history of severe allergic reactions to plasma. We also decided early on that we would not include patients who had received rituximab or another anti-CD20 monoclonal antibody within the last 12 months. These patients, for instance patients receiving rituximab during a lymphoma treatment, are unable to produce antibodies. We deemed it unethical to expose these patients to a possible inclusion in the control group.”
What was the primary outcome of the study?
“The primary outcome of the study was the number of patients alive without mechanical ventilation, measured at day 15 after hospitalization. The rationale behind the DAWN-Plasma trial was the prevention of disease worsening and of having to transfer patients to the intensive care units. Plasma donors had to have recovered from their acute COVID-19 infection at least 17 days prior to be considered for donation. After two weeks, the body develops sufficient antibodies against the SARS-CoV-2 virus, but some persons develop higher titer levels than others. It is important to measure antibody titers to select optimal donors and to follow the evolution of the antibody titers in studied patients. There are basically two methods to do so: the first is an enzyme linked immunosorbent assay (ELISA). This method measures the titers rapidly and shows the total level of antibodies in the blood, without measuring the specific antiviral activity against SARS-CoV-2. The second method is the Virus Neutralization Assay (VNA), which is more specific for antiviral activity, but also takes longer – 5 days – and requires a much more sophisticated laboratory setting. For the DAWN-Plasma trial, therefore, it was decided to use the VNA method.”
“In total, 22 hospitals throughout Belgium participated in the DAWN-plasma trial. The trial was funded by the Belgian Health Care Knowledge Centre KCE, while UZ Leuven coordinated the study. The national principal investigator is Professor Geert Meyfroidt and I’m the principal investigator of the study at UZ Leuven. Considerable effort were made by the entire study team, the DAWN consortium, the blood institutions, the laboratories and all the study sites, to organize this trial in the stressful and difficult period of the pandemic. The total number of inclusions was reached on January 26. We hope to present our findings soon.”
‘Concerns regarding thrombosis as a result of CP administration are largely theoretical’
Can you perhaps highlight the potential risk of thrombosis that is associated with CP transfusions? The FDA in the United States cautions against the risk of thrombosis particularly in the elderly and in patients with cardiovascular risk factors or hypercoagulable conditions. Should CP therefore be limited to younger patients or to patients without risk factors?
“A very interesting study was recently published in the New England Journal of Medicine by Libster et al.2 This study meant to investigate early administration of high-titer convalescent plasma therapy as a means of preventing severe COVID-19 in older adults. Its main conclusion was: early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. I mention this study because, in the context of your question, no increased risk for thrombo-embolic events was seen in the study group receiving CP compared to the control group (receiving placebo). I think the concerns regarding thrombosis as a result of CP administration are largely theoretical. As more high quality randomized CP-trials are being published, these also do not show reasons to be concerned about thrombosis after CP-administration.”
In March, following research by Joyner et al3, the FDA announced it had changed its policies regarding the use of CP as treatment for COVID-19. According to the updated emergency use authorization, only high-titer CP should be used, and only for hospitalized patients early in disease course, as well as for patients with impaired humoral immunity who cannot produce an adequate endogenous antibody response. Use of low-titer CP is no longer authorized. Can you comment on this research?
“In my answer, I will focus on the importance of using high-titer CP, as I already commented the importance of early administration in the course of the disease. The study by Joyner et al. is retrospective, but it refers to a huge data set (3,082 patients given CP in the context of the national expanded-access program in the US) and is therefore interesting. Joyner et al. noticed that patients receiving CP with higher antibody titers did better than patients who received lower titer plasma. So, transfusion of plasma with higher antibody levels was associated with a lower risk of death in patients not receiving mechanical ventilation. Following this analysis, the FDA has adapted its recommendations. From the beginning of the DAWN-plasma trial, in April last year, we decided to go for a treatment with high titer plasma, in a high dose and at an early stage of hospitalization. So, we were not surprised about the American results and subsequent FDA recommendations.”
What options for use would you consider feasible in clinical practice for the treatment of COVID-19 patients with haematological and haemato-oncological disorders in Belgium?
“That’s a really interesting question, especially with regard to B-cell depleting therapies. Monoclonal antibodies against B-cells are frequently used in haematology, and mostly in B-cell lymphoma patients. When we gave convalescent plasma in Belgian hospitals to patients who had received rituximab, they frequently were haematological patients. I have to clarify why some patients in Belgium received, and are still receiving CP in this setting: as I mentioned earlier, patients who had been treated with B-cell depleting therapies were excluded from the DAWN-Plasma trial. However, the two national blood institutions in Belgium (Rode Kruis Vlaanderen and Croix Rouge de Belgique) worked together and introduced an urgent medical need programme called MEURI (Monitored Emergency use of Unregistered and Investigational Inventions). This is not a clinical trial, but an emergency program that allows us to treat patients who are unable to clear the virus because the B-cell depletion therapy has impaired their production of antibodies. Thanks to the MEURI protocol we are able to administer one or two units of convalescent plasma, and we have been seeing very good results with that treatment. A case series describing the evolution of some of these patients at our hospital has been published in the British Journal of Haematology.4”
“To clarify: not all COVID-19 patients having received B-cell depleting therapy should be given CP at an early stage of hospitalisation. Some of them are improving with standard of care, but others are not capable of clearing the virus and end up with protracted (prolonged) COVID-19. They are excellent candidates for receiving CP. Thanks to the MEURI protocol this treatment is available in Belgium.”
‘For COVID-19 patients who are not developing sufficient antibodies, convalescent plasma can be a viable treatment option’
“Summarizing, there is a large amount of literature, but if we follow the current scientific evidence, I think that for COVID-19 patients who are not developing sufficient antibodies, CP can be a viable treatment option. However, in all the other settings, a definitive conclusion cannot be drawn at the moment. The Libster et al. research is very valuable, showing an advantage of the administration of high-titer CP to older patients at an early stage of the disease. But there are also other trials coming out now, such as the RECOVERY study5, a big English trial –currently pre-published- that did not show any benefit.”