Periodic Reporting for period 2 - Ebola_Tx (Emergency evaluation of convalescent blood and plasma for Ebola Viral Disease (EVD) in affected West African countries.)
Reporting period: 2015-11-01 to 2016-10-31
In September 2014, the World Health Organization (WHO) prioritized convalescent whole blood (CWB) and convalescent plasma (CP) transfusion among potential Ebola therapies in the hope they could rapidly be implemented if proven safe and effective. The emergency evaluation of CP to treat EVD in Guinea (Ebola_Tx) Consortium, led by the Institute of Tropical Medicine-Antwerp (ITM-A), brought together a number of partners with complementary expertise to undertake a phase 2/3, open-label, non-randomized, controlled clinical trial to evaluate CP additional to standardized supportive care in confirmed EVD patients in Conakry, Guinea (Clinicaltrials.Gov. NCT02342171).
The project was organized around four work packages (see Figure 1)
The primary objective of the study was to assess if CP combined with supportive care improves the 14 day survival of patients, compared to supportive care alone. An effect of CP would be considered clinically significant if there was an absolute decrease in the case fatality rate of 20% or more, compared to supportive care alone (e.g. from 70% to 50%).
As per WHO guidance, two consecutive transfusions of 200 to 250 ml of ABO-compatible CP was given. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration, as assays to determine this were not unavailable in the affected countries.
The rationale of the use of CP as EVD treatment is based on the notion that CP contains EVD neutralizing antibodies or other types of antibodies that can block EVD infection. Hence, to fully understand the efficacy of CP, detailed information on how much of these neutralizing and other antibodies were given in the donated CP is required. However, tests to determine this can only be done in high biosafety (BSL4) laboratories, which are not available in the affected West African countries. Shipment of these samples abroad has however proven very complex and time-consuming. Hence, as a public health intervention, CP would be used once available without awaiting these test results.
The first analysis of the trial data looked at the use of unselected CP – meaning the use of CP without knowing the exact amount of anti EVD antibodies present. The use of unselected CP as per WHO guidance (2 units of 200-250 ml) was not associated with the 20% reduction in mortality the trial was designed to detect. There was a small reduction in mortality, with an adjusted absolute risk reduction of 2.6% but the confidence interval excluded a 20% absolute reduction (confidence interval: -13.1 to 8.0) see Table 2 and Abstract 1.
One of the reasons for failing to find a clear effect of unselected CP could have been that the levels of antibodies present in the plasma were low, and to assess this, additional laboratory analyses had to be done in France.
Once the samples were shipped to France and the results of the laboratory analyses were available further statistical analyses on the trial data were done. With this information, we could evaluate how much antibodies each patient had received, and importantly assess whether individuals receiving higher doses would have a greater benefit from CP.
• Key findings are that
- Transfusion of up to 500ml of unselected CP - meaning with unknown quantities of Ebola virus antibodies - was well tolerated but not found to significantly improve survival.
- Higher doses of Ebola virus antibodies were not associated with improved survival
- The level of Ebola virus neutralizing antibodies (among the Ebola virus antibodies) in donor plasma was generally low.
- Higher doses of IgG Ebola virus antibodies (targeting different components of the virus, irrespective of the neutralizing activity) were associated with more pronounced reductions in Ebola viral load.
- In conclusion, while higher doses of IgG Ebola virus antibodies could give stronger reductions in the amount of Ebola virus present in the blood of patients, this did not result in increased survival (see abstract 2).
• Further studies should assess the effectiveness of higher Ebola virus antibody doses
EXPLOITATION AND DISSEMINATION
- Real-time and continuous sharing of information at the national and international level
- Confidential sharing of preliminary findings with WHO, MSF and Guinean authorities
- Confidential sharing of preliminary findings with the WHO Blood Regulatory Network:
- Conference presentations
- Scientific symposia at international conferences:
- Project website: www.ebolatx.eu
- Project film (versions of 3 and 11 minutes) (www.ebolatx.eu)
- Extensive media coverage
The main trial findings were published in the New England Journal of Medicine (NEJM) http://www.nejm.org/doi/full/10.1056/NEJMoa1511812.
A follow research letter containing information on the amount of antibodies present in the donor plasma and the relation between the dose of antibodies given and the patient outcomes has been published at NEJM. Links to other Ebola-Tx publications can be found on the Ebola-Tx website (www.ebolatx.eu).
At the same time, we also generated data on how efficacy of convalescent plasma could potentially be increased. Higher doses of IgG Ebola virus antibodies gave stronger reductions in the amount of Ebola virus present, and possibly higher or more frequent doses than used in our study – which followed WHO guidance – might be required to achieve even more pronounced reductions in viral load, and potentially an associated reduction in mortality . Further studies in animal models should provide insights on that.