Since its discovery in the Democratic Republic of Congo (DRC) in 1976, the EBOV virus has been responsible for numerous epidemics. Outbreaks have occurred in the DRC, Gabon, Guinea, Liberia and Sierra Leone. Imported cases were also discovered in 1996 in South Africa, and in 2014 in Mali, Nigeria, Senegal, Italy, Spain, UK and USA (1). To date, the largest EVD epidemic occurred in West Africa between 2014 and 2016. It was responsible for over 28,000 infections and more than 11,000 deaths (2-4). Since this epidemic, EVD has emerged and re-emerged regularly in Sub-Saharan Africa (SSA).
Post-exposure prophylaxis (PEP) is the treatment of people at high risk of EVD. The main aim of PEP is to intervene during the asymptomatic incubation period (2-21 days) to prevent the development of EVD.
In addition to preventing the disease in individuals, an effective PEP strategy could reduce the rate of secondary attacks, thus interrupting transmission chains. If introduced rapidly, this tool could halt the spread of the disease and contribute to the fight against EVD epidemics (5). The particular vulnerability of healthcare personnel has been highlighted during several outbreaks, due to their close contact with infected patients and contaminated equipment (6). With an effective and accessible PEP tool, it will be possible to ensure the safety and protection of these essential personnel and minimize the risk of nosocomial transmission within healthcare establishments. PEP could also benefit contact tracing efforts by providing an appropriate preventive measure. By integrating PEP into comprehensive epidemic response strategies, it will be possible to improve countries' ability to control and mitigate the public health impact of EVD epidemics and prevent future outbreaks.
There is currently no comprehensive PEP strategy, i.e. one that combines several interventions. Several prophylactic interventions have been evaluated, including vaccination and mAb immunotherapy, each with its advantages and limitations (7-9). Although not intended for this use, Ervebo vaccine is currently administered as PEP during EVD epidemics, by being administered to contacts regardless of exposure levels.
MAbs have been administered as PEP on a compassionate basis, to healthcare workers following occupational exposure, in line with WHO expert advice from 2018 (10). In addition, mAbs are recommended as PEP for newborns of Ebola-infected mothers, within seven days of birth (11). PEP can prevent the risk of infection associated with a particular contact, but not the persistent risk of infection during an epidemic. A comprehensive strategy to protect high-risk contacts must therefore be put in place, including both a drug to prevent EVD after contact (mAb or antiviral) and a vaccine for long-term immunity, to guarantee both immediate and prolonged protection.
Inmazeb (REGN-EB3), developed by Regeneron, is a cocktail of 3 neutralizing humanized mAbs directed against 3 EBOV GP epitopes (atoltiviMab, maftiviMab and odesiviMab). It is indicated for the treatment of EVD in adult patients (including pregnant women) and in children, including neonates whose mothers have EVD at the time of delivery. Inmazeb inhibits viral entry into the target cell (12). This mechanism of action makes Inmazeb a promising candidate for PEP (34,40-44). In phase 1, the optimal dose was set at 150 mg/kg as a single intravenous (IV) dose, with good tolerability, except for moderate side effects such as headache and myalgia in 30% and 10% of participants respectively. The longest half-life of the three antibodies was 27.3 days (21.7 and 23.3 for the other two antibodies). At 180 days, the residual concentration of each antibody (administered at 150 mg/kg) is less than 10 mg/l (13). In the PALM trial, overall mortality after a single 150 mg/kg dose was estimated at 33.5% (versus 51.3% in the ZMapp control arm). However, the effect of treatment is strongly influenced by viral load. In patients with a high viral load at inclusion (NP Ct \< 22), mortality was 63.6% (versus 86.2% in the Zmapp subgroup), while in patients with a low viral load at inclusion (NP Ct \> 22), mortality was 11.2% (versus 25.8% in the Zmapp subgroup) (14). Following the PALM trial, Inmazeb was approved by the FDA for the treatment of EVD in adults and children (15).
A study conducted during the 10éme EVD epidemic in the DRC evaluated PEP with mAbs as part of a compassionate program (Post-Exposure Prophylaxis Monitored Emergency Used for Unregistered Intervention - PEP MEURI). In this study, 23 vaccine-naïve high-risk contacts received mAbs (21 Ebanga and 2 Inmazeb) after a median delay of one day between contact and PEP. At D14, none of the participants were symptom-free and their PCR was negative (16).
EBO-PEP is a multicentre, multi-epidemic, phase III, comparative, controlled, randomised, strict superiority trial in two unblinded parallel arms.
The trial will be open during EVD epidemics, and will recruit asymptomatic participants at high risk of developing EVD. Participants will be randomized (1:1) into one of two trial arms:
* Arm 1 (control arm): Ervebo D1 (72 million PFU IM)
* Arm 2: Ervebo D1 (72 million PFU IM) + Inmazeb IV (150 mg/kg) D1 + Ervebo D56 (revaccination)
Definition of high-risk:
Direct contact with a person with EBOV PCR-confirmed EVD with diarrhea, vomiting or external bleeding ("wet symptoms"), or with their body fluids; Direct contact with the dead body of a person with confirmed or probable EVD; Needlestick with a syringe contaminated by the blood of a person with confirmed or probable EVD; Or a child born to or breastfed by an individual with EVD
