Phase IIa, Randomized, Open-label, Parallel-group Trial to Assess the Immunogenicity, Safety and Tolerability of Ervebo Vaccine Administered With Inmazeb to Healthy Adult Volunteers.
Phase IIa, Randomized, Open-label, Parallel-group Trial to Assess the Immunogenicity, Safety and Tolerability of Ervebo Vaccine Administered With Inmazeb to Healthy Adult Volunteers.
Ebola virus disease (EVD) is emerging regularly in various African countries for various reasons: during contact with mortal remains, during an unsafe burial or following the viral dissemination around a recovered patient.
However, tools to fight the spread of the disease are being made available to countries affected by EVD. A vaccine (Ervebo), developed by the Merck laboratory, demonstrated its efficacy in protecting contacts and contacts of contacts in the "Ebola That's Enough" trial and two monoclonal antibodies (Mabs) have demonstrated their efficacy in reducing mortality in patients with EVD: REGN-E3B (Inmazeb) and Mab114 (Ebanga).
The question of their use in post-exposure prophylaxis (PEP), defined as the treatment of contacts at very high risk of contracting EVD, is essential. Vaccination with Ervebo does not appear to be a good standalone option for PEP, particularly because antibody synthesis is delayed, and the vaccine is likely to be inactive for 10 days after administration. Monoclonal antibodies, on the other hand, seem to be a promising avenue in this indication because of their rapid action on the inhibition of virus entry into the cell.
Moreover, Ervebo vaccine expresses the viral target recognized by mAbs, GP EBOV. It is therefore possible that the vaccine response (production of vaccine antibodies) is inhibited by mAbs, which bind to GP EBOV and prevent vaccine replication, particularly in the case of concomitant administration.
However, no data on vaccine efficacy in combination are available. The question of the interaction between the monoclonal antibody and Ervebo and the delay between the administration of these two strategies remains unresolved.
The hypothesis of this trial is that Ervebo vaccine efficacy is diminished with the concomitant administration of a monoclonal antibody, especially if this administration is close (short time between Mabs and vaccination). We hypothesize that with an optimal delay between Mabs and vaccination, the immunogenicity of the vaccine when administered with monoclonal antibodies could be non-inferior to the vaccine alone, thus providing optimal short and long term protection.
The main objective of this study is to evaluate the extent of effect, if any, of Inmazeb administration on vaccine-induced neutralizing antibody responses to Zaire Ebola virus by Ervebo vaccine. If an interaction is observed, this will possibly enable determination of the time interval required between the administration of Inmazeb and Ervebo vaccine.
The trial will have 6 arms. A control arm of vaccination alone will serve to characterize the immune response to the vaccine and it will be used as a comparator of vaccine immune response in the intervention arms. A control arm of mAb alone will serve to characterize the pharmacokinetic profile of mAb in the Guinean population. The 4 arms including different doses of Inmazeb plus vaccination were designed to mimic a time interval between Ervebo and Inmazeb administration (15, 57 and 169 days after Inmazeb).
Ebola virus disease (EVD) is emerging regularly in various African countries for various reasons: during contact with mortal remains, during an unsafe burial or following the viral dissemination around a recovered patient. In Guinea, 5 years after the end of the 2014-2016 epidemic that killed 11,000 people, a new epidemic has been declared in the southeast of the country and in Conakry in early 2021. In the Democratic Republic of Congo (DRC), the thirteenth epidemic was declared in early October 2021 in North Kivu province. However, more and more tools to fight the spread of the disease are being made available to countries affected by EVD. During the 2014 West African epidemic, a vaccine (Ervebo), developed by the Merck laboratory, demonstrated its efficacy in protecting contacts and contacts of contacts in the "Ebola That's Enough" trial. This vaccine has since been widely used as part of ring vaccination strategies during the most recent epidemics (2018-2021) in the DRC and the epidemic in Forest Guinea in 2021. In addition, during the tenth DRC epidemic (2018-2020), a compassionate trial (MEURI) and then a randomized controlled therapeutic trial was evaluating 4 molecules (3 passive immunotherapies and 1 direct antiviral) as a specific treatment for EVD. Two monoclonal antibodies (Mabs) have demonstrated their efficacy in reducing mortality in patients with EVD: REGN-E3B and Mab114.
With the availability of these management and prevention tools, the question of their use in post-exposure prophylaxis (PEP), defined as the treatment of contacts at very high risk of contracting EVD, is more essential than ever. Indeed, it seems clear that PEP is one of the major axes to be deployed to effectively control EVD. Several PEP strategies have therefore been discussed. Vaccination with Ervebo does not appear to be a good standalone option for PEP, particularly because antibody synthesis is delayed, and the vaccine is likely to be inactive for 10 days after administration. On the other hand, monoclonal antobodies seem to be a promising in this indication because of their rapid action on the inhibition of virus entry into the cell or on the virus itself, both in animal models and in humans.
However, while monoclonal antibodies are good candidates for PEP, they certainly do not provide sustained immunity. Specifically, in high-risk contacts with EVD, PEP with use of mAbs may allow them to avoid the infection associated with that specific contact, but not the persistent risk of infection during the epidemic. Therefore, vaccination is also necessary.
Moreover, Ervebo vaccine expresses the viral target recognized by mAbs, GP EBOV. It is therefore possible that the vaccine response (production of vaccine antibodies) is inhibited by mAbs, which bind to GP EBOV and prevent vaccine replication, particularly in the case of concomitant administration. However, no data on vaccine efficacy in combination are available. The question of the interaction between the monoclonal antibody and Ervebo and the delay between the administration of these two strategies remains unresolved.
The hypothesis of this trial is that vaccine efficacy is diminished with concomitant administration of a monoclonal antibody, especially if this administration is close (short time between Mabs and vaccination). We hypothesize that with an optimal delay between Mabs and vaccination, the immunogenicity of the vaccine combined with monoclonal antibodies could be non-inferior to that of the vaccine alone, thus providing optimal short and long term protection.
The trial will have 6 arms. A control arm of vaccination alone will serve to characterize the immune response to the vaccine and it will be used as a comparator of vaccine immune response in the intervention arms. A control arm of mAb alone will serve to characterize the pharmacokinetic profile of mAb in the Guinean population. The 4 arms including different doses of Inmazeb plus vaccination were designed to mimic a time interval between Ervebo and Inmazeb administration (15, 57 and 169 days after Inmazeb).
From an operational point of view, the ideal solution would be to be able to administer the vaccine at the same time as the Mab (simultaneous arm) or as soon as possible after the Mab is administered. Indeed, when implementing a PEP strategy during an epidemic, delaying vaccination represents a double risk for the patient: i) not being protected between the end of the Mab action and the vaccine and ii) not receiving the vaccine at all due to lack of compliance because of the long delay between contact and vaccination. The early, intermediate and late arms of the IMOVA trial will therefore assess the immunological response when the vaccine is administered 15, 57 or 169 days after Mab and thus determine the optimal time between the two interventions. For this purpose, the vaccine response will be analyzed in order to be put in perspective with the acceptable operational delay to guarantee protection and patient compliance.
The trial will take place in Guinea, in Conakry during a non-epidemic period for EVD on healthy volunteers. Indeed, it is important that participants in the IMOVA trial are not exposed to Ebola virus during their follow-up, to ensure the absence of potential infection in the late arms in particular. Therefore, if an epidemic were to occur in Guinea, enrollment in the IMOVA trial would be immediately halted and be restarted at the end of the epidemic period. The National Health Research Ethics Committee of Guinea (CNERS) will of course be informed of such a situation
Inclusion Criteria:
Exclusion Criteria:
marie.jaspard@aphp.fr0658809012 ext. +33
beatrice.serra@coral.alima.ngo