Clinical trial NCT05202288: Pilot Study Evaluating the Impact of Delay Between Administration of Inmazeb Administration and Vaccination by Ervebo on Vaccine Immune Response on Healthy Volunteers
Official title: Phase IIa Pilot Study Evaluating the Impact of Delay Between Administration of Inmazeb Administration and Vaccination by Ervebo on Vaccine Immune Response on Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Ebola Virus Disease
Keywords: Post Exposure Prophylaxis
Ebola vaccine
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Alliance for International Medical Action
name: University of Bordeaux
name: Institut National de la Santé Et de la Recherche Médicale, France
name: Programme PAC-CI, Site ANRS-MIE de Côte d'Ivoire
name: Agence Nationale de Sécurité Sanitaire de Guinée (ANSS)
name: Clinical and Operational Research Alliance (CORAL)
name: Méthodologie et Evaluation pour la Recherche clinique et Epidémiologique sur le VIH en Afrique (MEREVA)
First posted: 2022-01-21
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The trial will have 5 arms. The control arm (vaccination alone) will serve as a comparator of vaccine response in the intervention arms. The 4 intervention arms will assess the minimum time between Mab and vaccination.

The early, intermediate and late arms of the IMOVA trial will therefore assess the immunological response when the vaccine is administered 3, 6 or 12 weeks after Mab and thus determine the optimal time between the two interventions.
Primary purpose: PREVENTION

Brief summary: 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 MVE. 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 EVM: REGN-E3B and Mab114.

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 alone does not appear to be a good 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 and monoclonal antibodies share the same viral target. It is therefore possible that the vaccine is inhibited by the monoclonal antibodies, 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 combined with monoclonal antibodies could be non-inferior to the vaccine alone, thus providing optimal short and long term protection.

The primary objective of this study is to compare the vaccine immune response at 24 weeks induced by Ervebo administered on the same day (D0) or at S3, S6, or S12 of Inmazeb administration, in healthy volunteers, with vaccination with Ervebo alone.

The trial will have 5 arms. The control arm (vaccination alone) will serve as a comparator of vaccine response in the intervention arms. The 4 intervention arms will assess the minimum time between Mab and vaccination.

Detailed description: 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 MVE. 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 alone does not appear to be a good 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 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.

Ervebo vaccine and monoclonal antibodies share the same viral target. It is therefore possible that the vaccine is inhibited by the monoclonal antibodies, 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 5 arms. The control arm (vaccination alone) will serve as a comparator of vaccine response in the intervention arms. The 4 intervention arms will assess the minimum time between Mab and vaccination.

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 3, 6 or 12 weeks 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

Eligibility criteria: Inclusion Criteria:

* Available for the duration of the protocol follow-up;
* Consent to participate ;
* Agreed not to participate in another clinical research study until the end of the trial follow-up.

Exclusion Criteria:

* Prior history of EVD (self-reported);
* Previous vaccination with r-VSV-ZEBOV or any other Ebola vaccine (self-reported);
* Previous administration of Ebola antibody-based PEP;
* HIV-1 and/or 2 positive serology;
* Pregnant women (positive pregnancy test);
* To the opinion of the investigator, any clinically significant acute/chronic condition that would limit the participant's ability to meet the requirements of the study protocol;
* Immunosuppressive drugs;
* Participation in another clinical research study within the last 30 days;
* Allergy to any component of the vaccine or Mabs;
* Any other reason that, at the investigator's discretion, would compromise the participant's safety and cooperation in the trial.

Primary outcomes:
measure: EBOV GP IgG rate at S24 post-vaccination
timeFrame: Week 24 after vaccination
Secondary outcomes:
measure: VSV viremia
timeFrame: Day 2 after vaccination
measure: EBOV GP IgG rate at W4
timeFrame: Week 4 post-vaccination
measure: EBOV GP IgG rate at W12
timeFrame: Week 12 after vaccination
measure: Ratel of neutralizing antibodies at W12 post-vaccination
timeFrame: Week 12 after vaccination
measure: Ratel of neutralizing antibodies at W24 post-vaccination
timeFrame: Week 24 after vaccination
measure: Proportion of participants with grade 3 or 4 adverse events 2 days after vaccination
timeFrame: Day 2 after vaccination
measure: Proportion of participants with grade 3 or 4 adverse events 4 weeks after vaccination
timeFrame: Week 4 after vaccination
measure: Proportion of participants lost to follow-up at W24 after vaccination
timeFrame: Week 24 after vaccination
Other outcomes:
Locations:
city: Conakry
country: Guinea
facility: Research center of Landreah
Study officials:
affiliation: Centre Hospitalier Universitaire de Bordeaux, FRANCE
name: Denis MALVY, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CNFRSR, Maferinyah, Guinée
name: Abdoul Habib BEAVOGUI, Dr
role: PRINCIPAL_INVESTIGATOR
References: