Staged Phase 3 Study to Assess the Safety and Immunogenicity of Ebola Candidate Vaccines Ad26.ZEBOV and MVA-BN-Filo

Study Overview
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Brief Summary
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The purpose of this study is the evaluation of the safety and immunogenicity of two candidate Ebola vaccines Ad26.ZEBOV and MVA-BN-Filo, in a 2-dose heterologous regimen.

Detailed Description
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This is staged Phase 3 study to gather information on the safety and immunogenicity of a 2-dose heterologous regimen. In this regimen, Ad26.ZEBOV will be administered as a Dose 1 vaccination followed by the candidate vaccine MVA-BN-Filo (Dose 2 56 days later) and a booster dose of A26.ZEBOV will be administered 2 years post Dose 1 vaccination to participants in Stage 1 who consent to this. The study will take place in Sierra Leone and will consist of a screening phase, an active phase (vaccination) and a follow-up phase. The active phase of the study will be conducted initially in two stages. In the first stage approximately 40 adults aged 18 years or older will be vaccinated to gain information about the safety and immunogenicity of the 2-dose heterologous vaccine regimen. In stage 2 a larger group of approximately 976 individuals will be vaccinated to further evaluate the safety and immunogenicity of the 2 dose heterologous vaccine regimen across different age groups. In this stage, children aged 1 year or older, adolescents and adults will be included. Solicited local and systemic adverse events will be collected until 7 days after the Dose 1 and Dose 2 vaccination. Unsolicited adverse events will be collected from signing of the informed consent form (ICF) onwards until 56 days after the Dose 2 vaccination in Stage 1 and then again from the day of the booster vaccination until 28 days after the booster vaccination, and until 28 days after each vaccination in stage 2. Serious adverse events will be collected from signing of the ICF onwards until 12 and 36 months after the Dose 1 vaccination in Stage 2 and Stage 1, respectively. These data will be reviewed by an independent data monitoring committee (IDMC) to assess whether initiation of vaccination in the next stage or age group can be provided. Safety evaluations will include assessment of adverse events, which will be monitored throughout the study. Participants in Stage 2 will be followed up for safety and immunogenicity until 12 months (children and adolescents) or 24 months (adults) after the Dose 1 vaccination. Participants in Stage 1 will be followed up for safety and immunogenicity until 36 months after the Dose 1 vaccination or until 1 year after the booster vaccination.

Official Title
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A Staged Phase 3 Study, Including a Double-Blinded Controlled Stage to Evaluate the Safety and Immunogenicity of Ad26.ZEBOV and MVA-BN-Filo as Candidate Prophylactic Vaccines for Ebola

Conditions
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Ebola Virus Disease

Intervention / Treatment
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* Biological: Ad26.ZEBOV
* Biological: MVA-BN-Filo
* Biological: MenACWY
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Stage 1 and 2: Documented community engagement from community leader and a signed inform consent form (ICF) from each participant must be available Participant Stage 1 must be 18 years or older at screening and be resident in selected study community with no intention to move from study area within the next 5 months Participant must be healthy with no abnormalities in laboratory screening tests within 28 days before Dose 1 vaccination Female participants of childbearing potential must use adequate birth control measures and must have a negative pregnancy test at screening and immediately prior to each study vaccination Participant must pass the test of understanding (TOU) Additional Inclusion criteria Stage 2: One year or older at screening (children of enrolled parents are eligible) Parent/legal guardian (for children) must pass the TOU before signing the ICF Subjects aged 7 years and older will be asked to give positive assent in the presence of a witness Exclusion Criteria: Diagnosed with EVD or under quarantine/exposed to Ebola or body temperature equal of >= 38 degree Celsius (fever) Having an acute illness (mild in nature that can be treated at home) or any clinically significant acute/chronic medical condition or having a decreased number of red blood cells/hemoglobin in the blood (anemia) Previously participated in another Ebola interventional study or received any Ad26/MVA-based candidate vaccine Vaccinated with live attenuated vaccines within 30 days or with inactivated vaccines 15 days before Dose 1 vaccination Treated with an immunosuppressive drug at the time of screening Additional exclusion criteria: - Children up to 5 years of age with severe malnutrition (underweight or Z-score weight <2)

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Active vaccination<br>Ad26.ZEBOV will be administered as a 0.5 milliliter (mL) intramuscular (IM) injection (Dose 1); MVA-BN-Filo will be administered as a 0.5 mL IM injection (Dose 2). The booster vaccination using Ad26.ZEBOV will be administered as a 0.5 mL IM injection (2 years post Dose 1). | Biological: Ad26.ZEBOV<br>* Ebola Zaire vaccine, replication incompetent vaccine, sterile suspension of 0.5 milliliter (mL) intramuscular (IM) injection of 5*10^10 viral particles.<br>Biological: MVA-BN-Filo<br>* MVA-BN-Filo- is a non-replicating vaccine, 0.5 mL IM injection of 1*10^8 Infectious Unit (Inf. U.).<br>|
| Experimental: Stage 2: Active vaccination<br>Ad26.ZEBOV will be administered as a 0.5 mL IM injection (Dose 1); MVA-BN-Filo will be administered as a 0.5 mL IM injection (Dose 2). | Biological: Ad26.ZEBOV<br>* Ebola Zaire vaccine, replication incompetent vaccine, sterile suspension of 0.5 milliliter (mL) intramuscular (IM) injection of 5*10^10 viral particles.<br>Biological: MVA-BN-Filo<br>* MVA-BN-Filo- is a non-replicating vaccine, 0.5 mL IM injection of 1*10^8 Infectious Unit (Inf. U.).<br>|
| Experimental: Stage 2: Active vaccination for children<br>Ad26.ZEBOV will be administered as a 0.5 mL IM injection (Dose 1); MVA-BN-Filo will be administered as a 0.5 mL IM injection (Dose 2). Children aged less than 2 years at randomization will receive a booster dose of vaccination at 3 months post Dose 2 with Placebo. | Biological: Ad26.ZEBOV<br>* Ebola Zaire vaccine, replication incompetent vaccine, sterile suspension of 0.5 milliliter (mL) intramuscular (IM) injection of 5*10^10 viral particles.<br>Biological: MVA-BN-Filo<br>* MVA-BN-Filo- is a non-replicating vaccine, 0.5 mL IM injection of 1*10^8 Infectious Unit (Inf. U.).<br>|
| Active Comparator: Stage 2: Control vaccination<br>MenACWY will be administered as a 0.5 mL IM injection on Day 1 (Dose 1) and placebo on Day 57 (Dose 2). | Biological: MenACWY<br>* MenACWY is a WHO-prequalified Meningococcal Group A, C, W135 and Y conjugate vaccine.<br>Biological: Placebo<br>* 0.9% saline for injection.<br>|
| Active Comparator: Stage 2: Control vaccination for children<br>MenACWY will be administered as a 0.5 mL IM injection on Day 1 (Dose 1) and placebo on Day 57 (Dose 2). Children aged less than 2 years at randomization will receive a booster dose of MenACWY vaccination at 3 months post Dose 2 with MenACWY. | Biological: MenACWY<br>* MenACWY is a WHO-prequalified Meningococcal Group A, C, W135 and Y conjugate vaccine.<br>Biological: Placebo<br>* 0.9% saline for injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stages 1 and 2: Number of Participants With Solicited Local Adverse Events (AEs) (Day 8) | Number of participants with solicited local AEs were reported. Solicited local AEs were pre-defined local (at the injection site) AEs for which participants were specifically questioned and which were noted by participants in their diary for 7 days post vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. | 7 days post dose 1 (Day 8) | 
| Stages 1 and 2: Number of Participants With Solicited Local AEs (Day 64) | Number of participants with solicited local AEs were reported. Solicited local AEs were pre-defined local (at the injection site) AEs for which participants were specifically questioned and which were noted by participants in their diary for 7 days post vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. | 7 days post dose 2 (Day 64) | 
| Stage 1: Number of Participants With Solicited Local AEs (Day 738) | Number of participants with solicited local AEs were reported. Solicited local AEs were pre-defined local (at the injection site) AEs for which participants were specifically questioned and which were noted by participants in their diary for 7 days post vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. | 7 days post dose 3 (Day 738) | 
| Stages 1 and 2: Number of Participants With Solicited Systemic AEs (Day 8) | Number of participants with solicited systemic AEs were reported. Solicited systemic AEs included body temperature, vomiting, reduced activity, somnolence, fatigue, irritability/fussiness/crying/screaming, and loss of appetite (for preverbal children/infants) and body temperature, nausea/vomiting, fatigue/malaise, muscle pain, chills, joint pain and headache (for young children, adolescents, and adults). | 7 days post dose 1 (Day 8) | 
| Stages 1 and 2: Number of Participants With Solicited Systemic AEs (Day 64) | Number of participants with solicited systemic AEs were reported. Solicited systemic AEs included body temperature, vomiting, reduced activity, somnolence, fatigue, irritability/fussiness/crying/screaming, and loss of appetite (for preverbal children/infants) and body temperature, nausea/vomiting, fatigue/malaise, muscle pain, chills, joint pain and headache (for young children, adolescents, and adults). | 7 days post dose 2 (Day 64) | 
| Stage 1: Number of Participants With Solicited Systemic AEs (Day 738) | Number of participants with solicited systemic AEs were reported. Solicited systemic AEs included body temperature, vomiting, reduced activity, somnolence, fatigue, irritability/fussiness/crying/screaming, and loss of appetite (for preverbal children/infants) and body temperature, nausea/vomiting, fatigue/malaise, muscle pain, chills, joint pain and headache (for young children, adolescents, and adults). | 7 days post dose 3 (Up to Day 738) | 
| Stages 1: Number of Participants With Serious Adverse Events (SAEs) | Number of Participants with SAEs were reported. SAE is any untoward medical occurrence that at any dose may result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. | Up to 36 months | 
| Stages 2: Number of Participants With SAEs | Number of Participants with SAEs were reported. SAE is any untoward medical occurrence that at any dose may result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. | Up to 24 months | 
| Stage 1: Number of Participants With Unsolicited AEs (Day 759) | Number of participants with unsolicited AEs were reported. Unsolicited AEs were all AEs for which the participant is not specifically questioned in the participant diary. | 28 days post booster dose (Day 759) | 
| Stage 1: Number of Participants With Unsolicited AEs (Day 29) | Number of participants with unsolicited AEs were reported. Unsolicited AEs were all AEs for which the participant is not specifically questioned in the participant diary. | 28 days post dose 1 (Day 29) | 
| Stage 2: Number of Participants With Unsolicited AEs (Day 29) | Number of participants with unsolicited AEs were reported. Unsolicited AEs were all AEs for which the participant is not specifically questioned in the participant diary. | 28 days post dose 1 (Day 29) | 
| Stage 1: Number of Participants With Unsolicited AEs (Day 85) | Number of participants with unsolicited AEs were reported. Unsolicited AEs were all AEs for which the participant is not specifically questioned in the participant diary. | 28 days post dose 2 (Day 85) | 
| Stage 2: Number of Participants With Unsolicited AEs (Day 85) | Number of participants with unsolicited AEs were reported. Unsolicited AEs were all AEs for which the participant is not specifically questioned in the participant diary. | 28 days post dose 2 (Day 85) | 
| Stage 1: Number of Participants With Deaths | Number of participants with deaths were reported. | Up to 36 months | 
| Stage 2: Number of Participants With Deaths (Children and Adolescents) | Number of participants (children and adolescents) with deaths were reported. | Up to 12 months | 
| Stage 2: Number of Participants With Deaths (Adults) | Number of participants (adults) with deaths were reported. | Up to 24 months | 
| Stage 1: Number of Participants With Immediate Reportable Event (IREs) | Number of participants with IREs were reported. The following list of neuroinflammatory disorders are categorized as IREs: Cranial nerve disorders, including paralyses/paresis, optic neuritis, multiple sclerosis, transverse myelitis, guillain-Barré syndrome, acute disseminated encephalomyelitis, including site specific variants, myasthenia gravis and Lambert-Eaton myasthenic syndrome, immune-mediated peripheral neuropathies and plexopathies, narcolepsy, isolated paresthesia of greater than (>) 7 days duration. | Up to 36 months | 
| Stage 2: Number of Participants With IREs (Children and Adolescents) | Number of participants (children and adolescents) with IREs were reported. The following list of neuroinflammatory disorders are categorized as IREs: Cranial nerve disorders, including paralyses/paresis, optic neuritis, multiple sclerosis, transverse myelitis, guillain-Barré syndrome, acute disseminated encephalomyelitis, including site specific variants, myasthenia gravis and Lambert-Eaton myasthenic syndrome, immune-mediated peripheral neuropathies and plexopathies, narcolepsy, isolated paresthesia of greater than (>) 7 days duration. | Up to 12 months | 
| Stage 2: Number of Participants With IREs (Adults) | Number of participants (adults) with IREs were reported. The following list of neuroinflammatory disorders are categorized as IREs: Cranial nerve disorders, including paralyses/paresis, optic neuritis, multiple sclerosis, transverse myelitis, guillain-Barré syndrome, acute disseminated encephalomyelitis, including site specific variants, myasthenia gravis and Lambert-Eaton myasthenic syndrome, immune-mediated peripheral neuropathies and plexopathies, narcolepsy, isolated paresthesia of greater than (>) 7 days duration. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stages 1 and 2: Geometric Mean Concentrations (GMCs) of Binding Antibody Levels Against Ebola Virus Glycoprotein (EBOV GP) Measured Using Enzyme-linked Immunosorbent Assay (ELISA) | GMCs of antibodies binding to EBOV GP using ELISA were reported and were measured in ELISA units per milliliter (EU/mL). Serum samples were collected for analysis of binding antibodies against EBOV GP using ELISA to determine humoral responses following vaccination. For ELISA binding antibody responses, values below the lower limit of quantification (LLOQ) (36.11 ELISA units/mL). | 21 days post-dose 2 (Day 78) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ebola, Vaccine, Ebola virus disease, EVD, Hemorrhagic fever, Sierra Leone, Human adenovirus serotype 26 (Ad26) encoding the Ebola virus Mayinga variant glycoprotein (Ad26.ZEBOV), Safety, Immunogenicity, Modified Vaccinia Virus Ankara - Bavarian Nordic Filo-vector, (MVA-BN Filo)