Safety, Tolerability and Immunogenicity Study of 3 Prime-boost Regimens for Ebola Vaccines Ad26.ZEBOV/MVA-BN-Filo in Healthy Adults, Children and Human Immunodeficiency Virus Positive (HIV+) Adults

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability and immunogenicity of three heterologous prime-boost regimens for Ebola vaccines Ad26.ZEBOV and MVA-BN-Filo. The study will include healthy adults and elderly participants, HIV infected participants and healthy children in 2 age strata.

Detailed Description
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This is a randomized, observer-blind, placebo-controlled, parallel-group, multicenter, Phase 2 study evaluating the safety, tolerability and immunogenicity of 3 heterologous prime-boost regimens using Ad26.ZEBOV as prime and MVA-BN-Filo as boost vaccination, administered at 28-, 56- and 84-day (Group 1, 2 and 3 as above) intervals, in healthy adults and elderly participants. A 28- and 56-day (Groups 1 and 2, as above) schedule will be evaluated in HIV-infected participants and in healthy children in 2 age strata. The study consists of a screening phase of up to 8 weeks, a vaccination phase in which participants will be vaccinated at baseline (Day 1) followed by a boost vaccination on Day 29, 57 or 85, a post-vaccination phase and long-term follow-up phase until Day 365. Participants in Cohort 1 substudy (Group 1 and 2) who received Ad26.ZEBOV and MVA-BN-Filo (at selected sites) will receive Ad26.ZEBOV as third vaccination and who received placebo will receive placebo as third vaccination (at least 1 year post prime vaccination). All participants within a cohort will be followed in a blinded manner by the site until the last subject in that cohort has completed the study. This study will be conducted in Africa and the enrollment will take place sequentially in three cohorts: the first cohort will consist of healthy participants (18 - 70 years); the second cohort (2a) will include HIV-infected participants (18 to 50 years) and healthy children 12 to 17 years (cohort 2b); the third cohort will include children aged 4 to 11 years inclusive will be enrolled. Within each cohort, participants will be randomized in a 5:1 ratio to receive active vaccine versus placebo. Safety evaluations will include assessments of adverse events, an electrocardiogram (ECG) for adult participants at screening, physical examination, vital signs (blood pressure, pulse/heart rate, body temperature), clinical laboratory and pregnancy testing. An independent data monitoring committee (IDMC) will be established to monitor data on a regular basis to ensure the continuing safety of the participants enrolled in the study.

Official Title
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A Randomized, Observer-blind, Placebo-controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Immunogenicity of Different Prime-boost Regimens of the Candidate Prophylactic Vaccines for Ebola Ad26.ZEBOV and MVA-BN-Filo in Healthy Adults, Including Elderly Subjects, HIV-infected Subjects, and Healthy Children in Two Age Strata in Africa

Conditions
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Hemorrhagic Fever, Ebola

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Criteria for healthy adults and elderly participants: Participant must be healthy in the investigator's clinical judgment on the basis of clinical laboratory tests, medical history, ECG, physical examination and vital signs performed at screening. Participants with hemoglobin values outside the local laboratory reference ranges may be included if the hemoglobin is above the age/gender specific limits Female participants of childbearing potential must use adequate birth control measures, must have a negative pregnancy test at screening and immediately prior to each study vaccination A man who is sexually active with a woman of childbearing potential must be willing to use condoms for sexual intercourse beginning prior to enrollment, unless a vasectomy was performed more than 1 year prior to screening Participant must pass the test of understanding (TOU) Participant must be available and willing to participate for the duration of the study visits and follow-up, provide verifiable identification, and have a means to be contacted Additional Inclusion Criteria HIV-infected Participants Participant must be between 18 to 50 years of age and must have a documented HIV-infection for at least 6 months prior to screening Participant must be on a stable 3 drug regimen of Highly Active Antiretroviral Therapy for at least 4 weeks prior to screening and having a CD4 positive cell count of >350 cells/microliter. Also participant must be in an otherwise reasonable good medical condition Additional Inclusion Criteria Children Participants Parent/legal guardian must pass the TOU before signing the inform consent form. Informed assent must be obtained from adolescents and older children, depending on local regulations and practice Pediatric participant's age on the day of randomization must be within one of the 2 age strata: 12-17 years or 4-11 years (all ages inclusive) Pediatric participants must have received all routine immunizations appropriate for his or her age as reported by the parent(s)/legal guardian, according to local routine vaccination schedules Exclusion criteria: Diagnosed with Ebola virus disease or previously exposed to Ebola virus including travel to epidemic Ebola areas less than 1 month prior to screening Having received any candidate Ebola vaccine or any experimental candidate Ad26- or MVA-based vaccine in the past Having HIV type 1 or type 2 infection (for healthy adults/elderly/children) Pediatric participants with weight-per-height below 10th percentile according to the Centers for Disease Control and Prevention (CDC) growth charts (4- to 11-year-olds) A woman who is pregnant, breast-feeding or planning to become pregnant while enrolled in the study or within at least 3 months after the prime vaccination or up to 1 month after the boost vaccination (whichever takes longer) or within at least 3 months after the third vaccination For HIV+ adults, no AIDS-defining illnesses

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 70 Years

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Participants will receive Ad26.ZEBOV, MVA-BN-Filo (Day 1/Day 29) or placebo (Day 1/Day 29) followed by a subset of participants who received Ad26.ZEBOV and MVA-BN-Filo (at selected sites) will receive Ad26.ZEBOV as third vaccination and who received placebo will receive placebo as third vaccination (at least 1 year post prime vaccination). | Biological: Ad26.ZEBOV<br>* One 0.5 mL intramuscular (IM) injection of (5x10*10 viral particles)<br>Biological: MVA-BN-Filo<br>* One 0.5 mL IM injection of (1x10*8 infectious units)<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9% saline<br>|
| Experimental: Group 2<br>Participants will receive Ad26.ZEBOV, MVA-BN-Filo (Day 1/Day 57) or placebo (Day 1/Day 57) followed by a subset of participants who received Ad26.ZEBOV and MVA-BN-Filo (at selected sites) will receive Ad26.ZEBOV as third vaccination and who received placebo will receive placebo as third vaccination (at least 1 year post prime vaccination). | Biological: Ad26.ZEBOV<br>* One 0.5 mL intramuscular (IM) injection of (5x10*10 viral particles)<br>Biological: MVA-BN-Filo<br>* One 0.5 mL IM injection of (1x10*8 infectious units)<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9% saline<br>|
| Experimental: Group 3<br>Participants will receive Ad26.ZEBOV, MVA-BN-Filo (Day 1/Day 85) or placebo (Day 1/Day 85) | Biological: Ad26.ZEBOV<br>* One 0.5 mL intramuscular (IM) injection of (5x10*10 viral particles)<br>Biological: MVA-BN-Filo<br>* One 0.5 mL IM injection of (1x10*8 infectious units)<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9% saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (Day 29) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. | Up to 28 days post-dose 1 (Day 29) | 
| Number of Participants With Adverse Events (AEs) (28-Day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. | Up to 28 days post-dose 2 (Day 57 for Cohorts 1, 2a, 2b and 3 [28-Day Interval]) | 
| Number of Participants With Adverse Events (56-day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. | Up 28 days post-dose 2 (Day 85 for Cohorts 1, 2a, 2b and 3 [56-Day Interval]) | 
| Number of Participants With Adverse Events (84-day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. | Up to 28 days post-dose 2 (Day 113 for Cohort 1 [84-Day Interval]) | 
| Number of Participants With Adverse Events Post-dose 3 (Day 393) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. | Up 28 days post-dose 3 (Day 393) | 
| Number of Participants With Serious Adverse Events | A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Up to 3 years and 3 months | 
| Number of Participants With Immediate Reportable Events (IREs) | The following neuroinflammatory disorders were considered immediate reportable events which had to be reported to the sponsor within 24 hours of becoming aware of the event. Neuroinflammatory disorders included: cranial nerve disorders including paralyses/paresis (example: bell's palsy), optic neuritis, multiple sclerosis, transverse myelitis, guillain-barre syndrome including miller fisher syndrome, bickerstaff's encephalitis and other variants, acute disseminated encephalomyelitis, including site-specific variants (example: non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis), myasthenia gravis and lambert-eaton myasthenic syndrome, immune-mediated peripheral neuropathies and plexopathies, including chronic inflammatory, demyelinating polyneuropathy, multifocal motor neuropathy, and polyneuropathies associated with monoclonal gammopathy, narcolepsy, isolated paresthesia of more than 7 days duration. | Up to 3 years and 3 months | 
| Number of Participants With Solicited Local Adverse Events (Day 8) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. 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) | 
| Number of Participants With Solicited Local Adverse Events (28-day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. 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. | Up to 7 days post-dose 2 (Day 36 for Cohort 1, 2a, 2b and 3 [28-Day Interval]) | 
| Number of Participants With Solicited Local Adverse Events Post-dose 2 (56-day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. 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. | Up to 7 days post-dose 2 (Day 64 for Cohort 1, 2a, 2b and 3 [56-Day Interval]) | 
| Number of Participants With Solicited Local Adverse Events (84-day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. 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. | Up to 7 days post-dose 2 (Day 92 for Cohort 1 [84-Day Interval]) | 
| Number of Participants With Solicited Local Adverse Events (Day 372) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. 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. | Up 7 days post-dose 3 (Day 372) | 
| Number of Participants With Solicited Systemic Adverse Events (Day 8) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | Up to 7 days post-dose 1 (Day 8) | 
| Number of Participants With Solicited Systemic Adverse Events (28-Day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | Up to 7 days post-dose 2 (Day 36 for Cohorts 1, 2a, 2b and 3 [28-Day Interval]) | 
| Number of Participants With Solicited Systemic Adverse Events (56-Day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | Up 7 days post-dose 2 (Day 64 for Cohort 1, 2a, 2b and 3 [56-Day Interval]) | 
| Number of Participants With Solicited Systemic Adverse Events (84-Day Interval) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | Up 7 days post-dose 2 (Day 92 for Cohort 1 [84-Day Interval]) | 
| Number of Participants With Solicited Systemic Adverse Events (Day 372) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | Up to 7 days post-dose 3 (Day 372) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentrations (GMCs) of Binding Antibody Levels Against Ebola Virus Glycoprotein (EBOV GP) Measured Using Filovirus Animal Non-Clinical Group (FANG) Enzyme-linked Immunosorbent Assay | GMCs of antibodies binding to EBOV GP using FANG ELISA were reported and were measured in ELISA unit per milliliter (EU/mL). Serum samples were collected for analysis of binding antibodies against EBOV GP using FANG 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 50 for Cohorts 1, 2a, 2b, 3 [28-day interval] , Day 78 for Cohort 1, 2a, 2b, 3 [56-day interval] and Day 106 Cohort 1 [84-day interval] | 
| Number of Participants With Serious Adverse Events Post-dose 3 | A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Up 28 days post-dose 3 (Day 393) | 

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