Safety and Immunogenicity of the rVSVΔG-ZEBOV-GP Ebola Virus Vaccine Candidate in Children Living in Lambaréné, Gabon (EBOLAPED)

Safety and Immunogenicity of the rVSVΔG-ZEBOV-GP Ebola Virus Vaccine Candidate in Children Living in Lambaréné, Gabon

A Phase 1/2, Randomized, Controlled Open-label Trial to Evaluate the Safety and Immunogenicity of the rVSVΔG-ZEBOV-GP Ebola Virus Vaccine Candidate in Healthy Children Aged 1 to 12 Years and in Their Relatives Living in Lambaréné, Gabon

LA rVSVΔG-ZEBOV-GP -02-PED is a Phase 1/2, randomized, controlled open label trial. The LA rVSVΔG-ZEBOV-GP -02-PED trial aims primarily to assess the clinical significance of shedding of the rVSV RNA following vaccination with the rVSVΔG-ZEBOV-GP vaccine in children. The vaccine doses of ≥7.8 x 107 pfu will be evaluated and compared to vaccination with varicella vaccine as a control. In addition, the closest contact persons of the vaccinees will be monitored for possible transmission of the viral vaccine vector. The study will enroll children of two age groups living in Lambaréné, Gabon. Children will be followed-up for 12 months post vaccination. The 1-2 closest contact persons of each participant will be involved in the monitoring of rVSV transmission. They will be followed until day 56 post- vaccination of their children/ sibling.

LA-rVSVΔG-ZEBOV-GP -02-PED is a Phase 1/2, randomized, controlled, open label, trial and is designed to generate further safety, tolerability and immunogenicity data of the 7.8 x 107 PFU rVSVΔG-ZEBOV-GP vaccine in children aged 1 -12 years living in a sub-Saharan Africa. The study will enroll participants into two age groups. A total of 120 children will be enrolled and followed-up for 12 months post injection. In addition, a maximum of 240 relatives of the study participants will be enrolled to assess the transmission of the rVSVΔG-ZEBOV-GP vaccine. Group 1: 60 participants aged 6-12 years will be randomized in group 1. 40 participants will receive a single intramuscular dose of 7.8 x 107 pfu rVSVΔG-ZEBOV-GP vaccine. 20 participants will receive a single subcutaneous dose of varicella vaccine The participants will be allocated to each treatment at a ratio of 2:1 respectively Group 2: 60 participants aged 1 -5 years will be randomized into group 2. 40 will receive a single intramuscular dose of 7.8 x 107 pfu of rVSV-ZEBOV vaccine. 20 participants will receive a single subcutaneous dose of varicella vaccine The participants will be allocated to each treatment at a ratio of 2:1 respectively Vaccinations will start in group 2 after the first 10 participants of group 1 have completed the day 28 post vaccination visit and the SMC has done a review of safety data until that point. For each vaccinee there will be a 365 -day period of follow-up after vaccination. The contact persons of the vaccinees will be followed-up until day 56 after the vaccination of their relative.

The vaccine doses of ≥7.8 x 107 pfu will be evaluated and compared to vaccination with varicella vaccine as a control. In addition, the closest contact persons of the vaccinees will be monitored for possible transmission of the viral vaccine vector. The study will enroll children of two age groups living in Lambaréné, Gabon. Children will be followed-up for 12 months post vaccination. The 1-2 closest contact persons of each participant will be involved in the monitoring of rVSV transmission.

Participants of the experimental arm will receive a single intramuscular dose of ≥7.8 x 107 pfu of the rVSVΔG-ZEBOV-GP vaccine. In total, 80 participants will receive the experimental vaccine: 40 participants aged 6-12 years and 40 aged 1-5 years.

The control arm consists of the chickenpox vaccine. Forty children will receive a single subcutaneous dose of Varilix, the active comparator vaccine, 20 aged 6-12 years and 20 aged 1-5 years

Participants were assigned to receive two meals daily ( breakfast and lunch) for 21 days. About 30 children are randomly assigned to fibre and equilibrate diet.

The following pathogens: P. falciparum, Ascaris lumbricoides, Trichuris trichiura, Necator americanus, intestinal protozoa, BG+, BG- colonies and pathogens, SARS-CoV2 are actively detected and treated according to the standard of care every month. About 30 children are randomly assigned to this arm.

Participants were assigned to receive two meals daily ( breakfast and lunch) for 21 days and concomitantly assigned to active detection of P. falciparum, Ascaris lumbricoides, Trichuris trichiura, Necator americanus, intestinal protozoa, BG+, BG- colonies and pathogens, SARS-CoV2 every month. About 30 children are assigned to receive combined interventions

Participants receive fibres and caloric equilibrate diet during breakfast and lunch every day for 21 consecutive days.

Monthly diagnostic and treatment of childhood infections Active detection and treatment of pathogens.

Participants receive fibres and caloric equilibrate diet during breakfast and lunch every day for 21 consecutive days and diagnostic and treatment of childhood infections Active detection and treatment of pathogens every month for 12 months

Concentration of rVSVΔG-ZEBOV-GP in blood, urine, or saliva as detected by RT-PCR and expressed as copy number in vaccinees

Proportion (percent ) of participant experiencing unsollicited adverse event (AEs) and serious adverse events (SAEs) and relative risk of AEs and SAEs in participant by vaccine groups

Proportion (percent) of participants experiencing SAEs and relative risk of SAEs in until study last visit (at 365 days)

Transmission intensity of the viral vector in blood, saliva and urine among the the relatives of the vaccinees

Concentration of rVSVΔG-ZEBOV-GP in blood, urine, or saliva as detected by RT-PCR and expressed as copy number in the close relatives of the vaccinees

Affinity/avidity of GP-specific serum antibodies as assessed by Surface Plasmon Resonance platform at D28 and D180 expressed as percent of affinity maturation

Cytokines (IL-1RN (IL-1Ra), IL-6, TNF-α, IL-10), chemokines and soluble adhesion molecules (MCP-1/CCL2, and MIP-1β/CCL4) plasma expressed in microgram per milliliter .

Proportion (percent ) and concentration ( microgram/ mililiter) of Lipids, glutamine, Alanine, Aspargine in plasma samples

Titres of antibody induced by diphtheria, tetanus, Bordetella, poliomyelitis, hepatitis B, measles, yellow fever ( EPI vaccines)

Inclusion Criteria: Healthy children aged 1 to 12 years (inclusive) at the time of inclusion. Willingness of parent or legal guardian to provide written informed consent prior to screening procedures. Willingness of the relatives of the participant to provide written informed consent if they are ≥ 18 years (or an assent when they are 13 to 17 years old). Available, able, and willing to participate in all study visits and procedures Exclusion Criteria: History of severe local or systemic reactions to any vaccination or a history of severe allergic reactions, or known allergy to the components of the vaccines. Ongoing participation in another clinical trial Participation in previous Ebola vaccine trials Receipt of a licensed vaccine within 14 days of planned study immunization (30 days for live vaccines) Presence of any febrile illness (fever >38°C) or any moderate to severe illness within one week prior to vaccination; Administration of immunoglobulins and/or any blood products within the 120 days preceding study entry or planned administration during the study period Any other significant finding that in the opinion of the investigator would increase the risk of the individual having an adverse outcome from participating in this study.

The Principal investigator or his designee will be the data manager with responsibility for delegating the receiving, entering, cleaning, querying, analysing and storing all data that accrues from the study. All data will be entered in paper case record forms and transcribed by double entry into an electronic database. This includes safety data, laboratory data (both clinical and immunological) and outcome data.

From preliminary intererim analysis until the final report fo the study.The site owns the data and it is agreed that publication will occur in a timely manner.

All files and source documents will be kept confidentially in locked safety cabinets. The Principal investigator, co-investigators and clinical research nurses will have access to records. The investigators will permit authorized representatives of the sponsor, regulatory agencies and the monitors to examine (and when required by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits and evaluation of the study safety and progress.