Study of Purified Vero Rabies Vaccine Compared With Two Reference Rabies Vaccines, Given in a Pre-exposure Regimen to Children and Adults and as Single Booster Dose to a Subset of Adults

Study Overview
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Brief Summary
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The primary objective of this study is: To demonstrate the VRVg-2 is non-inferior to Verorab and Imovax Rabies vaccines in each age group (pediatric and adult populations) when administered as a 3-dose PrEP regimen, in terms of proportion of participants achieving a rabies virus neutralizing antibody (RVNA) titer ≥ 0.5 IU/mL at Day 42, ie. 14 days after the 3rd injection (for Primary Series Cohort 1). The secondary objectives of this study are: First 1-5 with hypotheses testing will be evaluated sequentially - only if the previous objective is achieved, will the next objective be tested To demonstrate that: the observed proportion of participants in the VRVg2(VRVg) group at D42 is at least 99% with a lower limit of the 95% confidence interval (CI) of at least 97% VRVg is non inferior (NI) to Verorab and Imovax Rabies vaccines (Imovax) in each age group at D28 2-dose VRVg at D28 is NI to 3-dose Imovax at D42 in each age group the observed proportion of participants in the VRVg group at D28 is at least 99% with a lower limit of the 95% CI of at least 97% 2-dose Imovax at D28 is NI to 3-dose Imovax at D42 in overall participants (Cohort1) To describe: the immune response induced by VRVg versus Verorab and Imovax at D28 and at D42 in all age groups the immune response induced by VRVg at D14 after a booster dose of VRVg administered at M12 (Cohort1) and between M24 up to M36 (Cohort2) the persistence of immune response at M6,12,18, and pre-booster between M24 up to M36 post-primary series vaccination (Cohort2) safety profile of VRVg versus Verorab and Imovax in primary series and after a booster dose of VRVg

Detailed Description
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The duration of each participant's participation in the primary series Cohort 1 of the study will be approximately 7 months (28 day-vaccination period followed by 6-month safety follow-up period). For the subset of adult participants in Booster Phase Cohort 1 who received a single booster dose of VRVg-2 (1 booster dose 365 days after primary series followed by 6-month safety follow-up period), the duration will be approximately 18 months. For Primary Series Cohort 2, the duration of each participant's participation in the study will be approximately 7 months (one week vaccination period followed by 6-month safety follow-up period). For the subset of adult participants in Immunogenicity Persistence and Booster Phase Cohort 2 who will be followed-up for evaluation of immunogenicity persistence after primary series (including blood samples collection at M6, M12, M18, and between 24 up to 36 months) and who will receive a single booster dose of VRVg-2 (after the blood sample collection between 24 up to 36 months), the duration will be approximately 30 to 42 months.

Official Title
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Immunogenicity and Safety of a Purified Vero Rabies Vaccine - Serum Free in Comparison With Verorab® and Imovax® Rabies, in a Pre-exposure Regimen in Both Pediatric and Adult Populations and a Single Booster Dose of Purified Vero Rabies Vaccine - Serum Free Administered at 1 Year Post-3-dose Primary Series, and Between 2 up to 3 Years Post-One Week 2-Dose Primary Series in a Subset of Adults in Thailand

Conditions
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Rabies (Healthy Volunteers)

Intervention / Treatment
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* Biological: Purified vero rabies vaccine - serum free - VRVg-2
* Biological: Purified inactivated rabies vaccine - Verorab®
* Biological: Purified inactivated rabies vaccine - Imovax® Rabies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥1 year on the day of inclusion Cohort 1 - pediatrics (>1 to 17 years old) and adult (≥18 years old) Cohort 2 - all adults (≥18 years old) Informed consent form has been signed and dated by the participant and /or and parent(s) or legally acceptable representative (LAR) and by an independent witness (if required by local regulations), as necessary; and assent form has been signed and dated by the participant, as required Participant (adult ≥18 years) or participant and parent/LAR (1 year to <18 years) are able to attend all scheduled visits and to comply with all study procedures. Exclusion Criteria: Participant is pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until 1 month after each vaccination. To be considered of non-childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, or surgically sterile. Participation at the time of study enrollment or, planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure. Receipt of any vaccine in the 4 weeks (28 days) preceding the first study vaccination or planned receipt of any vaccine prior to Visit 5 for pediatric participants and adult participants in Cohort 1, and prior to Visit 4 for adult participants in Cohort 2. Previous vaccination against rabies (in pre- or post-exposure regimen) with either the study vaccines or another vaccine. Bite by, or exposure to a potentially rabid animal in the previous 6 months with or without post-exposure prophylaxis. Receipt of immune globulins, blood or blood-derived products in the past 3 months. Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months). At high risk for rabies exposure during the study. Known systemic hypersensitivity to any of the study/control vaccine components, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances. Self-reported thrombocytopenia, contraindicating intramuscular vaccination. Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily. Current alcohol or substance abuse that, in the opinion of the investigator, might interfere with the study conduct or completion. Chronic illness(1) that, in the opinion of the Investigator, is at a stage where it might interfere with study conduct or completion. Moderate or severe acute illness/infection (according to Investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0°C). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided. Personal history of Guillain-Barré syndrome. Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (ie, parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study. Chronic illness may include, but is not limited to, neurological, cardiopulmonary, gastrointestinal, renal, genitourinary, metabolic, hematologic, auto-immune, or psychiatric disorders or infection

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
Interventional Model Description: Primary series will be observer-blinded for both Cohort 1 (3-dose pre-exposure prophylaxis [PrEP] regimen) and Cohort 2 (one week 2-dose PrEP regimen). Booster phase will be conducted in a blinded manner (vaccine received in the primary series) with an adult subset from Cohort 1 and hereafter referred as Booster Phase Cohort 1 (with booster dose 1 year after the 1st primary series vaccine injection). Evaluation of immunogenicity persistence after primary series and a booster phase will be conducted in an open label manner with an adult subset from Cohort 2 and hereafter referred as Immunogenicity Persistence and Booster Phase Cohort 2 (including blood samples collection at Month 6, Month 12, Month 18, pre-booster between Month 24 up to Month 36, and post-booster between Month 24 up to Month 36+Day 14; and a booster dose between Month 24 up to Month 36).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group1:VRVg2 Cohort1(C1)-1ry Series:pediatric&adult participants-Booster:102 adult participants<br>VRVg-2, 3 injections at Day 0, Day 7, and Day 28 Booster dose of VRVg-2 for a subset of 102 adult participants at Month 12 | Biological: Purified vero rabies vaccine - serum free - VRVg-2<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>|
| Active Comparator: Group 2:Verorab C1-1ry Series:pediatric&adult participants-Booster Phase:34 adult participants<br>Verorab, 3 injections at Day 0, Day 7, and Day 28 Booster dose of VRVg-2 for a subset of 34 adult participants at Month 12 | Biological: Purified vero rabies vaccine - serum free - VRVg-2<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>Biological: Purified inactivated rabies vaccine - Verorab®<br>* Pharmaceutical form:Freeze-dried Route of administration: Intramuscular<br>|
| Active Comparator: Group 3:Imovax Rabies C1-1ry Series:pediatric&adult participants-Booster Phase:34 adult participants<br>Imovax Rabies, 3 injections at Day 0, Day 7, and Day 28 Booster dose of VRVg-2 for a subset of 34 adult participants at Month 12 | Biological: Purified vero rabies vaccine - serum free - VRVg-2<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>Biological: Purified inactivated rabies vaccine - Imovax® Rabies<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>|
| Experimental: Group 4:VRVg-2 Cohort 2(C2)-1ry Series:Adult participants-Booster Phase:138 adult participants<br>VRVg-2, 2 injections at Day 0 and Day 7 Booster dose of VRVg-2 for a subset of 138 adult participants between Month 24 up to Month 36 | Biological: Purified vero rabies vaccine - serum free - VRVg-2<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>|
| Active Comparator: Group 5:Verorab C2-1ry Series:adult participants-Booster Phase:46 adult participants<br>Verorab, 2 injections at Day 0 and Day 7 Booster dose of VRVg-2 for a subset of 46 adult participants between Month 24 up to Month 36 | Biological: Purified vero rabies vaccine - serum free - VRVg-2<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>Biological: Purified inactivated rabies vaccine - Verorab®<br>* Pharmaceutical form:Freeze-dried Route of administration: Intramuscular<br>|
| Active Comparator: Group 6:Imovax Rabies C2-1ry Series:adult participants-Booster Phase:46 adult participants<br>Imovax Rabies, 2 injections at Day 0 and Day 7 Booster dose of VRVg-2 for a subset of 46 adult participants between Month 24 up to Month 36 | Biological: Purified vero rabies vaccine - serum free - VRVg-2<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>Biological: Purified inactivated rabies vaccine - Imovax® Rabies<br>* Pharmaceutical form: Freeze-dried Route of administration: Intramuscular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant (pediatrics and adults from Primary Series Cohort 1) with RVNA titer ≥ 0.5 IU/mL | Percentage of participants (pediatrics and adults from Primary Series Cohort 1) with RVNA titer above threshold (≥ 0.5 IU/mL). RVNA titers are measured by the rapid fluorescent focus inhibition test (RFFIT) assay | Day(D) 42 for participants in Primary Series Cohort 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with immediate adverse events | Percentage of participants reporting unsolicited systemic adverse events in the 30 minutes after vaccination | Within 30 minutes after vaccination | 
| Number of participants with solicited injection site or systemic reactions | Percentage of participants reporting injection site reactions in participants aged <=23 months: tenderness, erythema, and swelling; in participants aged 2 years and above: pain, erythema and swelling systemic reactions in participants aged <=23 months: fever, vomiting, crying abnormal, drowsiness, appetite lost, and irritability; in participants aged 2 years and above: fever, headache, malaise, and myalgia | Within 7 days after vaccination | 
| Number of participants with unsolicited adverse events | Percentage of participants with unsolicited (spontaneously reported) injection site reactions occurring within 28 days after each injection and unsolicited systemic AEs between each injection and up to 28 days after the last injection | Within 28 days after vaccination | 
| Number of participants with serious adverse events (SAEs) and adverse events of special interest (AESIs) | Percentage of participants with SAEs, including AESIs, throughout the study | Within at least 6 months(M) after each vaccination as applicable to Cohort 1(C1) and Cohort 2 (C2) | 
| RVNA titers | RVNA titers are measured by RFFIT and expressed as geometric mean titers (GMT) | D0 & D28 for participants in 1ry Series C1 & C2;D42 for participants in 1ry Series C1;M12 & 12+D14 for participants in Booster C1;M6,M12,M18;Between M24 up to M36 & between M24 up to M36+D14 for participants in Immunogenicity Persistence & BoosterC2 | 
| RVNA titer ≥ 0.5 IU/mL | Percentage of participants with RVNA titers above threshold (≥ 0.5 IU/mL) RVNA titers are measured by RFFIT | D0 & D28 for participants in 1ry Series C1 & C2;D42 for participants in 1ry Series C1;M12 & 12+D14 for participants in Booster C1;M6,M12,M18;Between M24 up to M36 & between M24 up to M36+D14 for participants in Immunogenicity Persistence & BoosterC2 | 
| RVNA titer above lower limit of quantification (LLOQ) IU/Ml | Percentage of participants with RVNA titers above LLOQ IU/ml are measured by RFFIT | D0 & D28 for participants in 1ry Series C1 & C2;D42 for participants in 1ry Series C1;M12 & 12+D14 for participants in Booster C1;M6,M12,M18;Between:M24 up to M36 & between M24 up to M36+D14 for participants in Immunogenicity Persistence & BoosterC2 | 
| RVNA titer ratio | Individual RVNA titer ratio | Day 28/Day 0 on Primary Series Cohort 1 and Cohort 2 Day 42/Day 0 for participants in Primary Series Cohort 1 Month 12/Day 0, 14 days after Month 12/Day 0, and 14 days after Month12/Month12, for participants in Booster Phase Cohort 1 Month 6/Day 0, Month | 
| Participant with complete or incomplete neutralization at the starting dilution of the RFFIT assay | Percentage of participants with complete or incomplete neutralization at the dilution of 1/5 in RFFIT | D0 & D28 for participants in 1ry Series C1 & C2;D42 for participants in 1ry Series C1;M12 & 12+D14 for participants in Booster C1;M6,M12,M18;Between:M24 up to M36 & between M24 up to M36+D14 for participants in Immunogenicity Persistence & BoosterC2 |