Association of Host Genetics With Vaccine Efficacy and Study of Immune Correlates of Risk From a Tetravalent Dengue Vaccine

Study Overview
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Brief Summary
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Primary objectives: To assess how dengue vaccine efficacy varies across participant subgroups regarding polymorphism in human leukocyte antigen (HLA) alleles of interest. To assess the association between HLA alleles and, serotype-specific neutralization antibody titers and summary neutralization measure in the vaccine and placebo groups. To assess the association between the polymorphism in HLA alleles of interest and susceptibility to Dengue fever and Dengue Haemorrhagic fever. Secondary objectives: To assess whether dengue serotype-specific neutralizing antibody titers and associated summary neutralization measure at 28 days post-dose 3 are related to the rate of occurrence of symptomatic Virologically-confirmed dengue infection after post-dose 3 To evaluate whether the dengue serotype-specific neutralizing antibody and associated summary neutralization measure at 28 days post-dose 3 are related to the level of vaccine efficacy against dengue viruses after post-dose 3.

Detailed Description
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The enrolled population will include both, virologically-confirmed (VC) dengue cases and subjects not having experienced a VC dengue infection (control subjects) from the first Proof of Concept efficacy study conducted in Thailand Analyses for correlates will be performed on samples collected in the context of the first proof of concept efficacy study. Sequencing of dengue viruses will also be done on samples collected within the same context. Immunogenetic testing will be performed on saliva samples collected at the study enrollment visit. No intervention or vaccine will be provided or administered as part of this study.

Official Title
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Association of Host Genetics With Vaccine Efficacy, and Evaluation of Immune Correlates of Risk From the First Proof of Concept Efficacy Study With a Tetravalent Dengue Vaccine

Conditions
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Dengue Fever, Dengue Haemorrhagic Fever

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject currently enrolled in, or having recently finished, CYD57 (NCT01983553; long-term safety follow-up study of the first PoC efficacy study), included in the subjects list provided by the Sponsor, with or without past experience of virologically confirmed dengue. For children 7 to < 18 years. Assent form (AF) has been signed and dated by the subject, and informed consent form (ICF) has been signed and dated by the parents or another legally acceptable representative and by independent witness, as per local Ethics Committee (EC) requirement. For subjects ≥ 18 years. ICF has been signed and dated by the subject and by independent witness, as per local EC requirement. Subject (and parent(s) / legally acceptable representative for subject < 18 years) are able to attend the scheduled visit and can comply with all study procedures. Exclusion Criteria: Any illness that, in the opinion of the Investigator, might interfere with study procedures.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Case D1<br>Subject having experienced a Virologically confirmed dengue infection, from the first injection until the end of the active phase, excluding Case D3 subjects | |
| Case D3<br>Subject having experienced a Virologically confirmed dengue infection, from 28 days after the third injection until the end of the Active Phase of the proof of concept (PoC) efficacy study | |
| Control I<br>Subject having not experienced a Virologically confirmed dengue infection in the Active Phase of the PoC efficacy study, and belonging to the PoC efficacy study immunogenicity subset | |
| Control E<br>Subject having not experienced a Virologically confirmed dengue infection in the Active Phase of the PoC efficacy study, and not belonging to the PoC efficacy study immunogenicity subset | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Symptomatic Virologically confirmed dengue cases having occurred during the Active Phase of the first proof of concept efficacy study after post dose 1 | A symptomatic Virologically confirmed (VC) dengue case is defined as (i) Acute febrile illness with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), and (ii) VC by reverse transcriptase polymerase chain reaction (RT PCR) and / or dengue non structural protein 1 (NS1) enzyme linked immunosorbent assay (ELISA) Antigen test | 28 days post-injection 1 up to 4 years (the end of the Active phase) | 
| Neutralizing Antibody level against each of the four parental dengue virus serotype strains of Sanofi Pasteur's dengue vaccine constructs measured at 28 days post dose 3 |  | 28 days post-dose 3 (1 year post-dose 1) | 
| Number of probable Dengue fever and Dengue Hemorrhagic Fever grade I, II, III, and IV occurring during the Active Phase of the first PoC efficacy study after post dose 1. | Probable Dengue fever is an acute febrile illness with two or more of the following manifestations: Headache, Retro orbital pain, Myalgia, Arthralgia, Rash, Haemorrhagic manifestations, and Leukopaenia | Up to 6 months post-dose 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Symptomatic Virologically confirmed dengue cases having occurred during the Active Phase of the first proof of concept efficacy study after post dose 3 | A symptomatic Virologically confirmed (VC) dengue case is defined as (i) Acute febrile illness with fever lasting for at least 1 day (temperature ≥37.5°C measured at least twice with an interval of at least 4 hours), and (ii) VC by reverse transcriptase polymerase chain reaction (RT PCR) and / or dengue non structural protein 1 (NS1) enzyme linked immunosorbent assay (ELISA) Antigen test | 28 days post-injection 3 up to 4 years (end of the Active phase) | 
| Neutralizing Antibody level against each of the four parental dengue virus serotype strains of Sanofi Pasteur's dengue vaccine constructs measured at post dose 3 |  | Post-dose 3 (1 year post-dose 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue Fever, Dengue Haemorrhagic Fever, Tetravalent Dengue Vaccine