A Phase I/II Trial of a Tetravalent Live Attenuated DEN Vaccine in Flavivirus Antibody Naive Children

Study Overview
=================
Brief Summary
-----------------
One year follow-up on immunogenicity and safety of a booster dose of DEN vaccine administered approx. 1 year following the second dose

Detailed Description
-----------------
The purpose of this study is to find out more about the two doses of dengue vaccine, over a five year period, that the children received in the Dengue-003 study and to study a third dose of dengue that will be given to the children Do children still have dengue antibodies intended to provide protection against dengue infection one year after the two doses of vaccine given in study Dengue-003? Were there any major medical problems that appeared as dengue-like symptoms during the one year after vaccinations? Will a third dose of dengue help to further stimulate the part of the immune system intended to help protect against dengue infection? Is a third dose as safe as the first two doses? Are the local reactions to a third dose of the vaccine similar to what your child experienced after the first two doses?

Official Title
-----------------
A Phase I/II, Open, Five-year, Clinical Follow-up Study of Thai Children Who Participated in Dengue-003 (A Phase I/II Trial of a Tetravalent Live Attenuated DEN Vaccine in Flavivirus Antibody Naive Children) With Evaluation of a Booster Dose Given One Year After Primary DEN Vaccination Series

Conditions
-----------------
Dengue

Intervention / Treatment
-----------------
* Biological: DEN vaccine F17


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who received two doses of DEN vaccine in the Dengue-003 study Subjects whos parents signed an informed consent form were eligible for participation in the five year follow-up study Exclusion Criteria: None

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 9 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Total vaccinated<br>The total vaccinated cohort included all enrolled subjects who received the DEN vaccine F17 for whom data were available. These subjects were Thai children previously enrolled and vaccinated in study Dengue-003 | Biological: DEN vaccine F17<br>* The dengue booster vaccine was administered subcutaneously in the non-dominant arm (deltoid). The tetravalent, live attenuated DEN F17 vaccine was administered in this study. This pre-transfection formulation contained dengue virus types 1, 2, 3 and 4 (DEN-1, -2, -3 and -4).<br>* Other names: Live attenuated tetravalent dengue (DEN) vaccine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Seropositivity Rates for Antibodies to DEN-1 - DEN-4 (ATP Cohort for Immunogenicity) | Neutralizing antibodies as measured by plaque reduction neutralization test (seropositivity rates to each dengue virus serotype at Prebooster Year 1, 30 Days Post Booster, Year 2, and Year 3 time points. | Prebooster Year 1, 30 Days Post Booster, Year 2, and Year 3 | 
| Geometric Mean Titers (GMTs) on All Subjects for Antibodies to DEN-1 - DEN-4 (ATP Cohort for Immunogenicity) | Neutralizing antibodies as measured by plaque reduction neutralization test (geometric mean titers [GMTs]) to each dengue virus serotype at Prebooster Year 1, 30 Days Post Booster, Year 2, and Year 3 time points. | Prebooster Year 1, 30 Days Post Booster, Year 2, and Year 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Solicited Local Adverse Events (AEs) Within 21 Day Follow-up | Incidence of solicited local symptoms reported during the 21-day post-vaccination (total vaccination cohort). | 21 days | 
| Unsolicited Adverse Events (AEs) Within 31 Days Post Vaccination | Percentage of subjects reporting unsolicited AEs within 31 days (Day 0-30) after the DEN vaccine dose (total vaccinated cohort) | 31 days | 
| Serious Adverse Events (SAE) Within 31 Days Post Vaccination | Occurrence of SAEs within 31 days (Day 0-30) after vaccination | 31 days | 
| Abnormal Findings Reported During Physical Exam 31-Days Post Vaccination | Incidence of dengue physical examination findings reported during the 31-day post-vaccination period (total vaccinated cohort) | 31 days | 
| Monovalent, Bivalent, Trivalent and Tetravalent Response for Neutralizing Antibodies 30 Days Post Booster | Monovalent, Bivalent, Trivalent and Tetravalent response for DEN neut. antibodies 30 days post booster dose vaccine (ATP cohort for immunogenicity) | Prebooster year 1, 30 Days Post Booster, Year 2, Year 3 | 
| Presence of Dengue Viremia 10 Days After the Dengue Vaccine Dose | Nested Polymerase Chain Reaction (PCR) for DEN was conducted on day 10 after DEN booster vaccination to evaluate the presence of Dengue viremia 10 days after vaccination | 10 days | 
| Flavivirus Infection in Terms of Dengue Immunoglobulin M and Immunoglobulin G Per Subject (ATP Cohort for Immunogenicity) | The ratio of DEN Immunoglobulin type M and G (IgM:IgG) measured at the time of booster vaccination and 30 days following was used to assess intercurrent flavivirus infection. Flavivirus infection in terms of dengue IgM and IgG and Japanese encephalitis virus (JEV) IgM and IgG is summarized. Flavivirus immunity= ratio IgM on IgG <1.8 with either IgM or IgM >1:40 If the antibody response is detectable by isotype capture enzyme immunoassay (either the IgM or IgG component ≥40 U), its anamnestic character can be inferred from detection of a DEN IgM to IgG ratio of <1.8. | 1 year, 30 Days Post Booster, 2 years | 
| Subject Biochemistry and Hematology Parameters Monitored for Alert Levels | Clinical safety laboratory test were monitored for alert levels. Tests were performed by Laser scattering using Cell Dyn 3500 and Serum chemistry conducted by Kinetic method using Hitachi 717. Normal Ranges: Alanine Aminotransferases (ALT): LNL=0 and UNL=30 Aspartate Aminotransferases (AST): LNL=0 and UNL=40 Platelet (PLA): LNL=150000 and UNL=350000 Hematocrit (HC): LNL=35 and UNL=45 Neutrophil (NEU): LNL=1500 and UNL=8000 | Year 1 (day 0); Year 1 (day 30); Year 2 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dengue, Vaccine, Thailand