Immunogenicity and Safety of a Tetravalent Dengue Vaccine Booster Injection in Subjects Who Previously Completed a 3-dose Schedule

Study Overview
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Brief Summary
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The aim of the study was to assess and describe the booster effect of a tetravalent CYD dengue vaccine dose administered about 5 years or more after the completion of a 3-dose vaccination schedule in Singapore. Primary Objective: To demonstrate the non-inferiority in terms of geometric mean of titer ratios (GMTRs) of a CYD dengue vaccine booster compared to the third CYD dengue vaccine injection in participants from CYD28 trial (participants from Group 1 only). Secondary Objectives: If the primary objective of non-inferiority achieved: To demonstrate the superiority, in terms of GMTRs, of a CYD dengue vaccine booster compared to the third CYD dengue vaccine injection in participants from CYD28 trial (participants from Group 1 only). To describe the immune responses elicited by the CYD dengue vaccine booster or placebo injection in participants who received three doses of the CYD dengue vaccine in the CYD28 trial in all participants. To describe the neutralizing antibody levels of each dengue serotype Post Dose 3 (CYD28 participants) and immediately prior to booster or placebo injection in all participants. To describe the neutralizing antibody persistence 6 months, 1 year and 2 years post booster or placebo injection in all study participants. To evaluate the safety of booster vaccination with CYD dengue vaccine in all participants.

Detailed Description
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Healthy adolescents and adults received 3 doses of the tetravalent dengue vaccine 5-6 years earlier in a previous CYD dengue vaccine trial (CYD28 - NCT00880893) received either a booster injection of CYD dengue vaccine or a placebo on Day 0. They were evaluated for safety and antibody persistence of the booster injection up to 2 years post-vaccination.

Official Title
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Immunogenicity and Safety of a Tetravalent Dengue Vaccine Given as a Booster Injection in Adolescents and Adults Who Previously Completed the 3-dose Schedule in a Study Conducted in Singapore

Conditions
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Dengue Hemorrhagic Fever, Dengue Fever

Intervention / Treatment
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* Biological: CYD Dengue Vaccine (5 dose formulation)
* Biological: Placebo, NaCl 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Had been identified as a potential participant by the Sponsor, and was included in the list provided to the investigator (i.e., aged 9 to 45 years on the day of first injection of CYD dengue vaccine in CYD28, had received 3 doses of CYD dengue vaccine in the CYD28 trial, and had a post-dose 3 serum sample available). Participants with good health, based on medical history and physical examination. Informed consent form (ICF) had been signed and dated by participant (based on local regulations), and ICF had been signed and dated by the parent(s) or another legally acceptable representative (and by an independent witness if required by local regulations). Participant and parent(s)/legally acceptable representative(s) was able to attend all scheduled visits to comply with all trial procedures. Exclusion Criteria: Participant who received any other dengue vaccination that was not part of CYD28. Participant was pregnant, or lactating, or of childbearing potential (considered of non childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to vaccination until at least 4 weeks after vaccination). Participation at the time of study enrollment (or in the 4 weeks preceding the trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure. Receipt of any vaccine in the 4 weeks preceding the trial vaccination or planned receipt of any vaccine in the 4 weeks following the trial vaccination 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). Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances. Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion. Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily. Current alcohol abuse or drug addiction. 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 had resolved or the febrile event had subsided. 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 (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 50 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYD Dengue Vaccine booster Group<br>Participants who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63). | Biological: CYD Dengue Vaccine (5 dose formulation)<br>* 0.5 mL, Subcutaneous<br>|
| Placebo Comparator: Placebo Group<br>Participants who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received an injection of a placebo at Day 0 in this study (CYD63). | Biological: Placebo, NaCl 0.9%<br>* 0.5 mL, Subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With CYD Dengue Vaccine in CYD63 Compared to the Third CYD Dengue Vaccine Injection Received in Study CYD28: CYD Dengue Vaccine Booster Group | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the plaque reduction neutralization test (PRNT). | 28 days post-dose 3 in CYD28 and 28 days post-booster injection in CYD63 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GMTs of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection (Inj.) With Either CYD Dengue Vaccine or Placebo | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. | Pre-booster injection (Day 0) and 28 days post-booster injection | 
| GMTRs of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. GMTRs were calculated as the ratio of GMTs post-booster injection and pre-booster injection. | Pre-booster injection (Day 0) and 28 days post-booster injection | 
| Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titers >=10 (1/dilution). | Pre-booster injection (Day 0) and 28 days post-booster injection | 
| Percentage of Participants With Seroconversion Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo | Seroconversion rates for each serotypes were defined as the percentages of participants with either a pre-booster titer < 10 (1/dilution) and a post-booster titer >= 40 (1/dilution), or a pre-booster titer >=10 (1/dilution) and a >= 4-fold increase in post-booster titer as determined by PRNT. | 28 days post-booster injection | 
| GMTs of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received In Study CYD28 and Before Booster Injection With Either CYD Dengue Vaccine or Placebo in CYD63 | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the PRNT. | 28 days post-dose 3 in CYD28 and pre-booster injection (Day 0) in CYD 63 | 
| GMTRs of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28 And Before Booster Injection With Either CYD Dengue Vaccine or Placebo | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the PRNT. GMTRs were calculated as the ratio of GMTs post-dose 3 in CYD28 and pre-booster injection in CYD63. | 28 days post-dose 3 in CYD28 and pre-booster injection (Day 0) in CYD63 | 
| Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28, and Following Booster Injection With Either CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titers >=10 (1/dilution). | 28 days post-dose 3 in CYD28 and 28 days post-booster injection in CYD63 | 
| GMTs of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. | 6 months, 12 months, and 24 months post-booster injection | 
| GMTRs of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo | GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. GMTRs were calculated as the ratio of GMTs post-booster injection and pre-booster injection. | Pre-booster injection (Day 0) and 6 months, 12 months, 24 months post-booster injection | 
| Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titers >=10 (1/dilution). | 6 months, 12 months, and 24 months post-booster injection | 
| Number of Participants Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Booster Injection With Either CYD Dengue Vaccine or Placebo | Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 injection site reactions: Pain: significant; prevents daily activity; Erythema and Swelling: >100 millimeter. | Within 7 days after booster injection | 
| Number of Participants Reporting Solicited Systemic Reactions (Fever, Headache, Malaise, Myalgia, Asthenia) Following Booster Injection With Either CYD Dengue Vaccine or Placebo | Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions: Fever: >=39 degree Celsius; Headache, Malaise, Myalgia, and Asthenia: significant, prevents daily activity. | Within 14 days after booster injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue Hemorrhagic Fever, Dengue Virus, CYD Dengue Vaccine