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

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

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.

Study Overview

• Status: Completed
• Conditions: Dengue Fever; Dengue Hemorrhagic Fever
• Intervention / Treatment: Biological: Placebo, NaCl 0.9%; Biological: CYD Dengue Vaccine (5 dose formulation)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169608
  • Singapore, Singapore, 119074
  • Singapore, Singapore, 529889

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CYD Dengue Vaccine booster Group; 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); 0.5 mL, Subcutaneous
Placebo Comparator: Placebo Group; 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%; 0.5 mL, Subcutaneous

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Sanofi Pasteur, a Sanofi Company

Publications and helpful links

General Publications

• Park J, Archuleta S, Oh MH, Shek LP, Jin J, Bonaparte M, Fargo C, Bouckenooghe A. Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5-6 years after completion of the primary series. Hum Vaccin Immunother. 2020 Mar 3;16(3):523-529. doi: 10.1080/21645515.2019.1661204. Epub 2019 Nov 5. Erratum In: Hum Vaccin Immunother. 2021 Aug 3;17(8):2819.
• Park J, Archuleta S, Oh MH, Shek LP, Wang H, Bonaparte M, Frago C, Bouckenooghe A, Jantet-Blaudez F, Begue S, Gimenez-Fourage S, Pagnon A. Humoral and cellular immunogenicity and safety following a booster dose of a tetravalent dengue vaccine 5+ years after completion of the primary series in Singapore: 2-year follow-up of a randomized phase II, placebo-controlled trial. Hum Vaccin Immunother. 2021 Jul 3;17(7):2107-2116. doi: 10.1080/21645515.2020.1861875. Epub 2021 Feb 24.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): March 18, 2017
• Study Completion (Actual): January 18, 2019

Study Registration Dates

• First Submitted: July 1, 2016
• First Submitted That Met QC Criteria: July 5, 2016
• First Posted (Estimate): July 6, 2016

Study Record Updates

• Last Update Posted (Actual): March 24, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Dengue Hemorrhagic Fever; Dengue Virus; CYD Dengue Vaccine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Body Temperature Changes; Fever; Hemorrhagic Fevers, Viral; Dengue; Severe Dengue
• Other Study ID Numbers: CYD63; U1111-1161-2813 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No