Immunogenicity and Safety of Different Vaccination Schedules of Tetravalent Dengue Vaccine in Healthy Subjects 9 to 50 Years of Age

NCT02628444 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: CYD65U1111-1161-32422020-002854-25
• Study Type: interventional
• Target: 1,050
• Locations: 2 countries
• Sites: 6

Brief Summary

The aim of the study was to assess the immune response and the safety of different vaccination schedules of CYD dengue vaccine. The primary objectives of the study were:

• To demonstrate the non-inferiority of the immune response elicited against each dengue serotype by CYD dengue vaccine given as a 2-dose schedule (Group 2) compared to the immune response elicited by CYD dengue vaccine given as a 3-dose schedule (Group 1), in previously dengue exposed participants 28 days after the last injection.
• To demonstrate the non-inferiority of the immune response elicited against each dengue serotype by CYD dengue vaccine given as a 2-dose schedule (Group 2) compared to the immune response elicited by CYD vaccine given as a 3-dose schedule (Group 1) in previously dengue exposed participants, 1 year after the last injection.
• To demonstrate the non-inferiority of the immune response elicited against each dengue serotype elicited by a booster dose of CYD dengue vaccine one year or two years after the last injection in the primary series in previously dengue exposed participants, compared to the immune response post dose 3 in Group 1. The secondary objectives of the study were:
• To demonstrate the superiority of the immune response elicited by CYD dengue vaccine given as a 2-dose schedule (Group 2) compared to the immune response elicited by CYD dengue vaccine given as a 3-dose schedule (Group 1), in previously dengue exposed participants, 28 days after the last injection.
• To demonstrate the superiority of the immune response elicited by CYD dengue vaccine given as a 2-dose schedule (Group 2) compared to the immune response elicited by CYD dengue vaccine given as a 3-dose schedule (Group 1), in previously dengue exposed participants, one year after the last injection.
• To describe the neutralizing antibody levels of each dengue serotype at 28 days post-injection 3 to the antibody levels immediately before receiving a booster dose, by baseline dengue serostatus.
• To describe the neutralizing antibody levels of each dengue serotype at 28 days post-injection 2 and 28 days post-injection 3 from Group 1 in a primary series schedule by baseline dengue serostatus.
• To demonstrate the superiority of the immune response elicited against each dengue serotype 28 days after administration of a booster dose of CYD dengue vaccine, in previously dengue exposed participants, at one year or two years after last injection in the primary series.
• To describe the seroconversion rate 28 days post-booster injection in all 3 groups.
• To describe all hospitalized virologically confirmed dengue (VCD) cases during the study.
• To evaluate the safety profile of CYD after each and any injection during the trial. Safety assessments include solicited reactions within 7 or 14 days after each injection, unsolicited adverse events within 28 days after each injection, and serious adverse events during the study period.

Conditions

Dengue Fever; Dengue Hemorrhagic Fever

Keywords

Dengue Fever; Dengue virus; Dengue Hemorrhagic Fever; CYD Dengue Vaccine

Outcome Measures

Primary Outcomes (6)

• STAGE-I: Geometric Mean Titers (GMTs) Against Each Dengue Virus Serotype 28 Days After Last CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline

  GMTs of antibodies against each of the 4 dengue virus serotypes (1, 2, 3, or 4) were assessed using plaque reduction neutralization test (PRNT) assay method. Titers were measured in terms of 1/dilution. Dengue seropositive participants at Baseline was defined as participants with titers \>=10 (1/dilution) for at least 1 serotype with parental dengue virus strains. Per-protocol analysis set (PPAS) included all participants who had no protocol violations; and who met any of following study violations were excluded from PPAS (STAGE I/II): had not met all protocol-specified inclusion/exclusion criteria, had not received correct doses or injections, received vaccine other than randomized schedule, did not receive vaccination in proper time window, had not provided post-dose serology sample in proper time window, received protocol-restricted medication, therapy, or vaccine.

  28 days after last CYD dengue vaccination

• STAGE-I: Geometric Mean Titers Against Each Dengue Virus Serotype 1 Year After Last CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline

  GMTs of antibodies against each of the 4 dengue virus serotypes (1, 2, 3 or 4) were assessed using the PRNT assay method. Titers were measured in terms of 1/dilution. Dengue seropositive participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strains.

  1 year after last CYD dengue vaccination

• STAGE-II: Geometric Mean Titers Against Each Dengue Virus Serotype Within Group 1a and Group 1 After the Third Dose of CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline

  GMTs of antibodies against each of the 4 dengue virus serotypes (1, 2, 3 or 4) were assessed using the PRNT assay method. Titers were measured in terms of 1/dilution. Dengue seropositive participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strains. Data of Group 1 (28 days post-dose 3 in STAGE-I) and Group 1a (28 days 12 months Booster dose) were reported and compared in this outcome measure. GMT paired ratio (given in statistical analysis section) was calculated by dividing geometric mean values of Group 1a: 28 days post 12 months booster dose in STAGE-II by Group 1: 28 days post-dose 3 in STAGE-I.

  Group 1: 28 days post-dose 3 in STAGE-I, Group 1a: 28 days post 12 months booster dose in STAGE-II

• STAGE-II: Geometric Mean Titers Against Each Dengue Virus Serotype Comparison Between Group 2a and Group 1 After the Third Dose of CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline

  GMTs of antibodies against each of the 4 dengue virus serotypes (1, 2, 3 or 4) were assessed using the PRNT assay method. Titers were measured in terms of 1/dilution. Dengue seropositive participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strains. Data of Group 1 (28 days post-dose 3 in STAGE-I) and Group 2a (28 days post 12 months Booster dose) were reported and compared in this outcome measure. GMT ratio (given in statistical analysis section) was calculated by dividing geometric mean values of Group 2a: 28 days post 12 months booster dose in STAGE-II by Group 1: 28 days Post-dose 3 in STAGE-I.

  Group 1: 28 days post-dose 3 in STAGE-I, Group 2a: 28 days post 12 months booster dose in STAGE-II

• STAGE-II: Geometric Mean Titers Against Each Dengue Virus Serotype Within Group 1b and Group 1 After the Third Dose of CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline

  GMTs of antibodies against each of the 4 dengue virus serotypes (1, 2, 3 or 4) were assessed using the PRNT assay method. Titers were measured in terms of 1/dilution. Dengue seropositive participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strains. Data of Group 1 (28 days post-dose 3 in STAGE-I) and Group 1b (28 days post 24 months booster dose) were reported and compared in this outcome measure. GMT paired ratio (given in statistical analysis section) was calculated by dividing geometric mean values of Group 1b: 28 days post 24 months booster dose in STAGE-II by Group 1: 28 days Post-dose 3 in STAGE-I.

  Group 1: 28 days post-dose 3 in STAGE-I, Group 1b: 28 days post 24 months booster dose in STAGE-II

• STAGE-II: Geometric Mean Titers Against Each Dengue Virus Serotype Comparison Between Group 2b and Group 1 After the Third Dose of CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline

  GMTs of antibodies against each of the 4 dengue virus serotypes (1, 2, 3 or 4) were assessed using the PRNT assay method. Titers were measured in terms of 1/dilution. Dengue seropositive participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strains. Data of Group 1 (28 days post-dose 3 in STAGE-I) and Group 2b (28 days post 24 months Booster dose) was reported and compared in this outcome measure. GMT ratio (given in statistical analysis section) was calculated by dividing geometric mean values of Group 2b: 28 days post 24 months booster dose in STAGE-II by Group 1: 28 days post-dose 3 in STAGE-I.

  Group 1: 28 days post-dose 3 in STAGE-I, Group 2b: 28 days post 24 months Booster dose in STAGE-II

Secondary Outcomes (18)

• STAGE-I: Geometric Mean Titers Against Each Serotype With the Parental Dengue Virus Strains After CYD Dengue Vaccination in Participants Who Were Seropositive at Baseline-Comparison Between Group 1 and Group 2

  28 days and 1 year after last CYD dengue vaccination

• STAGE-I: Geometric Mean Titers Against Each Serotype With the Parental Dengue Virus Strains in All Participants

  Baseline, 28 days post vaccination 3, and 1 year post vaccination 3

• STAGE-I: Geometric Mean Titers Against Each Serotype With the Parental Dengue Virus Strains (by Baseline Dengue Status) in Participants Who Were Seropositive and Seronegative at Baseline

  Baseline, 28 days post vaccination 3, and 1 year post vaccination 3

• STAGE-II: Geometric Mean Titers Against Each Serotype With the Parental Dengue Virus Strains After Booster CYD Dengue Vaccination in Participants Seropositive at Baseline

  Baseline, 28 days post vaccination-3, and 28 days post booster dose

• STAGE-I: Percentage of Participants With Antibodies Titer >=10 (1/Dilution) Against Each Serotype With the Parental Dengue Virus Strains in All Participants

  Baseline, 28 days post vaccination 3, and 1 year post vaccination 3

Study Arms (9)

STAGE-I Group 1: CYD Dengue Vaccine

EXPERIMENTAL

Participants received 3 doses of CYD dengue vaccine 0.5 milliliters (mL) subcutaneously (SC) at Day 0 (Vaccination 1), Month 6 (Vaccination 2), and Month 12 (Vaccination 3).

Biological: CYD Dengue Vaccine

STAGE-I Group 2: Placebo + CYD Dengue Vaccine (Months 6,12)

EXPERIMENTAL

Participants received a dose of placebo at Day 0 (Vaccination 1) along with 2 doses of CYD dengue vaccine 0.5 mL SC at Month 6 (Vaccination 2) and Month 12 (Vaccination 3).

Biological: CYD Dengue Vaccine; Biological: Placebo (Sodium chloride 0.9%)

STAGE-I Group 3: Placebo + CYD Dengue Vaccine (Month 12)

EXPERIMENTAL

Participants received 2 doses of placebo at Day 0 (Vaccination 1) and Month 6 (Vaccination 2) along with a dose of CYD dengue vaccine 0.5 mL SC at Month 12 (Vaccination 3).

Biological: CYD Dengue Vaccine; Biological: Placebo (Sodium chloride 0.9%)

STAGE-II Group 1a: CYD Vaccine + CYD Booster Vaccine (1 Year)

EXPERIMENTAL

Participants from Group 1 who received vaccination in STAGE-I; and were seropositive at Baseline received a booster dose of CYD dengue vaccine in STAGE-II at 1 year post last dose in STAGE-I (i.e., at Month 24).

Biological: CYD Dengue Vaccine

STAGE-II Group 2a: Placebo + CYD + CYD Booster (1 Year)

EXPERIMENTAL

Participants from Group 2 who received vaccination in STAGE-I and were seropositive at baseline received a booster injection of CYD dengue vaccine in STAGE-II at 1 year post last dose in STAGE-I (i.e., at Month 24).

Biological: CYD Dengue Vaccine; Biological: Placebo (Sodium chloride 0.9%)

STAGE-II Group 3a: Placebo + CYD + CYD Booster (1 Year)

EXPERIMENTAL

Participants from Group 3 who received vaccination in STAGE-I and were seropositive at Baseline received a booster injection of CYD dengue vaccine in STAGE-II at 1 year post last dose in STAGE-I (i.e., at Month 24).

Biological: CYD Dengue Vaccine; Biological: Placebo (Sodium chloride 0.9%)

STAGE-II Group 1b: CYD Vaccine + CYD Booster Vaccine (2 Years)

EXPERIMENTAL

Participants from Group 1 who received vaccination in STAGE-I and were seropositive at Baseline received a booster injection of CYD dengue vaccine in STAGE-II at 2 years post last dose in STAGE-I (i.e., at Month 36).

Biological: CYD Dengue Vaccine

STAGE-II Group 2b: Placebo + CYD + CYD Booster (2 Years)

EXPERIMENTAL

Participants from Group 2 who received vaccination in STAGE-I and were seropositive at Baseline received a booster injection of CYD dengue vaccine in STAGE-II at 2 years post last dose in STAGE-I (i.e., at Month 36).

Biological: CYD Dengue Vaccine; Biological: Placebo (Sodium chloride 0.9%)

STAGE-II Group 3b: Placebo + CYD + CYD Booster (2 Years)

EXPERIMENTAL

Participants from Group 3 who received vaccination in STAGE-I and were seropositive at baseline received a booster injection of CYD dengue vaccine in STAGE-II at 2 years post last dose in STAGE-I (i.e., at Month 36).

Biological: CYD Dengue Vaccine; Biological: Placebo (Sodium chloride 0.9%)

Interventions

CYD Dengue Vaccine BIOLOGICAL

0.5 mL, Subcutaneous

STAGE-I Group 1: CYD Dengue Vaccine; STAGE-I Group 2: Placebo + CYD Dengue Vaccine (Months 6,12); STAGE-I Group 3: Placebo + CYD Dengue Vaccine (Month 12); STAGE-II Group 1a: CYD Vaccine + CYD Booster Vaccine (1 Year); STAGE-II Group 1b: CYD Vaccine + CYD Booster Vaccine (2 Years); STAGE-II Group 2a: Placebo + CYD + CYD Booster (1 Year); STAGE-II Group 2b: Placebo + CYD + CYD Booster (2 Years); STAGE-II Group 3a: Placebo + CYD + CYD Booster (1 Year); STAGE-II Group 3b: Placebo + CYD + CYD Booster (2 Years)

Placebo (Sodium chloride 0.9%) BIOLOGICAL

0.5 mL, Subcutaneous

STAGE-I Group 2: Placebo + CYD Dengue Vaccine (Months 6,12); STAGE-I Group 3: Placebo + CYD Dengue Vaccine (Month 12); STAGE-II Group 2a: Placebo + CYD + CYD Booster (1 Year); STAGE-II Group 2b: Placebo + CYD + CYD Booster (2 Years); STAGE-II Group 3a: Placebo + CYD + CYD Booster (1 Year); STAGE-II Group 3b: Placebo + CYD + CYD Booster (2 Years)

Eligibility Criteria

• Age: 9 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Aged 9 to 50 years on the day of enrollment.
• Participant in good health, based on medical history and physical examination.
• Assent form or informed consent form (ICF) had been signed and dated by the 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) were able to attend all scheduled visits and to comply with all trial procedures.

You may not qualify if:

• Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be pre-menarche, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 4 weeks after the last vaccination).
• Participation at the time of study enrollment (or in the 4 weeks preceding the first trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device or medical procedure.
• Self-reported 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).
• Self-reported systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances.
• Chronic illness that, in the opinion of the investigator, was 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.
• Planned receipt of any vaccine in the 4 weeks following any trial vaccination.
• Previous vaccination against dengue disease with either the trial vaccine or another vaccine.
• Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Current alcohol abuse or drug addiction that, based on investigator's judgment, might interfere with the participant's ability to comply with trial procedures.
• Identified as a site employee of the Investigator, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members (i.e., immediate, husband, wife, and their children, adopted or natural) of the employees or the Investigator.
• A prospective participant must not be included in the study until the following conditions and/or symptoms were resolved:
• Febrile illness (temperature greater than or equal to \[\>=\] 38.0 degree Celsius) or moderate or severe acute illness/infection (according to Investigator's judgment) on the day of vaccination.
• Receipt of any vaccine in the 4 weeks preceding the first trial vaccination.

Sponsors & Collaborators

• Sanofi Pasteur, a Sanofi Company: lead

Study Sites (6)

Investigational Site 102

Barranquilla, Colombia

Location

Investigational Site 101

Cali, Colombia

Location

Investigational Site 103

Medellín, Colombia

Location

Investigational Primary Site Muntinlupa 201_Satellite Site San Pablo 202

City of Muntinlupa, Philippines

Location

Investigational Site 203

Manila, Philippines

Location

Investigational Site 204

Manila, Philippines

Location

Related Publications (2)

• Coronel-Martinez DL, Park J, Lopez-Medina E, Capeding MR, Bonfanti AAC, Montalban MC, Ramirez I, Gonzales MLA, Zambrano B, Dayan G, Chen Z, Wang H, Bonaparte M, Rojas A, Ramirez JC, Verdan MA, Noriega F. Immunogenicity and safety of booster CYD-TDV dengue vaccine after alternative primary vaccination schedules in healthy individuals aged 9-50 years: a randomised, controlled, phase 2, non-inferiority study. Lancet Infect Dis. 2022 Jun;22(6):901-911. doi: 10.1016/S1473-3099(21)00706-4. Epub 2022 Mar 29.

  PMID: 35364022 DERIVED

• Coronel-MartInez DL, Park J, Lopez-Medina E, Capeding MR, Cadena Bonfanti AA, Montalban MC, Ramirez I, Gonzales MLA, DiazGranados CA, Zambrano B, Dayan G, Savarino S, Chen Z, Wang H, Sun S, Bonaparte M, Rojas A, Ramirez JC, Verdan MA, Noriega F. Immunogenicity and safety of simplified vaccination schedules for the CYD-TDV dengue vaccine in healthy individuals aged 9-50 years (CYD65): a randomised, controlled, phase 2, non-inferiority study. Lancet Infect Dis. 2021 Apr;21(4):517-528. doi: 10.1016/S1473-3099(20)30767-2. Epub 2020 Nov 16.

  PMID: 33212067 DERIVED

MeSH Terms

Conditions

Dengue; Severe Dengue

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Mosquito-Borne Diseases; Vector Borne Diseases; Infections; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi Pasteur

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi Pasteur, a Sanofi Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2015
• First Posted: December 11, 2015
• Study Start: May 2, 2016
• Primary Completion: April 29, 2020
• Study Completion: April 29, 2020
• Last Updated: March 24, 2022
• Results First Posted: February 23, 2021

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

CO (3); PH (3)