Study of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Adacel® in Healthy Subjects

Phase 3

Terminated

Conditions: Dengue Fever
Dengue Hemorrhagic Fever

Interventions: Biological: CYD Dengue Vaccine

Registration Number: NCT02992418

Lead Sponsor: Sanofi Pasteur, a Sanofi Company

Brief Summary: The aim of the study was to investigate the immunogenicity and safety of CYD dengue vaccine and Tetanus Toxoid (T), Reduced Diphtheria Toxoid (D) and Acellular Pertussis Vaccine Adsorbed (ap) (Tdap) vaccine when both vaccines were administered concomitantly or sequentially.

Primary Objectives:

* To demonstrate the non-inferiority of the humoral immune response to the Tdap booster dose concomitantly administered with the first dose of CYD dengue vaccine as compared to sequential administration, measured 28 days after Tdap booster dose.

* To demonstrate the non-inferiority of the humoral immune response to the first dose of CYD dengue vaccine concomitantly administered with Tdap as compared to sequential administration, measured 28 days after the first dose of CYD dengue vaccine.

Secondary Objectives:

* To demonstrate the non-inferiority of the humoral immune response of 3 doses of CYD dengue vaccine with the first dose concomitantly administered with Tdap as compared to sequential administration, measured 28 days after the third dose of CYD dengue vaccine.

* To describe the humoral immune response at baseline and 28 days after the first and third doses of CYD dengue vaccine, in each and any group.

* To describe the humoral immune response of Tdap vaccine at baseline and 28 days after concomitant administration with the first dose of CYD dengue vaccine as compared to the sequential administration, in each and any group.

* To describe the safety of the CYD dengue vaccine and of the Tdap booster dose after each and any injection in each group.

Detailed Description: Participants were to receive CYD dengue vaccine according to a 3-dose schedule administered 6 months apart, with the first dose of CYD dengue vaccine administered either concomitantly or sequentially with a booster dose of the Tdap vaccine, Adacel®.

During the conduct of the study, a safety signal was identified which led to the Independent Data Monitoring Committee (IDMC) recommendation not to vaccinate participants who had never been infected by dengue prior to the first injection, i.e., dengue non-immune participants. The protocol was amended accordingly but never implemented due to absence of response of Health Authorities (HA) from The Philippines.

After having waited for more than 1.5 years, and as the participants became out of window to complete their immunization schedule and the last safety follow-up call (6 months after the last dose), the Sponsor decided to stop the trial. Participants only attended a last safety follow-up visit to terminate the study and were informed about the end of the study. As a consequence, the study was prematurely terminated before injection of the last dose (3rd dose) of the CYD dengue vaccine.

As a consequence of the IDMC recommendations, the main immunogenicity analyses were done in dengue immune participants which is not what was planned in the protocol (and this is why the primary endpoints are not exactly the same as those defined in the protocol as they were finally assessed only in dengue immune participants whereas initially it was planned to be assessed regardless of baseline status).

All participants were assessed for immunogenicity and safety. Safety assessments included 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 688

Inclusion Criteria

Participant aged 9 to 60 years (i.e., from the day of the 9th birthday to the day prior to the 61th birthday) on the day of inclusion.
Participant in good health, based on medical history and physical examination.
Informed consent form (ICF) or assent form was signed and dated by the participant (based on local regulations), and/or ICF was signed and dated by the parent(s) or another legally acceptable representative (and by an independent witness if required by local regulations).
For participant aged 9 to 11 years: known (documented) receipt of at least 4 previous doses of diphtheria toxoid, tetanus toxoid and acellular pertussis-containing (DTaP) vaccines, with the last dose not within the last 5 years prior to enrolment.

OR For participant aged at least 12 years: known (documented or self-reported) receipt of at least 3 previous doses of diphtheria toxoid, tetanus toxoid, and whole cell pertussis-containing (DTwP) vaccines, with the last dose not within the last 5 years prior to enrolment.

Participant (or participant and parent[s]/legally acceptable representatives) was able to attend all scheduled visits and complied with all trial procedures.

Exclusion Criteria

Participant was pregnant, or lactating, or of childbearing potential (to be 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 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.
Planned receipt of any vaccine in the 4 weeks following any trial vaccination.
Previous vaccination against dengue disease with the trial CYD dengue vaccine.
Receipt of immune globulins, blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response.
Known or suspected congenital or acquired immunodeficiency (including human immunodeficiency virus (HIV) infection with impaired immune function); or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroids therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
A previous severe reaction to pertussis, diphtheria or tetanus vaccine including immediate anaphylaxis, encephalopathy within 7 days or seizure within 3 days of receiving the vaccine.
Known 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.
Thrombocytopenia, contraindicating IM vaccination.
Bleeding disorder or receipt of anticoagulants within 3 weeks preceding inclusion, which might be a contraindication for IM vaccination, at the discretion of the Investigator.
Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily.
Current alcohol abuse or drug addiction that, based on Investigator's judgment, may interfere with the participant's ability to comply with trial procedures.
Chronic illness that, in the opinion of the Investigator, was at a stage where it might interfere with trial conduct or completion.
Identified as an Investigator or employee of the Investigator 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.
Self-reported HIV, Hepatitis B, or Hepatitis C infection.
Personal history of Guillain-Barré syndrome.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sequential Administration Group	CYD Dengue Vaccine	Participants will be administered the first dose of CYD dengue vaccine 28 days after a dose of Tdap vaccine.
Concomitant Administration Group	CYD Dengue Vaccine	Participants will be administered the first dose of CYD dengue vaccine concomitantly with a dose of Tdap vaccine.

Primary Outcome Measures

Name	Time	Method
Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants	28 days after first CYD dengue vaccination	The GMTs against each of the four parenteral dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine were assessed using the 50% plaque reduction neutralization test (PRNT50) assay method. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Titers were measured in terms of 1/dilution.
Geometric Mean Concentrations (GMCs) of Antibodies Against Pertussis Antigens (Pertussis Toxoid, Filamentous Hemagglutinin, Pertactin, and Fimbriae 2+3) 28 Days After Dose of Tdap Vaccine in Previously Dengue Immune Participants	28 days after Tdap vaccination	GMCs against each pertussis antigens (pertussis toxoid \[PT\], filamentous hemagglutinin \[FHA\], pertactin \[PRN\], fimbriae types 2 and 3 \[FIM2+3\]) were assessed using an enzyme-linked immunosorbent assay (ELISA) method and were measured in ELISA unit/milliliter (EU/mL). Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain.
Percentage of Participants With Seroprotection Against Diphtheria and Tetanus Antigens 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Participants	28 days after Tdap vaccination	Seroprotection against diphtheria (Anti-D) and tetanus (Anti-T) antigens was performed by Micrometabolic Inhibition Test - Toxin Neutralization assay (MIT-TNA) and ELISA, respectively. Seroprotection was defined as anti-D and anti-T Ab concentration greater than 0.1 international units (IU)/mL. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Reporting Unsolicited Adverse Events Following Vaccination With Tdap or CYD Dengue Vaccine	Within 28 days after any and each vaccination	An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the eCRF in terms of diagnosis and/or onset post-vaccination. At Visit 1, participants of Group 1 received no vaccination and participants of Group 2 received only Tdap vaccination. At Visit 2, participants of Group 1 received both CYD and Tdap vaccinations and participants of Group 2 received only CYD vaccination. At Visit 4, participants of Groups 1 and 2 received CYD vaccination.
Number of Participants With Immediate Unsolicited Adverse Events (AE) Following Vaccination With Tdap or CYD Dengue Vaccine	Within 30 minutes after any and each vaccination	An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the electronic case report form (eCRF) in terms of diagnosis and/or onset post-vaccination. Any unsolicited AE occurred during first 30 minutes post-vaccination was recorded on the CRF as immediate AE. At Visit 1, participants of Group 1 received no vaccination and participants of Group 2 received only Tdap vaccination. At Visit 2, participants of Group 1 received both CYD and Tdap vaccination and participants of Group 2 received only CYD vaccination. At Visit 4, participants of Groups 1 and 2 received CYD vaccination.
Number of Participants With Solicited Systemic Reactions Following Vaccination With Tdap or CYD Dengue Vaccine	Within 14 days after any and each vaccination	A SR reaction was an AE observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. Solicited injection site reactions included fever, headache, malaise, myalgia, and asthenia. At Visit 1, participants of Group 1 received no vaccination and participants of Group 2 received only Tdap vaccination. At Visit 2, participants of Group 1 received both CYD and Tdap vaccinations and participants of Group 2 received only CYD vaccination. At Visit 4, participants of Groups 1 and 2 received only CYD vaccination.
Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype at Baseline and 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants	Baseline (Pre-CYD vaccination 1) and 28 days after the first CYD dengue vaccination	The GMTs against each of the four parenteral dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine were assessed using PRNT50 assay method. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Titers were measured in terms of 1/dilution.
Percentage of Participants With Neutralizing Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD at Baseline and 28 Days After First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants	Baseline (Pre-CYD vaccination 1) and 28 days after the first CYD dengue vaccination	The GMTs against each of the four parenteral dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine were assessed using PRNT50 assay method. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain.
Percentage of Participants With Neutralizing Antibody Titers Above Predefined Thresholds Against at Least 1, 2, 3, or 4 Serotypes of CYD at Baseline and 28 Days After the First Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants	Baseline (Pre-CYD vaccination 1) and 28 days after the first CYD dengue vaccination	Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (1, 2, 3, and 4) were measured by PRNT50. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain. Percentage of participants with neutralizing antibody titers above pre-defined thresholds (\>=10 and \>=100 \[1/dilution\]) against at least 1, 2, 3, or 4 serotypes of CYD were reported. Here, 'dil'=dilution and "vac"=vaccination in the specified categories.
Geometric Mean Concentrations of Serum Antibodies Against Pertussis Antigens (Pertussis Toxoid, Filamentous Hemagglutinin, Pertactin, and Fimbriae 2+3) at Baseline and 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Participants	Baseline (Pre-Tdap vaccination) and 28 days after the Tdap vaccination	GMCs against each pertussis antigens (PT, FHA, PRN, FIM2+3) were assessed using ELISA assay method and were measured in EU/mL. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain.
Percentage of Participants Achieving Serum Antibody (>=0.1 IU/mL) Against Diphtheria and Tetanus Antigens at Baseline and 28 Days After the Dose of Tdap Vaccine in the Previously Dengue Immune Participants	Baseline (Pre-Tdap vaccination) and 28 days after the dose of Tdap vaccination	The GMC against diphtheria and tetanus antigens was performed by MIT-TNA and ELISA, respectively. Dengue immune participants at Baseline were defined as participants with titers \>=10 (1/dilution) for at least one serotype with the parental dengue virus strain.
Number of Participants With Solicited Injection Site Reactions Following Vaccination With Tdap or CYD Dengue Vaccine	Within 7 days after any and each vaccination	A solicited reaction (SR) was an AE observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the eCRF and considered as related to vaccination. Solicited injection site reactions included pain, erythema, and swelling. At Visit 1, participants of Group 1 received no vaccination and participants of Group 2 received only Tdap vaccination. At Visit 2, participants of Group 1 received both CYD and Tdap vaccinations and participants of Group 2 received only CYD vaccination. At Visit 4, participants of Groups 1 and 2 received only CYD vaccination.
Number of Participants Reporting Serious Adverse Events (SAEs) and Serious AESIs Following Vaccination With Tdap or CYD Dengue Vaccine	From Day 0 up to 6 months after the last Tdap or CYD vaccination	SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; required hospitalization or prolonged existing hospitalization; persistent or significant disability/incapacity; congenital anomaly or a medically important event. Serious AESIs were SAEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine.
Number of Participants Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Tdap or CYD Dengue Vaccine	Within 7 days post any and each vaccination	Non-serious AESIs were non-serious AEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. At Visit 1, participants of Group 1 received no vaccination and participants of Group 2 received only Tdap vaccination. At Visit 2, participants of Group 1 received both CYD and Tdap vaccinations and participants of Group 2 received only CYD vaccination. At Visit 4, participants of Groups 1 and 2 received CYD vaccination.
Number of Participants Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalization Following Vaccination With Tdap or CYD Dengue Vaccine	From Day 0 up to 6 months after the last Tdap or CYD vaccination	Hospitalized suspected dengue case was defined as an acute febrile illness with diagnosis of dengue requiring hospitalization (with bed attribution). In such cases, 1 unplanned acute blood sample (within the first 5 days after fever onset) was collected for virological confirmation of hospitalized suspected dengue case. A suspected case was considered VCD if there was a detection of wild type dengue virus by dengue non-structural protein 1 antigen ELISA and/or dengue reverse transcriptase-polymerase chain reactions.