Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Gardasil®

Study Overview
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Brief Summary
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The aim of the study was to assess the safety and immunogenicity of the CYD dengue vaccine and Gardasil (Human Papillomavirus Quadrivalent [Types 6, 11, 16, and 18] Vaccine, Recombinant) when administered concomitantly or sequentially. Primary objectives: To demonstrate that the humoral immune response (in terms of geometric mean titers [GMTs]) to Gardasil after concomitant administration was non-inferior to sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Gardasil. To demonstrate that the humoral immune response to the CYD dengue vaccine after concomitant administration was non-inferior to sequential administration with Gardasil measured 28 days after the last dose of the CYD dengue vaccine. Secondary Objectives: To demonstrate that the humoral immune response (in terms of seroconversion) to Gardasil vaccine after concomitant administration was non-inferior to sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Gardasil. To describe the humoral immune response to Gardasil at baseline and after each dose of Gardasil in each and any group. To describe the humoral immune response to the CYD dengue vaccine at baseline and after each dose of the CYD dengue vaccine in each and any group. To describe the safety of Gardasil and the CYD dengue vaccine after each and any dose in each group.

Detailed Description
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Participants received 3 doses of CYD dengue vaccine and 2 doses of Gardasil administered either concomitantly or sequentially. The study activities were put on hold for several months (up to 6 months for some participants) to obtain the approval of Protocol Amendment 1 by the competent authorities and completed the associated logistic tasks. Due to this protocol amendment as per Independent Data Monitoring Committee recommendation, only previously dengue immune participants (seropositive for dengue before vaccination) were eligible to complete the vaccination schedule. Dengue non-immune participants (seronegative for dengue before vaccination) did not receive any additional CYD dengue vaccine injections, but were followed for safety up to 6 months after the last injection. Due to the change in amendment 1, the number of evaluable dengue immune participants at baseline did not meet the predefined number of participants that would have allowed for a global power of at least 80% for non-inferiority testing of Gardasil vaccine and CYD dengue vaccine (121 per group for the co-primary objectives and 194 per group for the secondary objectives). All participants were assessed for immunogenicity and safety. Safety assessments included solicited reactions within 7 or 14 days after each injection, unsolicited adverse events (AEs) within 28 days after each injection, non-serious AEs of Special Interests (AESIs) within 7 days after each injection, and serious adverse events including AESI and hospitalized virologically-confirmed dengue cases during the study period.

Official Title
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Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Gardasil® in Healthy Subjects Aged 9 to 13 Years in Malaysia

Conditions
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Dengue Fever, Dengue Hemorrhagic Fever, Human Papillomavirus Disease

Intervention / Treatment
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* Biological: CYD Dengue Vaccine
* Biological: CYD Dengue Vaccine
* Biological: Human Papillomavirus Quadrivalent [Types 6, 11, 16, and 18] Vaccine, Recombinant.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants aged 9 to 13 years (i.e., from the day of the 9th birthday to the day prior to the 14th birthday) on the day of inclusion. Informed consent form (ICF) or Assent form (AF) had been signed and dated by the participant (based on local regulations), and/or 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 (or participant and parent[s] or another legally acceptable representative) was (were) able to attend all scheduled visits and complied with all trial procedures. Participant in good health, based on medical history, and physical examination. Exclusion Criteria: Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female had to be pre-menarche, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and 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 vaccine. Previous vaccination against human papillomavirus (HPV) disease with either the trial vaccine or another vaccine. Receipt of immune globulins, blood or blood-derived products in the past 3 months. Known or suspected congenital or acquired immunodeficiency (including human immunodeficiency virus 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 corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months). History of HPV infection, confirmed either clinically, serologically, or microbiologically as reported by participant or parent(s) or another legally acceptable representative. 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. Thrombocytopenia, contraindicating IM vaccination. Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating IM vaccination. 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 interfered 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 interfered 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 Hepatitis B, Hepatitis C infection.

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 13 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYD Dengue Vaccine + Gardasil (Concomitant Administration)<br>Dengue immune participants received 3 doses of CYD dengue vaccine 0.5 milliliter (mL) subcutaneously (SC) at Day 0, Month 6, and Month 12; whereas dengue non-immune participants received only 2 doses of CYD vaccine at Day 0 and Month 6. Both immune and non-immune participants received 2 doses of Gardasil vaccine 0.5 mL Intramuscular (IM), concomitantly with the first 2 doses of CYD dengue vaccine. | Biological: CYD Dengue Vaccine<br>* 0.5 mL, SC injection at Day 0, Month 6 and 12, respectively.<br>* Other names: Dengvaxia®;Biological: Human Papillomavirus Quadrivalent [Types 6, 11, 16, and 18] Vaccine, Recombinant.<br>* 0.5 mL, IM injection at Day 0 and Month 6, respectively.<br>* Other names: Gardasil®;|
| Experimental: CYD Dengue Vaccine + Gardasil (Sequential Administration)<br>Dengue immune participants received 3 doses of CYD dengue vaccine 0.5 mL SC at Month 1, Month 7, and Month 13; whereas dengue non-immune participants received only 2 doses of CYD vaccine at Month 1 and Month 7. Both immune and non-immune participants received 2 doses of Gardasil vaccine 0.5 mL IM at Day 0 and Month 6 sequentially (i.e., one month before) to each of the first 2 doses of CYD dengue vaccine. | Biological: CYD Dengue Vaccine<br>* 0.5 mL, SC injection at Month 1, 7 and 13, respectively.<br>* Other names: Dengvaxia®;Biological: Human Papillomavirus Quadrivalent [Types 6, 11, 16, and 18] Vaccine, Recombinant.<br>* 0.5 mL, IM injection at Day 0 and Month 6, respectively.<br>* Other names: Gardasil®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMTs) Against Each Gardasil Vaccine Human Papillomavirus (HPV) Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Gardasil Vaccination in the Previously Dengue Immune Participants | GMTs (measured in milli-Merck Units per mL [mMU/mL]) against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) were assessed using competitive Luminex immunoassay (cLIA) method. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. | 28 days after the last Gardasil vaccination | 
| Geometric Mean Titers Against Each Parental Dengue Virus Serotype 28 Days After Third CYD Dengue Vaccination in the Previously Dengue Immune Participants | The GMTs against each of the four parental dengue virus serotypes (1, 2, 3, and 4) of CYD dengue vaccine was assessed using the 50% plaque reduction neutralization test (PRNT50) assay. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. | 28 days after third CYD dengue vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroconversion Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Dose of Gardasil in the Previously Dengue Immune Participants | Neutralizing antibodies against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) was assessed using cLIA method. Seroconversion was defined as changing serostatus from seronegative at baseline to seropositive (participants with a pre-vaccination titer < lower limit of quantification [LLOQ] (mMU/mL) to a post-vaccination titer >=LLOQ) or >=4-fold rise in antibody titer if seropositive at baseline. The LLOQ for HPV-6 and HPV-16 was 11 mMU/mL, 8 mMU/mL for HPV-11, and 10 mMU/mL for HPV-18. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. | 28 days after the last Gardasil vaccination | 
| Geometric Mean Titers Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) at Day 0 and 28 Days After Each Dose of Gardasil in the Previously Dengue Immune Participants | The GMTs (measured in mMU/mL) against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) was assessed using cLIA method. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. | Day 0 (pre-vaccination) and 28 days after Gardasil vaccination 1 and 2 | 
| Geometric Mean Titers Against Each Dengue Virus Serotype of CYD Dengue Vaccine at Day 0 and 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants | The GMTs against each of the four parental dengue virus serotypes (1, 2, 3, and 4) of CYD dengue vaccine was assessed using the PRNT50 assay. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. | Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination | 
| Percentage of Participants With Neutralizing Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants | Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (1, 2, 3, and 4) was measured by PRNT50. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. | Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination | 
| Percentage of Participants With Neutralizing Antibody Titers Above Pre-defined Thresholds Against at Least 1,2,3,or4 Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in Previously Dengue Immune Participants | Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (1, 2, 3, and 4) was measured by PRNT50. Dengue immune participants at Baseline were defined as participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Percentage of participants with neutralizing antibody titers above pre-defined thresholds (>=10 and >=100 [1/dil]) against at least 1, 2, 3, or 4 serotypes of CYD dengue vaccine were reported. | Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination | 
| Number of Participants Reporting Immediate Adverse Events (AEs) Following Vaccination With Gardasil or CYD Dengue Vaccine | Any unsolicited systemic AE occurred during the first 30 minutes post-vaccination was recorded on the case report form (CRF) as immediate AE. At Visit 1 and Visit 4, participants from Group 1 received both Gardasil and CYD vaccination and participants from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only participants from Group 2 received CYD vaccination whereas the participants from Group 1 received no vaccination. | Within 30 minutes after any and each vaccination | 
| Number of Participants Reporting Solicited Injection Site Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine | A solicited reaction (SR) was an adverse reaction (AR) 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 pain, erythema, and swelling. | Up to 7 days after any and each vaccination | 
| Number of Participants Reporting Solicited Systemic Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine | A SR was an AR observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. Solicited systemic reactions included fever, headache, malaise, myalgia, and asthenia. At Visit 1 and Visit 4, participants from Group 1 received both Gardasil and CYD vaccination and participants from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only participants from Group 2 received CYD vaccination whereas the participants from Group 1 received no vaccination. | Up to 14 days after any and each vaccination | 
| Number of Participants Reporting Unsolicited Adverse Events Following Vaccination With Gardasil or CYD Dengue Vaccine | An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRF in terms of diagnosis and/or onset post-vaccination. At Visit 1 and Visit 4, participants from Group 1 received both Gardasil and CYD vaccination and participants from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only participants from Group 2 received CYD vaccination whereas the participants from Group 1 received no vaccination. | Up to 28 days after any and each vaccination | 
| Number of Participants Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Gardasil or CYD Dengue Vaccine | AESI were AEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. At Visit 1 and Visit 4, participants from Group 1 received both Gardasil and CYD vaccination and participants from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only participants from Group 2 received CYD vaccination whereas the participants from Group 1 received no vaccination. | Within 7 days after any and each vaccination | 
| Number of Participants Reporting Serious Adverse Events (SAEs) Including Serious Adverse Event of Special Interests Following Vaccination With Gardasil or CYD Dengue Vaccine | SAEs were AEs that resulted in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. An AESIs were AEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. | From Day 0 up to 6 months after the last Gardasil or CYD vaccination | 
| Number of Participants Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalization Following Vaccination With Gardasil or CYD Dengue Vaccine | 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 enzyme-linked immunosorbent assay and/or dengue reverse transcriptase-polymerase chain reactions. | From Day 0 up to 6 months after the last Gardasil or CYD vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Papillomavirus Disease, Dengvaxia®, Gardasil®, Dengue Fever, Dengue Hemorrhagic Fever, CYD Dengue Vaccine