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

Study Overview
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Brief Summary
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The aim of this study was to investigate the immunogenicity and safety of CYD dengue vaccine and Cervarix when administered concomitantly or sequentially in healthy female participants aged 9-14 years of age. Primary objectives: To demonstrate that the humoral immune response (in terms of geometric mean titers [GMTs]) to Cervarix after concomitant administration with the CYD dengue vaccine is non-inferior to the humoral immune response (in terms of GMTs) after sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Cervarix. To demonstrate that the humoral immune response (in terms of GMTs) to the CYD dengue vaccine after concomitant administration with Cervarix is non-inferior to the humoral immune response (in terms of GMTs) to the CYD dengue vaccine after sequential administration with Cervarix 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 Cervarix after concomitant administration with the CYD dengue vaccine is non-inferior to the humoral immune response (in terms of seroconversion) to Cervarix sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Cervarix. To describe the humoral immune response to Cervarix at baseline and after each dose of Cervarix 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 Cervarix and CYD dengue vaccine after each and any dose in each group.

Detailed Description
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Participants received 3 doses of the CYD dengue vaccine and 2 doses of Cervarix administered either concomitantly or sequentially. Due to a protocol amendment, only previously dengue exposed participants (seropositive for dengue before vaccination) were eligible to complete the vaccination schedule and be assessed for CYD immunogenicity and human papilloma virus (HPV) immunogenicity. Dengue unexposed participants (seronegative for dengue before vaccination) did not receive the third CYD dengue vaccine injection, but were followed for safety up to 6 months after the last injection. 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. All participants were included in the assessment of safety up to 6 months after the last injection.

Official Title
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Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Cervarix® in Healthy Female Subjects Aged 9 to 14 Years in Mexico

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 Bivalent [Types 16 and 18] Vaccine, Recombinant
* Biological: Human Papillomavirus Bivalent [Types 16 and 18] Vaccine, Recombinant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged 9 to 14 years (i.e., from the day of the 9th birthday to the day prior to the 15th 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 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 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 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 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 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 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 Hepatitis B, Hepatitis C infection.

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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Female

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 + Cervarix (Concomitant Administration)<br>Participants received 3 doses of CYD dengue vaccine 0.5 milliliter (mL) subcutaneously (SC) at Day 0, Month 6, and Month 12 and 2 doses of Cervarix vaccine 0.5 mL Intramuscularly (IM) concomitantly with the 2 first doses of CYD dengue vaccine. | Biological: CYD Dengue Vaccine<br>* 0.5 mL, SC at Day 0, Months 6 and 12<br>* Other names: Dengvaxia®;Biological: Human Papillomavirus Bivalent [Types 16 and 18] Vaccine, Recombinant<br>* 0.5 mL, IM at Day 0 and Month 6<br>* Other names: Cervarix®;|
| Experimental: CYD Dengue Vaccine + Cervarix (Sequential Administration)<br>Participants received 3 doses of CYD dengue vaccine 0.5 mL SC at Month 1, Month 7, and Month 13 along with the 2 doses of Cervarix vaccine 0.5 mL IM at Day 0 and Month 6 sequentially (i.e., one month before) to each of the 2 first doses of CYD dengue vaccine. | Biological: CYD Dengue Vaccine<br>* 0.5 mL, SC at Months 1, 7, and 13<br>* Other names: Dengvaxia®;Biological: Human Papillomavirus Bivalent [Types 16 and 18] Vaccine, Recombinant<br>* 0.5 mL, IM at Day 0 and Month 6<br>* Other names: Cervarix®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMTs) Against Each Cervarix Human Papillomavirus (HPV) Antigen (HPV-16 and HPV-18) 28 Days After Last Cervarix Vaccination in the Previously Dengue Seropositive Participants | GMTs against each Cervarix HPV antigen (HPV-16 and HPV-18) were assessed using an enzyme-linked immunosorbent assay (ELISA) method. Dengue seropositive participants at baseline were defined as those participants with titers greater than or equal to (>=) 10 (1/dilutions [dil]) for at least one serotype with the parental dengue virus strain. | 28 days after the last Cervarix vaccination | 
| GMTs Against Each Dengue Virus Serotype 28 Days After the Third CYD Dengue Vaccination in the Previously Dengue Seropositive Participants | The GMTs against each of the four parental dengue virus serotypes (Serotypes 1, 2, 3, and 4) of CYD dengue vaccine were assessed using the 50% plaque reduction neutralization test (PRNT50) assay. Dengue seropositive participants at baseline were defined as those participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. | 28 days after third CYD dengue vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GMTs Against Each Cervarix HPV Antigen (HPV-16 and HPV-18) at Day 0 and 28 Days After Each Cervarix Vaccination in the Previously Dengue Seropositive Participants | The GMTs against each Cervarix HPV antigen (HPV-16 and HPV-18) were assessed using an ELISA method. Dengue seropositive participants at baseline were defined as those participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. | Day 0 and 28 days after each Cervarix vaccination | 
| Percentage of Participants With Seroconversion Against Each Cervarix HPV Antigen (HPV-16 and HPV-18) 28 Days After Each Dose of Cervarix Vaccination in the Previously Dengue Seropositive Participants | Neutralizing antibodies against each Cervarix HPV antigen (HPV-16 and HPV-18) were assessed using an ELISA method. Seroconversion was defined as changing serostatus from seronegative at baseline to seropositive (greater than [>] lower limit of quantitation [LLOQ] of the assay) or >=4-fold rise in antibody titer if seropositive at baseline (i.e., at least one antibody levels against Cervarix HPV antigens > LLOQ at baseline). The LLOQ for HPV-16 and HPV-18 was less than (<) 2.0 International Units per milliliter (IU/mL). | 28 days after each Cervarix vaccination | 
| GMTs 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 Seropositive Participants | The GMTs against each of the four parental dengue virus serotypes (Serotypes 1, 2, 3, and 4) of CYD dengue vaccine were assessed using the PRNT50 assay. Dengue seropositive participants at baseline were defined as those participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. | Day 0 and 28 days after each CYD dengue vaccine vaccination | 
| Percentage of Participants With Neutralizing Antibody Titers >=10 (1/Dil) 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 Seropositive Participants | Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (Serotypes 1, 2, 3, and 4) were measured by PRNT50. Dengue seropositive participants at baseline were defined as those participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. | Day 0 and 28 days after each CYD dengue vaccine vaccination | 
| Percentage of Participants With Neutralizing Antibody Titers >=10 (1/Dil) Against At Least 1,2,3,or4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in Previously Dengue Seropositive Participants | Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (Serotypes 1, 2, 3, and 4) were measured by PRNT50. Dengue seropositive participants at baseline were defined as those participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. | Day 0 and 28 days after each CYD dengue vaccination | 
| Percentage of Participants With Neutralizing Antibody Titers Above Pre-defined Thresholds Against Each Dengue Virus Serotypes of CYD at Baseline And 28 Days After Each Dose of CYD Dengue Vaccination in Dengue Seropositive Participants | Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (Serotypes 1, 2, 3, and 4) were measured by PRNT50. Dengue seropositive participants at baseline were defined as those participants with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. Percentage of participants with neutralizing antibody titers above pre-defined thresholds (<10, >=10 and >=100 [1/dil]) against each dengue virus serotypes of CYD were reported. | Day 0 and 28 days after each CYD dengue vaccination | 
| Number of Participants Reporting Immediate Adverse Events (AEs) Following Vaccination With Cervarix 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. | Within 30 minutes after each and any vaccination | 
| Number of Participants Reporting Solicited Injection Site Reactions Following Vaccination With Cervarix or CYD Dengue Vaccine | Solicited injection site reactions included pain, erythema, and swelling. | Up to 7 days after each and any vaccination | 
| Number of Participants Reporting Solicited Systemic Reactions Following Vaccination With Cervarix or CYD Dengue Vaccine | Solicited systemic reactions included Fever, Headache, Malaise, Myalgia, and Asthenia. At Visit 1 and Visit 4, participants from Group 1 received both Cervarix and CYD vaccination and participants from Group 2 received only Cervarix 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 AEs Following Vaccination With Cervarix or CYD Dengue Vaccine | An unsolicited AE is an observed AE that does 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 Cervarix and CYD vaccination and participants from Group 2 received only Cervarix 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 Cervarix 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. | Up to 7 days after any and each vaccination | 
| Number of Participants Reporting Serious Adverse Events (SAEs) Including Serious AESIs Following Vaccination With Cervarix or CYD Dengue Vaccine | An SAEs were AEs resulting 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 CYD or Cervarix vaccination | 
| Number of Participants Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalization Following Vaccination With Cervarix 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 ELISA and/or dengue reverse transcriptase-polymerase chain reactions. | From Day 0 up to 6 months after the last CYD or Cervarix vaccination | 

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