Partially Blind Study to Evaluate Immunogenicity & Safety of GSK Bio's HPV Vaccine 580299 in Healthy Women Aged 9-25 Yrs

Study Overview
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Brief Summary
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Human Papillomavirus (HPV) infection has been established as a necessary cause of cervical cancer. GlaxoSmithKline (GSK) Biologicals has developed an HPV vaccine (580299) which targets the 2 most common oncogenic HPV types (HPV-16 and HPV-18), found in approximately 70% of all cervical cancers. In previous trials this vaccine has been found to be efficacious in the prevention of incident and persistent HPV-16/18 infections and associated cytological abnormalities and cervical dysplasia. In this partially-blind study, GSK Biologicals will evaluate the safety and immunogenicity of the HPV vaccine using an alternative schedule and an alternative dosing when administered in healthy young females aged 9 to 25 years, as compared to the standard HPV vaccine. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007. The protocol posting has been updated following a protocol amendment.

Official Title
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Evaluation of the Safety and Immunogenicity of GSK Biologicals' HPV Vaccine 580299 When Administered in Healthy Females Aged 9 - 25 Years Using an Alternative Schedule and an Alternative Dosing as Compared to the Standard Schedule and Dosing

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: Cervarix
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they and/or their parents can and will comply with the requirements of the protocol should be enrolled in the study. A female subject between, and including, 9 and 25 years of age at the time of the first vaccination. Written informed consent/assent obtained from the subject prior to enrolment. For subjects above the legal age of consent, written informed consent must be obtained from the subject. For subjects below the legal age of consent, written informed consent from the subject's parents/legally acceptable representative, and written informed assent must be obtained from the subject. Healthy subjects as established by medical history and history-oriented clinical examination before entering into the study. Subject must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for two months after completion of the vaccination series. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 24). Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. Concurrently participating in another clinical study, at any time during the study period (up to Month 24), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after the first dose of vaccine. Planned administration/administration of routine vaccines, up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window. Pregnant or breastfeeding female. A woman planning to become pregnant or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose. Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (up to Month 24). Previous administration of components of the investigational vaccine. Cancer or autoimmune disease under treatment. Any medically diagnosed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Hypersensitivity to latex. Acute disease at the time of enrolment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory tests. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period (up to Month 24).

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 25 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix 1/Placebo Group<br>Subjects received 2 doses of the Cervarix vaccine, formulation 1, at Month 0 and Month 2, and 1 dose of placebo at Month 6. The Cervarix vaccine and placebo were administered intramuscularly into the deltoid of the non-dominant arm. | Biological: Cervarix<br>* Intramuscular injection, different dosing /schedule<br>* Other names: GlaxoSmithKline (GSK) Biologicals' Human Papillomavirus (HPV) vaccine 580299;Drug: Placebo<br>* Intramuscular injection, different dosing /schedule<br>|
| Experimental: Cervarix 1/Placebo/Cervarix 1 Group<br>Subjects received 2 doses of the Cervarix vaccine, formulation 1, at Month 0 and Month 6, and 1 dose of placebo at Month 2. The Cervarix vaccine and placebo were administered intramuscularly into the deltoid of the non-dominant arm. | Biological: Cervarix<br>* Intramuscular injection, different dosing /schedule<br>* Other names: GlaxoSmithKline (GSK) Biologicals' Human Papillomavirus (HPV) vaccine 580299;Drug: Placebo<br>* Intramuscular injection, different dosing /schedule<br>|
| Experimental: Cervarix 2/Placebo/Cervarix 2 Group<br>Subjects received 2 doses of the Cervarix vaccine, formulation 2, at Month 0 and Month 6, and 1 dose of placebo at Month 2. The Cervarix vaccine and placebo were administered intramuscularly into the deltoid of the non-dominant arm. | Biological: Cervarix<br>* Intramuscular injection, different dosing /schedule<br>* Other names: GlaxoSmithKline (GSK) Biologicals' Human Papillomavirus (HPV) vaccine 580299;Drug: Placebo<br>* Intramuscular injection, different dosing /schedule<br>|
| Experimental: Cervarix 2 Group<br>Subjects received 3 doses of the Cervarix vaccine, formulation 2, at Month 0, Month 2 and Month 6. The Cervarix vaccine was administered intramuscularly into the deltoid of the non-dominant arm. | Biological: Cervarix<br>* Intramuscular injection, different dosing /schedule<br>* Other names: GlaxoSmithKline (GSK) Biologicals' Human Papillomavirus (HPV) vaccine 580299;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies | Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | One month after vaccination with the last dose of the Cervarix vaccine (Cervarix 1/Placebo Group: Month 3; Other groups: Month 7). | 
| Number of Subjects With Report of Any, and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the solicited local symptom irrespective of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling larger than (>) 50 millimeters (mm). | Within 7 days (Day 0-6) after vaccination. | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever (defined as axillary temperature equal or above (≥) 37.5 degrees Celsius (°C), gastrointestinal symptoms, which included nausea, vomiting, diarrhoea and/or abdominal pain, headache, myalgia, rash and urticaria. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature ≥ 39 °C. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Related symptom = symptom assessed by the investigator to be causally related to vaccination. | Within 7 days (Day 0-6) after vaccination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies . | Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). The analysis was performed on the subjects who were administered a 2-dose vaccination schedule. | At Month 3, 1 month after the second dose of vaccine or placebo | 
| Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies | Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). Groups were stratified into 3 age strata: 9-14, 15-19 and 20-25 years of age at the time of first vaccination. The 15-19 years age stratum in the group receiving the Cervarix vaccine on a 3-dose vaccination schedule was considered an active comparator. | At Month 7, 1 month after the last dose of vaccine or placebo. | 
| Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies | Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Month 12, at Month 18, at Month 24, at Month 36, and at Month 48 during the safety follow-up phase. | 
| Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies | Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Month 7, 1 month after the last dose of vaccine or placebo. | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents BAS results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range.This outcome presents CREA results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents EOS results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents Hct results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents ALT results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents LYM results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents MON results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents NEU results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents RBC results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents WBC results. | At Month 7 (M7) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. | Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents PLA results. | At Month 7 (M7) | 
| Number of Seroconverted Subjects Against Human Papillomavirus 16 (HPV-16) and Human Papillomavirus 18 (HPV-18) | Seroconversion was defined as the appearance of antibodies (i.e.titers greater than or equal to (≥) cut-off value) in the serum of subjects seronegative before vaccination. Assay cut-off was defined as ≥ 8 ELISA units per milliliter (EL.U/mL) for HPV-16, and 7 EL.U/mL for HPV-18. Seronegative subjects are subjects who had an antibody concentration below cut-off value. Cut-off values were 8 EL.U/mL for antibody concentrations against HPV-16, and 7 EL.U/mL for antibody concentrations against HPV-18. | At Month 12, at Month 18, at Month 24, at Month 36, and at Month 48 during the safety follow-up phase. | 
| Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies | Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). The assay cut-off for Month 60 was defined as ≥ 19 ELISA units per milliliter (EL.U/mL). | At Month 60 of the safety follow-up phase | 
| Number of Seroconverted Subjects Against Human Papillomavirus 16 (HPV-16) and Human Papillomavirus 18 (HPV-18) | Seroconversion was defined as the appearance of antibodies (i.e. titers greater than or equal to (≥) cut-off value) in the serum of subjects seronegative before vaccination. Assay cut-off was defined as ≥ 19 ELISA units per milliliter (EL.U/mL). Seronegative subjects are subjects who had an antibody concentration below cut-off value. | At Month 60 of the safety follow-up phase | 
| Number of Subjects With Pregnancy Outcomes. | Pregnancy outcomes were ectopic pregnancy, elective termination with no apparent congenital anomaly (ACA), elective termination with congenital anomaly (CA), lost to follow up, pregnancy ongoing, spontaneous abortion with no ACA and live infant with no ACA. | From Month 0 to Month 48. | 
| Number of Subjects With Pregnancy Outcomes. | Pregnancy outcomes were ectopic pregnancy, elective termination with no apparent congenital anomaly (ACA), elective termination with congenital anomaly (CA), lost to follow up, pregnancy ongoing, spontaneous abortion with no ACA and live infant with no ACA. | Throughout the study period, from Month 0 to Month 60. | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs). | An unsolicited adverse event (AE) is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Grade 3 = an event that prevented normal activity. Related = an event assessed by the investigator as causally related to the study vaccination. | Within 30 days (Day 0-29) after vaccination. | 
| Number of Subjects With Medically Significant Conditions (MSCs). | MSCs were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. The following did not require reporting as long as they were not considered SAEs and occurred more than 30 days after each vaccination: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities, injury, visits for routine physical examination or visits for vaccination. | From Month 0 to Month 7. | 
| Number of Subjects With Medically Significant Conditions (MSCs). | MSCs were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. The following did not require reporting as long as they were not considered SAEs and occurred more than 30 days after each vaccination: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities, injury, visits for routine physical examination or visits for vaccination. | From Month 0 to Month 48. | 
| Number of Subjects With Medically Significant Conditions (MSCs). | MSCs were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. The following did not require reporting as long as they were not considered SAEs and occurred more than 30 days after each vaccination: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities, injury, visits for routine physical examination or visits for vaccination. | Throughout the study period, from Month 0 to Month 60. | 
| Number of Subjects With New Onset of Autoimmune Diseases (NOADs) | NOADs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies. | From Month 0 to Month 7. | 
| Number of Subjects With New Onset of Autoimune Diseases (NOADs) | NOADs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies. | From Month 0 to Month 48. | 
| Number of Subjects With New Onset of Autoimmune Diseases (NOADs) | NOADs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies. | Throughout the study period, from Month 0 to Month 60. | 
| Number of Subjects With New Onset of Chronic Diseases (NOCDs) | NOCDs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies. | From Month 0 to Month 7. | 
| Number of Subjects With New Onset of Chronic Diseases (NOCDs) | NOCDs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies. | From Month 0 to Month 48. | 
| Number of Subjects With New Onset of Chronic Diseases (NOCDs) | NOCDs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies. | Throughout the study period, from Month 0 to Month 60. | 
| Number of Subjects With Serious Adverse Events (SAEs). | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity, or are a congenital anomaly/birth defect in the offspring of a study subject. | From Month 0 to Month 7. | 
| Number of Subjects With Serious Adverse Events (SAEs). | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. | From Month 0 to Month 48. | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. | Throughout the study period, from Month 0 to Month 60. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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viral infections, Human Papillomavirus (HPV) vaccine, safety, vaccine, immunogenicity, cervical cancer