Study to Evaluate the Efficacy of the Human Papillomavirus Vaccine in Healthy Adult Women of 26 Years of Age and Older

Infections, Papillomavirus Clinical Trial

Official title:

A Study to Evaluate Safety, Immunogenicity and Efficacy of GSK Biologicals HPV-16/18 L1/AS04 Vaccine Administered Intramuscularly According to a Three-dose Schedule (0, 1, 6 Month) in Healthy Adult Female Subjects Aged 26 Years and Above

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00294047
• Other study ID #: 104820
• Secondary ID: 2005-002546-20
• Status: Completed
• Phase: Phase 3
• Start date: February 16, 2006
• Est. completion date: January 29, 2014

Study information

• Verified date: December 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicentre study in which women were planned to receive either the Human Papillomavirus Vaccine (HPV) vaccine or control. Under Protocol Amendment 3, study participation will last approximately 48 months and involves a total of eleven scheduled visits. Under Protocol Amendment 4, study participation will last up to 84 months and involves a maximum of seventeen scheduled visits.

Description:

The Protocol Posting has been updated due to protocol amendment 5 and in order to comply with the FDA Amendment Act, Sep 2007.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5752
• Est. completion date: January 29, 2014
• Est. primary completion date: January 29, 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 26 Years and older

Eligibility

Inclusion criteria:

• A woman who the investigator believes that she can and will comply with the requirements of the protocol.

• A women of at least 26 years of age at the time of the first vaccination.

• Written informed consent obtained from the subject prior to enrolment.

• Free of obvious health problems as established by medical history and clinical examination before entering into the study.

• Subject must have intact cervix.

• Subject must have a negative urine pregnancy test. This test is not applicable to women of non-childbearing potential.

• Subject must be of non-childbearing potential or, if of childbearing potential, she must be abstinent or must be using an effective method of birth control for 30 days prior to the first vaccination and must agree to continue such precautions for two months after completion of the vaccination series.

Exclusion criteria:

• Pregnant or breastfeeding (women must be at least three months post-pregnancy and not breastfeeding to enter the study).

• A women planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the vaccination phase of the study, i.e. up to two months after the last vaccine dose (Month 0 - 8).

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 84).

• Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.

• Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after (i.e. days 0 - 29) the first dose of study 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.

• Previous administration of components of the investigational vaccine

• Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period.

• History of HPV infection/treatment or planned treatment to evaluate an abnormal cervical cytology (Pap smear) test, e.g. colposcopy.

• Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination.

• History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccine.

• Hypersensitivity to latex.

• Known acute or chronic, clinically significant neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.

• History of chronic condition(s) requiring treatment.

• Administration of immunoglobulins and/or any blood product within three months preceding the first dose of study vaccine, or planned administration during the study period. Enrolment will be deferred until the subject is outside of specified window.

• Acute disease at the time of enrolment.

• Heavy bleeding (menstruation or other) or heavy vaginal discharge in which a pelvic exam cannot be performed (and no cervical sample can be taken). Enrolment will be deferred until condition is resolved according to investigators medical judgement.

Related Conditions & MeSH terms

• Infection
• Infections, Papillomavirus
• Papillomavirus Vaccines

Intervention

Biological:
• Cervarix
Subjects were planned to receive three doses of the study vaccine administered intramuscularly according to a 0, 1, 6 month vaccination schedule.
• Placebo control
Subjects were planned to receive three doses of the control vaccine administered intramuscularly according to a 0, 1, 6 month vaccination schedule.

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Parkville	Victoria
Australia	GSK Investigational Site	Perth	Western Australia
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Halifax	Nova Scotia
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Sherbrooke	Quebec
Canada	GSK Investigational Site	Truro	Nova Scotia
Canada	GSK Investigational Site	Vancouver	British Columbia
Canada	GSK Investigational Site	Waterloo	Ontario
Mexico	GSK Investigational Site	Cuenavaca	Morelos
Mexico	GSK Investigational Site	Jojutla / Morelos
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Delft
Netherlands	GSK Investigational Site	Rotterdam
Peru	GSK Investigational Site	Lima
Philippines	GSK Investigational Site	Laguna
Philippines	GSK Investigational Site	San Pablo City
Philippines	GSK Investigational Site	Taft Avenue, Manila
Portugal	GSK Investigational Site	Almada
Portugal	GSK Investigational Site	Coimbra
Portugal	GSK Investigational Site	Lisboa
Portugal	GSK Investigational Site	Porto
Portugal	GSK Investigational Site	Setúbal
Russian Federation	GSK Investigational Site	Ekaterinburg
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Sankt-Petersburg
Russian Federation	GSK Investigational Site	Sankt-Petersburg
Singapore	GSK Investigational Site	Singapore
Singapore	GSK Investigational Site	Singapore
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
United Kingdom	GSK Investigational Site	Aberdeen
United Kingdom	GSK Investigational Site	Cardiff
United Kingdom	GSK Investigational Site	Gateshead
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Manchester
United Kingdom	GSK Investigational Site	Northwood	Middlesex
United States	GSK Investigational Site	Akron	Ohio
United States	GSK Investigational Site	Albuquerque	New Mexico
United States	GSK Investigational Site	Augusta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Bardstown	Kentucky
United States	GSK Investigational Site	Carnegie	Pennsylvania
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Chaska	Minnesota
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Coral Gables	Florida
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Fountain Valley	California
United States	GSK Investigational Site	Golden	Colorado
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Iowa City	Iowa
United States	GSK Investigational Site	La Crosse	Wisconsin
United States	GSK Investigational Site	Lebanon	New Hampshire
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	New Bern	North Carolina
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	South Jordan	Utah
United States	GSK Investigational Site	Syracuse	New York
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Wenatchee	Washington
United States	GSK Investigational Site	Wexford	Pennsylvania
United States	GSK Investigational Site	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Mexico,  Netherlands,  Peru,  Philippines,  Portugal,  Russian Federation,  Singapore,  Thailand,  United Kingdom, 

References & Publications (5)

Descamps D, Hardt K, Spiessens B, Izurieta P, Verstraeten T, Breuer T, Dubin G. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin. 2009 May;5(5):332-40. Epub 2009 May 20. — View Citation

Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmerón J, Del Rosario-Raymundo MR, Verheijen RH, Quek SC, da Silva DP, Kitchener H, Fong KL, Bouchard C, Money DM, Ilancheran A, Cruickshank ME, Levin MJ, Chatterjee A, Stapleton JT, Martens M, Quint W, David MP, Meric D, Hardt K, Descamps D, Geeraerts B, Struyf F, Dubin G; VIVIANE Study Group. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet. 2014 Dec 20;384(9961):2213-27. doi: 10.1016/S0140-6736(14)60920-X. Epub 2014 Sep 1. — View Citation

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008 Dec 2;26(51):6630-8. doi: 10.1016/j.vaccine.2008.09.049. — View Citation

Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM, Chatterjee A, Lazcano-Ponce E, Salmerón J, McNeil S, Stapleton JT, Bouchard C, Martens MG, Money DM, Quek SC, Romanowski B, Vallejos CS, Ter Harmsel B, Prilepskaya V, Fong KL, Kitchener H, Minkina G, Lim YKT, Stoney T, Chakhtoura N, Cruickshank ME, Savicheva A, da Silva DP, Ferguson M, Molijn AC, Quint WGV, Hardt K, Descamps D, Suryakiran PV, Karkada N, Geeraerts B, Dubin G, Struyf F; VIVIANE Study Group. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet Infect Dis. 2016 Oct;16(10):1154-1168. doi: 10.1016/S1473-3099(16)30120-7. Epub 2016 Jun 28. — View Citation

Wheeler CM, Struyf F; HPV-015 study group. The safety of Cervarix? - Authors' reply. Lancet Infect Dis. 2017 Jan;17(1):20-21. doi: 10.1016/S1473-3099(16)30540-0. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection.	CIN1+ = CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Persistent HPV infection = detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.; DNA- and sero-/+: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and 6 and seronegative/positive (sero-/+) at Month 0 for the corresponding HPV-type by Enzyme-linked Immunosorbent Assay (ELISA); Overall: subjects DNA- at Month 0 and 6 for the corresponding HPV-type, regardless of initial serostatus	Up to Month 48
Primary	Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).	CIN1+ = CIN grades 1, 2 and 3, AIS and invasive cervical cancer. Persistent cervical HPV infection (6-month definition) = detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.; DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0).; Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 48
Primary	Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection.	CIN1+ = CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Persistent HPV infection = detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. - DNA- and sero-/+: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and 6 and seronegative/positive (sero-/+) at Month 0 for the corresponding HPV-type by Enzyme-linked Immunosorbent Assay (ELISA) - Overall: subjects DNA- at Month 0 and 6 for the corresponding HPV-type, regardless of initial serostatus	Up to Month 84
Primary	Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).	CIN1+ = CIN grades 1, 2 and 3, AIS and invasive cervical cancer. Persistent cervical HPV infection (6-month definition) = detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. - DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 84
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.; Detection was done in: DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0).; Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 48
Secondary	Number of Subjects With Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18	Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type(s) PCR in cervical samples at all available time points over approximately a 12-month interval (evaluations are planned at approximately 6-month intervals).; DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0).; Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 48
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types Individually or in Combinations.	Persistent cervical HPV infection (6-month definition) = detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.; Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.; Detection was done in subjects HPV DNA- for the corresponding HPV type at baseline (at month 0 and Month 6) regardless of initial serostatus.; HPV-HRW=All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18. HPV-HR=High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.	Up to Month 48
Secondary	Number of Subjects With Persistent Infection (12-month Definition) With Oncogenic HPV Types Individually or in Combinations.	Persistent HPV infection (12-month definition) = detection of the same HPV type(s) by PCR in cervical samples at available time points over approximately a 12-month interval (evaluations are planned at approximately 6-month intervals).; Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.; subjects HPV DNA- for the corresponding HPV type at Month 0 6, regardless of initial serostatus.; HPV-HRW=All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HPV-HR=High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 , 68	Up to Month 48
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen	CIN2+ was defined as CIN grades 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done in: DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0).; Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.; Note: Results for seropositive status were not analysed.	Up to Month 48
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done in: DNA- and sero-/+: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0).; Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 48
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus.	Up to Month 48
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Irrespective of HPV Cervical Infection and Irrespective of Baseline HPV DNA Status	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done on all subjects irrespective of their baseline HPV DNA status.	Up to Month 48
Secondary	Number of Subjects With Any Cytological Abnormalities Associated With HPV-16 or HPV-18 Cervical Infection	Cytological abnormalities = atypical squamous cells of undetermined significance (ASC-US).; Detection was done in: DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0).; Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.; Results for seropositive status were not analysed.	Up to Month 48
Secondary	Number of Subjects With Cytological Abnormalities Associated With Oncogenic HPV Types Individually or in Combinations	Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.; Detection was done in subjects who were HPV DNA negative for the corresponding HPV type at baseline (at month 0 and Month 6) regardless of initial serostatus.; HRW-HPV= All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HPV-HR= High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68	Up to Month 48
Secondary	Number of Subjects With Histopathologically Confirmed Reduction of Local Cervical Therapy	Detection was done on all subjects irrespective of their baseline HPV DNA status.	Up to Month 48
Secondary	Number of Subjects With First Colposcopy	Detection was done on all subjects irrespective of their baseline HPV DNA status.	Up to Month 48
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.; CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus.	Up to Month 48
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-confirmed CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.; Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus.; The lesion was assigned to an HPV type found in the lesion if (1) the same HPV type was found in at least 1 of the 2 (closest) preceding cytology samples, or (2) none of the HPV types found in the lesion were found in any of the 2 preceding cytology samples (isolate HPV types)	Up to Month 48
Secondary	Number of Seroconverted Subjects Against HPV-16 in the Immunogenicity Subset.	Seroconversion was defined as the appearance of antibodies (i.e.; titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination.; HPV-16 assay cut-off value was defined as greater than or equal to 8 ELISA units per millilitre (EL.U/mL). Seronegative (Sero-) subjects are subjects who had an antibody concentration below 8 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 8 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites N=1000, at least 250 per region	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
Secondary	Number of Seroconverted Subjects Against HPV-18 in the Immunogenicity Subset.	Seroconversion was defined as the appearance of antibodies (i.e.; titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination.; HPV-18 assay cut-off value was defined as greater than or equal to 7 ELISA units per millilitre (EL.U/mL). Seronegative (Sero-) subjects are subjects who had an antibody concentration below 7 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 7 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites N=1000, at least 250 per region	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
Secondary	Geometric Mean Concentrations (GMCs) Against HPV-16 Antibody in the Immunogenicity Subset.	GMCs were expressed in ELISA units per milliliter (EL.U/mL).; Seronegative (Sero-) subjects are subjects who had an antibody concentration below 8 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 8 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites (N=1000, at least 250 per region)	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
Secondary	Geometric Mean Concentrations (GMCs) Against HPV-18 Antibody in the Immunogenicity Subset.	GMCs were expressed in ELISA units per milliliter (EL.U/mL).; Seronegative (Sero-) subjects are subjects who had an antibody concentration below 7 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 7 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites (N=1000, at least 250 per region)	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
Secondary	Number of Seroconverted Subjects Against HPV-16 and HPV-18 Viral Neutralization in a Selected Subset of Subjects.	Seroconversion was defined as the appearance of antibodies (i.e.; titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. HPV-16/18 assay cut-off value was defined as greater than or equal to 40 Estimated dose 50% (ED50). Sero- subjects are subjects who had an antibody concentration below 40 ED50 prior to vaccination. Sero+ subjects are subjects who had an antibody concentration equal to or above 50 ED50 prior to vaccination. ED50 = the estimated serum dilution reducing the signal generated by viral infection by 50%	Prior to vaccination and at Months 7, 12, 18, 24, 48 and 84.
Secondary	Geometric Mean Titers (GMTs) Against HPV-16 and HPV-18 Viral Neutralization Antibodies in a Selected Subset of Subjects.	Titers are expressed as geometric mean antibody titers (GMTs).; Seronegative (Sero-) subjects are subjects who had an antibody titer below 40 ED50 prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody titer equal to or above 40 ED50 prior to vaccination.; ED50 = Estimated dose 50%, the estimated serum dilution reducing the signal generated by viral infection by 50%	Prior to vaccination and at Months 7, 12, 18, 24, 48 and 84.
Secondary	Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.	Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal activity. Grade 3 redness and swelling was defined as redness/swelling above 50 millimeter (mm).	Within 7 days (Days 0-6) after vaccination
Secondary	Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms.	Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, urticaria and fever (Fever = axillary temperature above 37.5 degrees Celsius (°C)). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Grade 3 fever = axillary temperature above 39.0°C.	Within 7 days (Days 0-6) after vaccination
Secondary	Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs).	An unsolicited adverse event 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 unsolicited AE = an event that prevented normal activity.; A related AE = event assessed by the investigator as causally related to the study vaccination.	Within 30 days (Days 0 - 29) post-vaccination period.
Secondary	Number of Subjects Reporting Any and Related Serious Adverse Events (SAEs).	SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. A related SAE was defined as an event assessed by the investigator as causally related to the study vaccination.	Up to Month 48 and up to Month 84
Secondary	Number of Subjects Reporting Related or Fatal Serious Adverse Event.	Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.	Up to Month 84
Secondary	Number of Subjects Reporting Any AE/SAE Leading to Premature Discontinuation of the Study.	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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.; Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.	Up to Month 84
Secondary	Number of Subjects Reporting New Onset of Chronic Disease (NOCDs).	NOCDs include autoimmune disorders, asthma and type I diabetes.	Up to Month 48
Secondary	Number of Subjects Reporting New Onset of Autoimmune Disease (NOADs).		Up to Month 48
Secondary	Number of Subjects Reporting Medically Significant Conditions (MAEs).	Medically significant conditions 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. Common diseases included: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury.	Up to Month 48
Secondary	Number of Subjects With Pregnancies and Their Outcomes.	Pregnancy outcomes are live infant, premature live infant, elective termination, ectopic pregnancy, spontaneous abortion, lost to follow-up and pregnancy ongoing. For each category it was specified if the infant presents congenital anomaly (CA) or no apparent congenital anomaly (No ACA).	Up to Month 48
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the Type Assignment Algorithm (TAA)	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done on subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.; TAA: Type assignment algorithm. The lesion was assigned to an HPV type found in the lesion if; the same HPV type was found in at least one of the two (closest) preceding cytology samples, or; none of the HPV types found in the lesion were found in any of the two preceding cytology samples (isolate HPV types)	Up to Month 48
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done in: - DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 84
Secondary	Number of Subjects With Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18	Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type(s) PCR in cervical samples at all available time points over approximately a 12-month interval (evaluations are planned at approximately 6-month intervals). - DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 84
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types Individually or in Combinations.	Persistent cervical HPV infection (6-month definition) = detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects HPV DNA- for the corresponding HPV type at baseline (at month 0 and Month 6) regardless of initial serostatus. HPV-HRW=All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18. HPV-HR=High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.	Up to Month 84
Secondary	Number of Subjects With Persistent Infection (12-month Definition) With Oncogenic HPV Types Individually or in Combinations.	Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. subjects HPV DNA- for the corresponding HPV type at Month 0 6, regardless of initial serostatus. HPV-HRW=All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HPV-HR=High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 , 68	Up to Month 84
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen	CIN2+ was defined as CIN grades 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done in: - DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Note: Results for seropositive status were not analysed.	Up to Month 84
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done in: - DNA- and sero-/+: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.	Up to Month 84
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen		Up to Month 84
Secondary	Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Irrespective of HPV Cervical Infection and Irrespective of Baseline HPV DNA Status	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done on all subjects irrespective of their baseline HPV DNA status.	Up to Month 84
Secondary	Number of Subjects With Any Cytological Abnormalities Associated With HPV-16 or HPV-18 Cervical Infection	Cytological abnormalities = atypical squamous cells of undetermined significance (ASC-US). Detection was done in: - DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Results for seropositive status were not analysed.	Up to Month 84
Secondary	Number of Subjects With Cytological Abnormalities Associated With Oncogenic HPV Types Individually or in Combinations	Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects who were HPV DNA negative for the corresponding HPV type at baseline (at month 0 and Month 6) regardless of initial serostatus. HRW-HPV= All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HPV-HR= High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68	Up to Month 48
Secondary	Number of Subjects With Histopathologically Confirmed Reduction of Local Cervical Therapy	Detection was done on all subjects irrespective of their baseline HPV DNA status.	Up to Month 84
Secondary	Number of Subjects With First Colposcopy	Detection was done on all subjects irrespective of their baseline HPV DNA status.	Up to Month 84
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus.	Up to Month 84
Secondary	Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-confirmed CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus. The lesion was assigned to an HPV type found in the lesion if (1) the same HPV type was found in at least 1 of the 2 (closest) preceding cytology samples, or (2) none of the HPV types found in the lesion were found in any of the 2 preceding cytology samples (isolate HPV types)	Up to Month 84

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