Human Papilloma Virus (HPV) Vaccine Efficacy Trial Against Cervical Pre-cancer in Young Adults With GlaxoSmithKline (GSK) Biologicals HPV-16/18

Study Overview
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Brief Summary
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Human Papilloma virus (HPV) are viruses that cause a common infection of the skin and genitals in men and women. Several types of HPV infection are transmitted by sexual activity and, in women, can infect the cervix (part of the uterus or womb). This infection often goes away by itself, but if it does not go away (this is called persistent infection), it can lead in women over a long period of time to cancer of the cervix. If a woman is not infected by HPV, it is very unlikely that she will get cervical cancer. This study will evaluate the efficacy of GSK Biologicals HPV 16/18 VLP/AS04 vaccine to prevent infection associated cervical pre-cancer and vaccine with HPV 16 or 18 and the vaccine safety, over 48 months, in young adolescents and women of 15/25 years of age at study start. Approximately 18.000 study subjects will either receive the HPV vaccine or a control vaccine (hepatitis A vaccine) administered intramuscularly according to a 0-1-6 month schedule. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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NOTE: Some 178 centers participate in this study. Given that the recruitment is completed, the researchers have listed one center per country in this website. If required, further details of centers available on request.

Official Title
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A Phase III, Double-blind, Randomized, Controlled, Multi-center Study to Evaluate the Efficacy of GlaxoSmithKline Biologicals. HPV-16/18 VLP AS04 Vaccine Compared to Hepatitis A Vaccine as Control in Prevention of Persistent HPV-16 or HPV-18 Cervical Infection and Cervical Neoplasia, Administered Intramuscularly According to a 0, 1, 6 Month Schedule in Healthy Females 15-25 Years of Age.

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: Cervarix™
* Biological: Havrix™-based investigational formulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A woman whom the investigator believes that she and/or her parents/legally acceptable representative can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits). A woman between, and including, 15 and 25 years of age at the time of the first vaccination. Written informed consent must be obtained from the subject prior to enrollment (for subjects below the legal age of consent, written informed consent must be obtained from a parent or legal guardian of the subject and, in addition, the subject should sign and personally date a written informed assent). Subject must be free of obvious health problems as established by medical history and clinical examination before entering into the study. Subject must have a negative urine pregnancy test. Subject must be of non-childbearing potential or, if of childbearing potential, she must be abstinent or must be using adequate contraceptive precautions for 30 days prior to the first vaccination and must agree to continue such precautions for two months after completion of the vaccination series. Has had no more than 6 lifetime sexual partners prior to enrollment. This criterion may not be applicable in subjects less than 18 years of age, according to local regulatory/ethical requirements. Subject must have intact cervix. Exclusion Criteria: Pregnant or breastfeeding. Women must be at least 3 months post-pregnancy and not breastfeeding to enter the study. A woman planning to become pregnant or planning to discontinue contraceptive precautions during approximately the first nine months of the study (Months 0-8). Previous administration of components of the investigational vaccine. Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. 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) each dose of vaccine. Administration of some routine vaccines up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window. Previous vaccination against human papillomavirus (HPV). History of vaccination against Hepatitis A or a known clinical history of Hepatitis A disease. History of having had colposcopy or has planned a colposcopy to evaluate an abnormal cervical cytology (Pap smear) test. 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 vaccines. Hypersensitivity to latex. Known acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests. History of chronic condition(s) requiring treatment. Received immunoglobulins and/or blood product within 90 days preceding enrollment. Enrollment 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. Enrollment will be deferred until condition is resolved according to investigator's medical judgement.

Ages Eligible for Study
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Minimum Age: 15 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix Group<br>Subjects received 3 doses of Cervarix™ (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6. | Biological: Cervarix™<br>* Intramuscular injection, 3 doses<br>* Other names: GSK Biologicals HPV 16/18 VLP/AS04 vaccine;|
| Active Comparator: Havrix Group<br>Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix™-based investigational formulation) at Months 0, 1 and 6. | Biological: Havrix™-based investigational formulation<br>* Intramuscular injection, 3 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline) | CIN2+ was defined as CIN grades 2 and 3, endocervical 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. | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post-dose 3 | 
| Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline) | CIN2+ was defined as CIN grades 2 and 3, endocervical adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done in subjects: DNA- and sero-: 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 HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. | at Month 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen | CIN1+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Detection was done in subjects: DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 | 
| Number of Subjects Reporting Solicited Local and General Symptoms | Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include arthralgia, fatigue, fever (measured in degree celsius (°C) by axillary route), gastrointestinal symptoms, headache, myalgia, rash and urticaria. Data are presented across the 3 doses. | Within 7 days after any vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events | Unsolicited adverse event (AE) covers any AE 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. | Within 30 days after any vaccination | 
| Number of Subjects Reporting 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 entire study period (Month 0 to Month 48) | 
| Number of Subjects Reporting New Onset of Chronic Disease (NOCDs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. | Throughout the entire study (Month 0 to 48) | 
| Number of Subjects Reporting Medically Significant Conditions | Medically significant conditions include adverse events (AEs) prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. | Throughout entire study period (Month 0 to Month 48) | 
| Number of Subjects With Outcome of Pregnancies, Overall and Stratified by Initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus | Pregnancy outcomes are normal infant, premature infant, abnormal infant, elective termination, therapeutic abortion, ectopic pregnancy, spontaneous abortion, still birth, lost to follow-up, no pregnancy/molar pregnancy, pregnancy ongoing. | Throughout the entire study period (Month 0 to Month 48) | 
| Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 | Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done in subjects: DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 | 
| Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 | Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done in subjects: DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. | at Month 48 | 
| Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types | Oncogenic 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 at baseline regardless of initial serostatus. HRW-HPV= All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HR-HPV= High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 | 
| Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types | Oncogenic 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 at baseline regardless of initial serostatus. HRW-HPV = All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HR-HPV = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 | at Month 48 | 
| Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen | CIN1+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Detection was done in subjects: DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline | at Month 48 | 
| Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18 | Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type (by PCR) over a 12-month interval (evaluations were planned at approximately 6-month intervals). Detection was done in subjects: DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 | 
| Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18 | Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type (by PCR) over a 12-month interval (evaluations were planned at approximately 6-month intervals). Detection was done in subjects: DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline | at Month 48 | 
| Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen | Oncogenic HPV types assessed 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 at baseline regardless of initial serostatus. | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 | 
| Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen | Oncogenic HPV types assessed 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 at baseline regardless of initial serostatus. | at Month 48 | 
| Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen | CIN2+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Oncogenic types detected 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 at baseline, regardless of initial serostatus. | Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 | 
| Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen | CIN2+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Oncogenic types detected 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 at baseline, regardless of initial serostatus. | at Month 48 | 
| Number of Seropositive Subjects for Anti-HPV-16 and Anti-HPV-18 Antibody Titers by ELISA in the Immunogenicity Subset, According to Initial (Month 0) HPV-16 or HPV-18 Serostatus | Cut-off values assessed for seropositivity include 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies. Results are presented for the total group and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus by ELISA - seronegative (sero-) or seropositive (sero+) | At Months 6, 7, 12, 24, 36 & 48 | 
| Anti-HPV-16 and Anti-HPV-18 ELISA Titers in the Immunogenicity Subset | Titers are given as Geometric Mean Titers (GMTs) expressed as ELISA Units per milliliter (EL.U/mL). GMTs are presented for the total group and also stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus by ELISA [seronegative (sero-) or seropositive (sero+)]. | At Months 6, 7, 12, 24, 36 and 48 | 
| HPV-16 and HPV-18 Seroconversion (V5/J4 Monoclonal Inhibition Test) | HPV-16 V5 cut-off was defined as greater than or equal to 41 ELU/mL. Only seronegative subjects were analysed. Seronegative subjects are subjects who had an antibody titer of less than 41 ELU/mL before vaccination. HPV-18 J4 cut-off was defined as greater than or equal to 110 EL.U/mL. Both seropositive and seronegative subjects were included in the analysis. Seropositive subjects were subjects with an antibody titer of greater than or equal to 110 EL.U/mL. Seronegative subjects were subjects with an antibody titer less than 110 EL.U/mL. | Month 0, 7, 12 and 24 | 
| HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 Monoclonal Inhibition Test) | Titers were expressed as GMTs in ELISA units per milliliter (EL.U/mL). | Month 0, 7, 12, 24 | 
| Number of Subjects Seropositive for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA) | Seropositivity was defined as subjects with a titer equal to or greater than 40. Subjects with an antibody titer smaller than 40 prior to vaccination were seronegative prior to vaccination and subjects with a titer equal to or greater than 40 were seropositive prior to vaccination. | At Month 0, 7, 12, 24, 36 and 48 | 
| Titers for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA) | Titers were expressed as GMTs. | At month 0, 7, 12, 24, 36 and 48 | 
| Geometric Mean Titers of Anti-HPV-16 in Subjects Without and With 6-month Persistent Infection | GMT for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. Due to the lack of seronegative subjects at Month 7, the hazard ratio (and Confidence Interval) was not calculated. | At Month 7 | 
| Number of Seroconverted Subjects for Anti-HPV-16 Without and With 6-month Persistent Infection. | Seroconversion rates for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. Due to the lack of seronegative subjects at Month 7, the hazard ratio (and Confidence interval) was not calculated. | At Month 7 | 
| Geometric Mean Titers of Anti-HPV-16 in Subjects Without and With 12-month Persistent Infection | GMTs for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. | At Month 7 | 
| Number of Seroconverted Subjects for Anti-HPV-16 Without and With 12-month Persistent Infection | Seroconversion rates for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. Due to the lack of seronegative subjects at Month 7, the hazard ratio (and Confidence Interval) was not calculated. | At Month 7 | 
| Geometric Mean Titers of Anti-HPV-18 in Subjects Without and With 6-month Persistent Infection | GMTs for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. | At Month 7 | 
| Number of Seroconverted Subjects for Anti-HPV-18 Without and With 6-month Persistent Infection. | Seroconversion rates for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. Due to the lack of seronegative subjects at Month 7, the hazard ratio (and Confidence Interval) was not calculated. | At Month 7 | 
| Geometric Mean Titers of Anti-HPV-18 in Subjects Without and With 12-month Persistent Infection | GMTs for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. | At Month 7 | 
| Number of Seroconverted Subjects for Anti-HPV-18 Without and With 12-month Persistent Infection | Seroconversion rates for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. Due to the lack of seronegative subjects at Month 7, the hazard ratio (and Confidence Interval) was not calculated. | At Month 7 |