The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medication: Cervarix Study No.: 104820 (HPV-015) Title: A phase III, double-blind, randomized, controlled study to evaluate the safety, immunogenicity and efficacy of GlaxoSmithKline Biologicals HPV-16/18 L1 VLP AS04 vaccine administered intramuscularly according to a three-dose schedule (0, 1, 6 month) in healthy adult female subjects aged 26 years and above. Cervarix - HPV-16/18 L1 VLP AS04 (HPV): GlaxoSmithKline (GSK) Biologicals candidate human papillomavirus (HPV) vaccine containing HPV 16/18 virus-like particles (VLPs). Rationale: The aim of the study was to evaluate the safety, immunogenicity and efficacy of the HPV vaccine in women aged 26 years and above. An interim analysis would be performed when at least 40 cases of persistent infection with HPV-16/18 and/or CIN1+ associated with HPV-16/18 were detected in the ATP cohort for efficacy, in HPV DNA negative and seronegative subjects at baseline or when all subjects had completed the Month 48 visit. A final analysis would be performed if (1) at least 405 cases of CIN1+ irrespective of HPV type found in the lesion, irrespective of HPV DNA and serological status at baseline in the TVC are reached before all subjects have completed the Month 84 visit, or (2) at study conclusion (Month 84). Since Study conclusion was reached, the final analysis was performed. Phase: III Study Period: - 16 February 2006 to 10 December 2010 (Month 48) - 29 January 2014 (Month 84) Study Design: Double-blind, multi-centre, randomized (1:1), controlled study with 2 parallel groups. Blinding will be maintained and follow-up will be continued for all subjects until Month 84 (end of the study). Centres: 76 study centres divided in 4 regions: Asia Pacific [Australia (2), Philippines (3), Singapore (3) and Thailand (2)], Europe [Portugal (5), Russia (6), Netherlands (3) and United Kingdom (6)], Latin America [Mexico (2) and Peru (1)] and North America [United States of America (36) and Canada (7)]. Indication: Active immunisation of females from 9 years of age onwards for the prevention of cervical cancer by protecting against incident and persistent infections, cytological abnormalities including atypical squamous cells of undetermined significance (ASC-US), cervical intraepithelial neoplasia (CIN) and pre-cancerous lesions (CIN 2/3) caused by oncogenic human papillomaviruses (HPV). Treatment: The study groups were as follows: HPV Group received the HPV vaccine Control Group received the control Aluminium Hydroxide [Al(OH)3] Both study groups received 3 doses of either the HPV vaccine or the control by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6 month schedule. Note: enrolment was stratified by (1) age, with the majority of subjects in age strata 26 35 years and 36 45 years (about 45% each) and about 10% in the age stratum 46+ years, and (2) previous HPV history (in each age stratum, the number of women with a history of HPV infection/treatment was limited to approximately 15%). Objectives: To demonstrate efficacy of the candidate vaccine in the prevention of (1) persistent infection (6-month definition) with HPV-16 or HPV-18 (by polymerase chain reaction [PCR]) and/or (2) histopathologically confirmed CIN1*+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by enzymelinked immunosorbent assay [ELISA]). If efficacy was demonstrated, the following objective would be assessed sequentially: To demonstrate efficacy of the candidate vaccine compared with control in the prevention of (1) persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR) and/or (2) histopathologically-confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected using the HPV Type Assignment Algorithm (TAA), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). *CIN1+: Cervical intraepithelial neoplasia CIN1, CIN2, CIN3, adenocarcinoma in-situ (AIS) and invasive cervical cancer. Primary Outcome/Efficacy Variable:
Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR) and/or histopathologically confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) (combined endpoint), overall and stratified according to initial (Month 0) HPV-16 or HPV- 18 serostatus (by ELISA). Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR) and/or histopathologically-confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected using the HPV TAA, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). Persistent cervical HPV infection (6-month definition) was defined as detection of the same HPV type(s) (by PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Note: Unless otherwise specified these primary outcomes were assessed post-dose 3 in adult women who were negative for HPV DNA (by PCR) at Months 0 and 6 for the corresponding HPV type. Secondary Outcome/Efficacy Variable(s): Virological Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). Persistent infection (12-month definition) with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). Persistent infection (6-month definition) with oncogenic HPV types (e.g. HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, by PCR), individually or in combinations, in subjects HPV DNA negative for the type considered, regardless of initial serostatus. Persistent infection (12-month definition) with oncogenic HPV types (e.g. HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, by PCR), individually or in combinations, in subjects HPV DNA negative for the type considered, regardless of initial serostatus. Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type(s) (by PCR) in cervical samples at all available time points over approximately a 12-month interval (evaluations are planned at approximately 6-month intervals). Histopathological Histopathologically confirmed CIN2+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA*, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). CIN2+ (cervical intraepithelial neoplasia) was defined as CIN2, CIN3, adenocarcinoma in-situ (AIS) and invasive cervical cancer. Histopathologically confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA*, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). Histopathologically-confirmed CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA*, irrespective of baseline HPV DNA and serostatus. Histopathologically-confirmed CIN1+ irrespective of HPV cervical infection and irrespective of baseline HPV DNA status. * As the vaccine efficacy was not demonstrated for the primary case definition (detection within the lesional component of the cervical tissue specimen by PCR), these analyses are not presented. Cytological Any cytological abnormality associated with HPV-16 or HPV-18 cervical infection (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). Any cytological abnormality associated with oncogenic HPV types (e.g. HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, by PCR),individually or in combinations, in subjects HPV DNA negative for the type considered, regardless of initial serostatus. Administration of colposcopy referrals and local cervical therapy (LEEP, CONE, KNIFE or LASER), irrespective of baseline HPV DNA status. Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR) and/or histopathologically-confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA, irrespective of baseline HPV DNA and serostatus. Results for seropositive status were not analysed. Note: Unless otherwise specified, the secondary outcomes listed here above were assessed post-dose 3 in adult women who
were negative for HPV DNA (by PCR) at Months 0 and 6 for the corresponding HPV type. Immunogenicity HPV-16 and HPV-18 ELISA titres and seroconversion* at Months 7, 24, 48 and 84 (all subjects) and at Months 12, 18, 36, 60 and 72 (in the immunogenicity subset).these analyses were stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus. Viral neutralization might be assessed in a selected subset of subjects. HPV-16 and HPV-18 ELISA titres and seroconversion were assessed in vaccine recipients with breakthrough HPV-16 and/or HPV-18 persistent infections and HPV-16 and/or HPV-18 associated CIN1+ lesions. These were compared with selected non-cases (vaccine recipients without persistent infection or CIN1+, matched for age, race and clinic site). Antibody titres and seroconversion for V5/J4 monoclonal antibody inhibition testing and/or viral neutralization might also be assessed on these samples. These analyses were restricted to subjects who were seronegative for the corresponding HPV type prior to vaccination **. * Seroconversion was defined as the appearance of antibodies (i.e. concentration/titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. **Due to the low number of breakthrough cases, this analysis could not be performed. Safety Occurrence, intensity, relationship to vaccination and resulting school or work absenteeism (as applicable) of solicited local or solicited general symptoms within 7 days (Days 0-6) after each vaccination. Occurrence, intensity, relationship to vaccination and resulting school or work absenteeism (as applicable) of unsolicited symptoms within 30 days (Days 0-29) after each vaccination. Occurrence and relationship to vaccination of serious adverse events (SAEs) throughout the entire study period (up to Month 48). Occurrence of any SAE related to vaccination, other GSK medication or study procedures, any fatal SAE and any AE/SAE leading to premature discontinuation of the study throughout the entire study period up to Month 84. Occurrence of new onset chronic diseases (NOCDs) (e.g. autoimmune disorders, asthma, type I diabetes) throughout the entire study period (up to Month 48). Occurrence of new onset autoimmune diseases (NOADs)(e.g. autoimmune disorders, asthma, type I diabetes) throughout the entire study period (up to Month 48). Occurrence of medically significant conditions (MSCs) throughout the entire study period (up to Month 48) #. Occurrence of pregnancies and their outcomes throughout the entire study period (up to Month 48). # 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. Statistical Methods: The analyses were performed on the Total Vaccinated cohort, the According To Protocol (ATP) cohort for efficacy and the ATP cohort for Immunogenicity. - The Total Vaccinated cohort included all subjects with at least one vaccine administration documented. - The ATP cohort for efficacy included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination violations) who had a normal or low-grade cytology (negative or ASC-US or LSIL) at Month 0, with no more than one cervix, who received 3 doses administered according to protocol, with no administration of vaccine forbidden and with negative pregnancy test at Month 0, 1 and 6. This cohort excluded the 15% subset of women enrolled with prior history of HPV disease/infection. - The ATP cohort for immunogenicity included all evaluable subjects (i.e. who meet all eligibility criteria, who comply with the procedures defined in the protocol, with no elimination criteria during the study) for whom data concerning any immunogenicity outcome measures were available. This included subjects for whom assay results were available for antibodies against at least one study vaccine antigen component after vaccination. This cohort included the 15% subset of women enrolled with prior history of HPV disease/infection. Note: Five blood samples were to be collected at Months 0, 7, 24, 48 and 84 in all subjects. Additional blood samples were to be drawn in a subset of subjects from selected sites (immunogenicity subset: N 1000, at least 250 per region) at Months 12, 18, 36, 60 and 72. Analysis of Efficacy: The analysis was performed on the ATP cohort for efficacy and the Total Vaccinated cohort. The significance level for the interim analysis was calculated as 0.023. Therefore a 97.7% confidence interval (CI) was calculated. Similarly, a significance level of 0.038 and a 96.2% CI was calculated for the final analysis.
The analysis of the primary outcome and cytological and histopathological outcome variables associated with HPV-16 or HPV- 18 in the ATP cohort for efficacy was stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA). Vaccine efficacy for comparison of the 2 groups, HPV and Control, was calculated by 1 minus the rate ratio (ratio of the event rate in HPV group versus Control group) with its exact 97.7% CI for interim analysis and exact 96.2% CI for final analysis, using the conditional exact method and taking into account the follow-up time of subjects within each group. This was assessed in the prevention of 6-month persistent infection with HPV-16/-18 (by PCR) and/or histopathologically-confirmed C1N1+ associated with HPV-16/-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) (combined endpoint) or detected using the HPV TAA. Attack rates in each group (number of subjects with an event divided by the total number of subjects) were also compared using the Fisher s exact test. Vaccine efficacy was also calculated using conditional exact method and tabulated for the following variables: - Incidence rates and vaccine efficacy against persistent infection (6-month definition and 12 month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and according to or regardless of the initial serostatus at baseline. - Incidence rates and vaccine efficacy against persistent infection (6-month definition and 12-month definition) with oncogenic HPV types individually or in combination, in HPV DNA negative subjects for the type considered, at baseline and regardless of initial status. - Incidence rates and vaccine efficacy against histopathologically confirmed CIN2+ associated with HPV-16 and/or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) in HPV DNA negative and seronegative subjects at baseline or regardless of the initial serostatus. - Incidence rates and vaccine efficacy against histopathologically confirmed CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) or detected using the TAA in HPV DNA negative and according to or regardless of the initial serostatus at baseline. - Incidence rates and vaccine efficacy against histopathologically confirmed CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) in all subjects, irrespective of their baseline HPV DNA status. - Incidence rates and vaccine efficacy against histopathologically confirmed CIN1+ irrespective of HPV DNA results in all subjects, irrespective of their baseline HPV DNA status. - Incidence rates and vaccine efficacy against cytological abnormalities (ASCUS+) associated with HPV-16 and/or HPV-18 cervical infection in HPV DNA negative and seronegative subjects at baseline or regardless of the initial serostatus. - Incidence rates and vaccine efficacy against cytological abnormalities (ASCUS+) associated with oncogenic HPV types individually or in combination, in HPV DNA negative subjects at baseline. - Incidence rates and vaccine efficacy in histopathologically confirmed reduction of local cervical therapy in all subjects, irrespective of their baseline HPV DNA status. - Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) or detected using the TAA in all subjects, irrespective of their baseline HPV DNA status and serostatus. Analysis of Immunogenicity: The analysis was performed on the ATP cohort for immunogenicity. For each group, at each time point that a blood sample result was collected (i.e. Months 0, 7, 24, 48 and 84 for all subjects, and Months 12, 18, 36, 60, 72 for the immunogenicity subset), seropositivity rate and geometric mean concentrations/titres (GMCs/GMTs) were tabulated with 95% CIs, by group and by initial HPV-16 and HPV-18 serostatus and overall. Viral neutralization was tabulated for both HPV-16 and HPV-18 antibodies by group and by initial status, up to Month 48. From Months 72 onwards, in order to increase the assay precision used to measure anti-hpv-16/-18 antibody titers, the assay cut-off value was changed from 8 EL.U/mL to 19 EL.U/mL for HPV-16 and from 7 EL.U/mL to 18 EL.U/mL for HPV-18. Analysis of safety: The analysis was performed on the Total Vaccinated cohort The percentages of subjects with at least one solicited local or general symptom and symptoms resulting in school/work absenteeism reported during the solicited follow-up period (Days 0-6) after each vaccination were tabulated with exact 95% CIs by group after each vaccine dose and across doses. The same tabulation was done for grade 3 solicited symptoms and solicited general symptoms assessed as related to vaccination by the investigator. The percentage of subjects with unsolicited adverse events (AEs) and unsolicited symptoms resulting in school/work absenteeism classified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, and reported within 30 days (Days 0-29) after each vaccination was tabulated by group. The percentages of grade 3 unsolicited AEs and unsolicited AEs with relationship to vaccination as assessed by the investigator were also tabulated by
group. The percentages of subjects with at least one report of NOCDs, NOADs and medically significant adverse events, classified by the MedDRA preferred terms and reported during the follow-up period up to Month 48 were tabulated by group. The percentage of pregnancies and their outcome up to Month 48 was tabulated by group. The percentage and relationship to vaccination of SAEs, was tabulated according to the MedDRA preferred terms, throughout the entire study period. The percentage of SAEs causally related to vaccination, other GSK medication or study procedures, any fatal SAE and any AEs/SAEs leading to premature discontinuation of the study throughout the follow-up period up to Month 84 was tabulated according to the MedDRA preferred terms. Study Population: Healthy female subjects aged at least 26 years of age at the time of first vaccination, free of obvious health problems before entering the study, and having had a negative pregnancy urine test were enrolled. Subjects had to be of non-childbearing potential, or if of childbearing potential, had to be abstinent or using an effective birth control method for 30 days prior to the first vaccination and had to agree to continue such precautions for 2 months after completion of vaccination series. Subjects had to have an intact cervix (no history of cauterization or surgical treatment involving damage to the transformation zone of the cervix) or have a cervix (if the subject had a previous history of HPV infection or an HPV treatment). In addition, written informed consent was obtained from the subject prior to any study procedure. Number of subjects (At the interim analysis Month 48) HPV Group Control Group Planned, N 2700 2700 Randomised, N (Total Vaccinated cohort) 2881 2871 Completed *, n (%) 2456 (85.2) 2438 (84.9) Total Number Subjects Withdrawn, n (%) 425 (14.8) 433 (15.1) Withdrawn due to Adverse Events, n (%) 28 (1.0) 13 (0.5) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 397 (13.8) 420 (14.6) Demographics HPV Group Control Group N (Total Vaccinated cohort) 2881 2871 Females:Males 2881:0 2871:0 Mean Age, years (SD) 37.0 (7.24) 37.0 (7.32) White/Caucasian, n (%) 1202 (41.7) 1215 (42.3) * Some subjects completed the study at Month 36 since they did not want to participate to the one-year extension up to Month 48. The number of subjects who participated up to Month 48 in the HPV Group = 2305 (80.0%) and in the Control Group = 2281 (79.4%). Number of subjects (At final analysis Month 84) HPV Group Control Group Planned, N 2700 2700 Randomised, N (Total Vaccinated cohort) 2877 2870 Consented for Extension at Month 84* 2146 2116 Completed for Month 84, n (%) 1904 (66.2) 1881 (65.5) Total Number Subjects Withdrawn, n (%) 242 (11.3) 235 (11.1) Withdrawn due to Adverse Events, n (%) 4 (0.2) 2 (0.1) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 238 (11.1) 233 (11.0) Demographics HPV Group Control Group N (Total Vaccinated cohort) 2877 2870 Females:Males 2877:0 2870:0 Mean Age, years (SD) 37.0 (7.2) 37.0 (7.3) Median Age, years (minimum, maximum) 37 (24, 72) 37 (26, 68) White/Caucasian, n (%) 1202 (41.8) 1215 (42.3) Hispanic, n (%) 801 (27.8) 802 (27.9) East & South East Asian, n (%) 629 (21.9) 620 (21.6) * Some subjects completed the study at Month 48 since they did not want to participate to the extension up to Month 84. Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection (combined endpoint) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method, at the Month 48 timepoint (ATP cohort for efficacy)
P-value (Per100) HPV-16/18 HPV 1898 7 6343.66 0.11 0.04 0.25 81.1 52.1 94.0 <0.0001 Control 1854 36 6156.53 0.58 0.39 0.85 - - - - HPV-16 HPV 1545 5 5197.33 0.10 0.03 0.25 82.0 46.3 95.6 <0.0001 Control 1521 27 5064.35 0.53 0.33 0.82 - - - - HPV-18 HPV 1597 2 5350.92 0.04 0.00 0.15 80.3-10.8 98.6 0.0212 Control 1571 10 5262.99 0.19 0.08 0.38 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection (combined endpoint) in HPV DNA negative and seropositive subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) P-value (Per100) HPV-16/18 HPV 900 2 2968.23 0.07 0.01 0.28 86.4 30.1 99.0 0.0019 Control 864 14 2824.56 0.50 0.24 0.89 - - - - HPV-16 HPV 605 1 1986.18 0.05 0.00 0.33 89.2 4.0 99.9 0.0107 Control 594 9 1938.48 0.46 0.19 0.96 - - - - HPV-18 HPV 574 1 1902.49 0.05 0.00 0.34 81.1-117.4 99.8 0.1166 Control 550 5 1800.48 0.28 0.07 0.72 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection (combined endpoint) in HPV DNA negative subjects at baseline and regardless of initial serostatus, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) P-value (Per100) HPV-16/18 HPV 2224 9 7408.96 0.12 0.05 0.25 82.8 61.2 93.5 <0.0001 Control 2190 51 7222.72 0.71 0.50 0.97 - - - - HPV-16 HPV 2167 6 7239.56 0.08 0.03 0.20 83.8 56.5 95.3 <0.0001 Control 2131 36 7057.52 0.51 0.34 0.74 - - - -
P-value (Per100) HPV-18 HPV 2203 3 7362.23 0.04 0.01 0.13 81.6 25.4 97.5 0.0023 Control 2165 16 7207.63 0.22 0.12 0.38 - - - - For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6 For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects are in the analysis of at least one single type) Subjects with an event were DNA negative for the corresponding HPV type at Month 0 and Month 6 Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected using the HPV TAA (combined endpoint) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) P-value (Per100) HPV-16/18 HPV 1898 7 6343.66 0.11 0.04 0.25 81.1 52.1 94.0 <0.0001 Control 1854 36 6156.53 0.58 0.39 0.85 - - - - HPV-16 HPV 1545 5 5197.33 0.10 0.03 0.25 82.0 46.3 95.6 <0.0001 Control 1521 27 5064.35 0.53 0.33 0.82 - - - - HPV-18 HPV 1597 2 5350.92 0.04 0.00 0.15 80.3-10.8 98.6 0.0212 Control 1571 10 5262.99 0.19 0.08 0.38 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type TAA: Type assignment algorithm. The lesion was assigned to an HPV type found in the lesion if a) the same HPV type was found in at least one of the two (closest) preceding cytology samples, or b) none of the HPV types found in the lesion were found in any of the two preceding cytology samples (isolate HPV types) Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected using the HPV TAA (combined endpoint) in HPV DNA negative and seropositive subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 900 2 2968.23 0.07 0.01 0.28 84.1 15.2 98.9 0.0062 Control 864 12 2828.35 0.42 0.20 0.80 - - - - HPV-16 HPV 605 1 1986.18 0.05 0.00 0.33 87.8-12.6 99.9 0.0200 Control 594 8 1941.33 0.41 0.15 0.88 - - - -
P-value HPV-18 HPV 574 1 1902.49 0.05 0.00 0.34 76.3-216.2 99.8 0.2083 Control 550 4 1801.43 0.22 0.05 0.63 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type TAA: Type assignment algorithm. The lesion was assigned to an HPV type found in the lesion if a) the same HPV type was found in at least one of the two (closest) preceding cytology samples, or b) none of the HPV types found in the lesion were found in any of the two preceding cytology samples (isolate HPV types) Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected using the HPV TAA (combined endpoint) in HPV DNA negative subjects at baseline and regardless of initial serostatus, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) P-value (Per100) HPV-16/18 HPV 2224 9 7408.96 0.12 0.05 0.25 82.1 59.4 93.3 <0.0001 Control 2190 49 7226.51 0.68 0.48 0.93 - - - - HPV-16 HPV 2167 6 7239.56 0.08 0.03 0.20 83.3 55.1 95.2 <0.0001 Control 2131 35 7060.36 0.50 0.33 0.72 - - - - HPV-18 HPV 2203 3 7362.23 0.04 0.01 0.13 80.4 19.3 97.3 0.0041 Control 2165 15 7208.57 0.21 0.11 0.37 - - - - For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6 For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative for the corresponding HPV type at Month 0 and Month 6 TAA: Type assignment algorithm. The lesion was assigned to an HPV type found in the lesion if a) the same HPV type was found in at least one of the two (closest) preceding cytology samples, or b) none of the HPV types found in the lesion were found in any of the two preceding cytology samples (isolate HPV types) Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV- 16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection (combined endpoint) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method, at the Month 84 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 1852 7 10474.31 0.07 0.03 0.14 90.5 78.6 96.5 <0.0001 Control 1818 71 10099.52 0.70 0.54 0.90 - - - -
HPV-16 HPV 1507 5 8619.70 0.06 0.02 0.14 90.9 76.3 97.4 <0.0001 Control 1491 53 8353.92 0.63 0.47 0.84 - - - - HPV-18 HPV 1565 3 8848.99 0.03 0.01 0.10 85.3 47.7 97.5 0.0002 Control 1541 20 8682.69 0.23 0.14 0.36 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for at least one HPV type (subjects are in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type Follow-up period starts at day after Dose 3 LL,UL=96.2% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV- 16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection (combined endpoint) in HPV DNA negative and seropositive subjects at baseline, using conditional exact method, at the Month 84 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 870 3 4795.50 0.06 0.01 0.19 82.2 34.2 97.0 0.0022 Control 849 16 4557.95 0.35 0.19 0.58 - - - - HPV-16 HPV 588 2 3196.47 0.06 0.01 0.24 80.6 2.7 98.2 0.0214 Control 584 10 3098.89 0.32 0.15 0.61 - - - - HPV-18 HPV 552 1 3079.13 0.03 0.00 0.19 84.3-41.1 99.7 0.0667 Control 540 6 2904.10 0.21 0.07 0.47 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for at least one HPV type (subjects are in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type Follow-up period starts at day after Dose 3 LL,UL=96.2% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV- 16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection (combined endpoint) in HPV DNA negative subjects at baseline, using conditional exact method, at the Month 84 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 2168 10 12165.18 0.08 0.04 0.16 89.3 78.7 95.3 <0.0001 Control 2147 90 11747.63 0.77 0.61 0.95 - - - - HPV-16 HPV 2112 7 11911.88 0.06 0.02 0.13 89.2 75.6 96.1 <0.0001 Control 2091 63 11538.44 0.55 0.41 0.71 - - - - HPV-18 HPV 2149 4 12111.47 0.03 0.01 0.09 86.5 59.8 96.9 <0.0001 Control 2123 29 11819.09 0.25 0.16 0.36 - - - - For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6
For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects are in the analysis of at least one single type) Subjects with an event are DNA negative for the corresponding HPV type at Month 0 and Month 6 Follow-up period starts at day after Dose 3 LL,UL=96.2% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV- 16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected using the HPV TAA (combined endpoint) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method, at the Month 84 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 1852 7 10474.31 0.07 0.03 0.14 90.5 78.6 96.5 <0.0001 Control 1818 71 10099.52 0.70 0.54 0.90 - - - - HPV-16 HPV 1507 5 8619.70 0.06 0.02 0.14 90.9 76.3 97.4 <0.0001 Control 1491 53 8353.92 0.63 0.47 0.84 - - - - HPV-18 HPV 1565 2 8850.45 0.02 0.00 0.09 90.2 57.2 99.0 <0.0001 Control 1541 20 8682.69 0.23 0.14 0.36 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for at least one HPV type (subjects are in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type TAA: Type assignment algorithm. The lesion is assigned to an HPV type found in the lesion if a) the same HPV type is found in at least one of the two (closest) preceding cytology samples, or b) none of the HPV types found in the lesion are found in any of the two preceding cytology samples (isolate HPV types) Follow-up period starts at day after Dose 3 LL,UL=96.2% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV- 16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected using the HPV TAA (combined endpoint) in HPV DNA negative and seropositive subjects at baseline, using conditional exact method, at the Month 84 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 870 3 4795.50 0.06 0.01 0.19 79.6 22.5 96.6 0.0067 Control 849 14 4567.83 0.31 0.16 0.53 - - - - HPV-16 HPV 588 2 3196.47 0.06 0.01 0.24 78.4-11.8 98.1 0.0371 Control 584 9 3104.72 0.29 0.13 0.57 - - - - HPV-18 HPV 552 1 3079.13 0.03 0.00 0.19 81.1-85.0 99.7 0.1201 Control 540 5 2908.15 0.17 0.05 0.42 - - - - For single type: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for at least one HPV type (subjects are in the analysis of at least one single type)
Subjects with an event are DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type TAA: Type assignment algorithm. The lesion is assigned to an HPV type found in the lesion if a) the same HPV type is found in at least one of the two (closest) preceding cytology samples, or b) none of the HPV types found in the lesion are found in any of the two preceding cytology samples (isolate HPV types) Follow-up period starts at day after Dose 3 LL,UL=96.2% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Primary Efficacy Results: Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV- 16 and/or HPV-18 (by PCR) and/or CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected using the HPV TAA (combined endpoint) in HPV DNA negative subjects at baseline, using conditional exact method, at the Month 84 time point (ATP cohort for efficacy) P-value HPV-16/18 HPV 2168 10 12165.18 0.08 0.04 0.16 89.0 78.2 95.2 <0.0001 Control 2147 88 11757.51 0.75 0.59 0.93 - - - - HPV-16 HPV 2112 7 11911.88 0.06 0.02 0.13 89.1 75.2 96.0 <0.0001 Control 2091 62 11544.27 0.54 0.41 0.70 - - - - HPV-18 HPV 2149 3 12112.93 0.02 0.00 0.08 89.5 64.4 98.2 <0.0001 Control 2123 28 11823.14 0.24 0.15 0.35 - - - - For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6 For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects are in the analysis of at least one single type) Subjects with an event are DNA negative for the corresponding HPV type at Month 0 and Month 6 TAA: Type assignment algorithm. The lesion is assigned to an HPV type found in the lesion if a) the same HPV type is found in at least one of the two (closest) preceding cytology samples, or b) none of the HPV types found in the lesion are found in any of the two preceding cytology samples (isolate HPV types) Follow-up period starts at day after Dose 3 LL,UL=96.2% Lower and Upper confidence limits P-value=Two-sided Fisher Exact test Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) (Per100) HPV-16/18 HPV 1859 6 6317.22 0.09 0.03 0.23 82.9 53.8 95.1 Control 1822 34 6134.98 0.55 0.36 0.81 - - - HPV-16 HPV 1518 5 5177.94 0.10 0.03 0.25 81.3 43.9 95.4 Control 1495 26 5044.59 0.52 0.31 0.80 - - - HPV-18 HPV 1566 1 5330.21 0.02 0.00 0.12 87.7-13.3 99.9 Control 1542 8 5245.20 0.15 0.06 0.33 - - - Subjects had at least 5 months of follow-up after Month 12 For single type: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event were DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV
type Follow-up period starts at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seropositive subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) (Per100) HPV-16/18 HPV 880 2 2952.13 0.07 0.01 0.28 82.6 5.0 98.8 Control 851 11 2820.09 0.39 0.17 0.75 - - - HPV-16 HPV 591 1 1974.83 0.05 0.00 0.33 87.8-12.7 99.9 Control 583 8 1933.16 0.41 0.15 0.89 - - - HPV-18 HPV 562 1 1893.45 0.05 0.00 0.34 68.4-447.0 99.7 Control 543 3 1797.29 0.17 0.03 0.55 - - - Subjects had at least 5 months of follow-up after Month 12 For single type: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type Follow-up period starts at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (6-month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline and regardless of initial serostatus, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) (Per100) HPV-16/18 HPV 2178 8 7377.56 0.11 0.04 0.23 82.6 58.9 93.9 Control 2152 45 7205.16 0.62 0.43 0.87 - - - HPV-16 HPV 2126 6 7208.82 0.08 0.03 0.20 82.8 53.6 95.1 Control 2094 34 7032.43 0.48 0.31 0.71 - - - HPV-18 HPV 2160 2 7332.38 0.03 0.00 0.11 82.2 2.5 98.7 Control 2127 11 7186.67 0.15 0.07 0.30 - - - Subjects had at least 5 months of follow-up after Month 12 For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6 For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects were in the analysis of at least one single type) Subjects with an event were DNA negative for the corresponding HPV type at Month 0 and Month 6 Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (12-month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy)
(Per100) HPV-16/18 HPV 1832 2 6296.52 0.03 0.00 0.13 89.2 47.0 99.2 Control 1800 18 6138.20 0.29 0.16 0.49 - - - HPV-16 HPV 1499 1 5165.39 0.02 0.00 0.13 91.9 33.4 99.9 Control 1476 12 5047.98 0.24 0.11 0.45 - - - HPV-18 HPV 1543 1 5304.73 0.02 0.00 0.12 83.6-70.9 99.8 Control 1525 6 5228.15 0.11 0.04 0.27 - - - Subjects had at least 10 months of follow-up after Month 12 For single type: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seronegative at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event were DNA negative at Month 0 and Month 6 and seronegative at Month 0 for the corresponding HPV type Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (12-month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seropositive subjects at baseline, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) HPV-16/18 HPV 864 0 2939.26 0.00 0.00 0.15 100-229.4 100 Control 839 3 2822.52 0.11 0.02 0.35 - - - HPV-16 HPV 579 0 1965.25 0.00 0.00 0.23 100-721.1 100 Control 577 2 1938.33 0.10 0.01 0.42 - - - HPV-18 HPV 553 0 1885.08 0.00 0.00 0.24 100-8060.5 100 Control 532 1 1789.64 0.06 0.00 0.36 - - - Subjects had at least 10 months of follow-up after Month 12 For single type: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 and seropositive at Month 0 for at least one HPV type (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative at Month 0 and Month 6 and seropositive at Month 0 for the corresponding HPV type Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (12-month definition) with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline and regardless of initial serostatus, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) (Per100) HPV-16/18 HPV 2146 2 7354.93 0.03 0.00 0.11 90.7 55.4 99.3 Control 2124 21 7216.80 0.29 0.17 0.47 - - - HPV-16 HPV 2095 1 7186.70 0.01 0.00 0.09 93.0 44.7 99.9 Control 2069 14 7040.99 0.20 0.10 0.36 - - - HPV-18 HPV 2128 1 7298.52 0.01 0.00 0.09 86.0-36.0 99.9
(Per100) Control 2099 7 7161.97 0.10 0.03 0.22 - - - Subjects had at least 10 months of follow-up after Month 12 For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6 For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects were in the analysis of at least one single type) Subjects with an event are DNA negative for the corresponding HPV type at Month 0 and Month 6 Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (6-month definition) with oncogenic HPV types individually or in combination, in HPV DNA negative subjects at baseline and regardless of initial serostatus, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) (Per100) HPV-16 HPV 2126 6 7208.82 0.08 0.03 0.20 82.8 53.6 95.1 Control 2094 34 7032.43 0.48 0.31 0.71 - - - HPV-18 HPV 2160 2 7332.38 0.03 0.00 0.11 82.2 2.5 98.7 Control 2127 11 7186.67 0.15 0.07 0.30 - - - HPV-31 HPV 2126 4 7211.14 0.06 0.01 0.16 79.1 27.6 95.9 Control 2132 19 7176.37 0.26 0.15 0.44 - - - HPV-33 HPV 2158 8 7304.56 0.11 0.04 0.23-31.9-460.8 66.3 Control 2136 6 7224.30 0.08 0.03 0.20 - - - HPV-35 HPV 2165 8 7337.07 0.11 0.04 0.23 39.3-81.2 81.5 Control 2144 13 7237.54 0.18 0.09 0.33 - - - HPV-39 HPV 2150 20 7263.84 0.28 0.15 0.45-79.0-372.4 26.9 Control 2119 11 7153.00 0.15 0.07 0.30 - - - HPV-45 HPV 2160 4 7324.42 0.05 0.01 0.16 76.9 18.5 95.6 Control 2130 17 7181.53 0.24 0.13 0.40 - - - HPV-51 HPV 2125 27 7163.67 0.38 0.23 0.58-3.0-100.6 47.0 Control 2113 26 7102.77 0.37 0.22 0.57 - - - HPV-52 HPV 2113 33 7112.26 0.46 0.30 0.68 14.2-51.4 51.7 Control 2101 38 7028.30 0.54 0.36 0.78 - - - HPV-56 HPV 2154 16 7286.64 0.22 0.11 0.38 21.4-77.4 65.9 Control 2123 20 7158.60 0.28 0.16 0.46 - - - HPV-58 HPV 2152 12 7277.55 0.16 0.08 0.31-48.7-393.4 51.5 Control 2135 8 7212.87 0.11 0.04 0.24 - - - HPV-59 HPV 2158 12 7301.39 0.16 0.08 0.31-7.3-208.4 62.2 Control 2126 11 7178.74 0.15 0.07 0.30 - - - HPV-66 HPV 2141 27 7212.65 0.37 0.23 0.57 0.9-91.5 48.7 Control 2122 27 7146.86 0.38 0.23 0.58 - - - HPV-68 HPV 2138 15 7232.82 0.21 0.11 0.37 35.4-43.1 72.0 Control 2128 23 7165.71 0.32 0.19 0.51 - - - HPV-31/45 HPV 2175 8 7365.57 0.11 0.04 0.23 77.6 45.4 92.3 Control 2152 35 7219.91 0.48 0.32 0.71 - - - HPV-31/45/33/52/58 HPV 2179 58 7286.83 0.80 0.58 1.07 31.7-2.0 54.6 Control 2154 83 7124.59 1.16 0.89 1.49 - - - HPV-39/45/59/68 HPV 2179 50 7304.28 0.68 0.48 0.94 18.0-28.9 48.1 Control 2154 60 7190.88 0.83 0.61 1.11 - - -
HPV-31/33/35/52/58 HPV 2179 63 7282.72 0.87 0.64 1.15 22.9-14.4 48.4 Control 2154 80 7129.11 1.12 0.86 1.44 - - - HPV-31/45/33/52/58/35/39/51/56/59 HPV 2179 132 7153.19 1.85 1.50 2.25 11.4-17.2 33.1 Control 2154 146 7008.14 2.08 1.71 2.51 - - - HPV-HRW HPV 2179 163 7087.01 2.30 1.91 2.74 13.7-10.8 32.8 Control 2154 185 6942.35 2.66 2.24 3.15 - - - HPV-HR HPV 2179 170 7074.10 2.40 2.00 2.86 23.8 3.4 40.0 Control 2154 217 6881.10 3.15 2.69 3.68 - - - Subjects had at least 5 months of follow-up after Month 12 For single type: Subjects DNA negative for the corresponding HPV type at Month 0 and Month 6 For combined types: Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects were in the analysis of at least one single type) Subjects with an event were DNA negative for the corresponding HPV type at Month 0 and Month 6 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 Follow-up period started at day after Dose 3 LL,UL=97.7% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (12-month definition) with oncogenic HPV types individually or in combination, in HPV DNA negative subjects at baseline and regardless of initial serostatus, using conditional exact method, at the Month 48 time point (ATP cohort for efficacy) (Per100) HPV-16 HPV 2095 1 7186.70 0.01 0.00 0.09 93.0 44.7 99.9 Control 2069 14 7040.99 0.20 0.10 0.36 - - - HPV-18 HPV 2128 1 7298.52 0.01 0.00 0.09 86.0-36.0 99.9 Control 2099 7 7161.97 0.10 0.03 0.22 - - - HPV-31 HPV 2096 2 7183.81 0.03 0.00 0.11 80.1-12.3 98.6 Control 2104 10 7163.82 0.14 0.06 0.28 - - - HPV-33 HPV 2126 5 7273.49 0.07 0.02 0.18 1.1-437.7 81.8 Control 2110 5 7197.45 0.07 0.02 0.18 - - - HPV-35 HPV 2133 3 7307.85 0.04 0.01 0.13 63.0-86.0 95.3 Control 2116 8 7214.00 0.11 0.04 0.24 - - - HPV-39 HPV 2119 12 7244.94 0.17 0.08 0.31-136.3-959.8 33.4 Control 2091 5 7132.18 0.07 0.02 0.18 - - - HPV-45 HPV 2129 4 7291.12 0.05 0.01 0.16 50.9-119.8 91.6 Control 2102 8 7164.97 0.11 0.04 0.24 - - - HPV-51 HPV 2093 11 7152.97 0.15 0.07 0.30 22.1-109.8 72.1 Control 2086 14 7091.84 0.20 0.10 0.35 - - - HPV-52 HPV 2081 21 7090.06 0.30 0.17 0.48 9.5-88.3 56.8 Control 2074 23 7029.84 0.33 0.19 0.52 - - - HPV-56 HPV 2124 4 7275.80 0.05 0.01 0.16 50.9-119.7 91.6 Control 2096 8 7147.50 0.11 0.04 0.24 - - - HPV-58 HPV 2120 8 7248.16 0.11 0.04 0.24-13.3-339.4 69.7 Control 2108 7 7183.44 0.10 0.03 0.22 - - - HPV-59 HPV 2126 4 7280.44 0.05 0.01 0.16-31.1-1122.5 82.9 Control 2098 3 7160.94 0.04 0.01 0.14 - - - HPV-66 HPV 2109 10 7210.98 0.14 0.06 0.28-23.8-325.9 62.2 Control 2094 8 7143.14 0.11 0.04 0.24 - - - HPV-68 HPV 2106 7 7210.13 0.10 0.03 0.22 46.6-65.5 84.9 Control 2100 13 7145.43 0.18 0.09 0.33 - - -