Study No.: Title: Rationale: Phase: Study Period: Study Design: Centers: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 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. Study No.: /008 (HPV-008) Title: A phase III, double-blind, randomized, controlled, multi-centre 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 years of age. HPV-16/18 VLP AS04 (Cervarix TM ): GlaxoSmithKline (GSK) Biologicals human papillomavirus (HPV) vaccine containing HPV-16 and HPV-18 virus-like particle (VLP) proteins and adjuvanted with AS04. Rationale: The aim of this study was to evaluate the vaccine efficacy in the prevention of cervical intraepithelial neoplasia (CIN) 2+ lesions associated with HPV-16 or HPV-18 infection (included CIN2, CIN3, endocervical adenocarcinoma in situ (AIS) and invasive cervical cancer) in adolescents and young adult women during the 42 months following the administration of 3 doses of HPV-16/18 VLP/AS04 vaccine on a 0, 1, 6-month vaccination schedule. A control Group received an investigational formulation of GSK Biologicals hepatitis A (HAV) vaccine. Note: the event-triggered final analysis was considered as the final analysis in the study protocol. However, the month 48 analysis is descriptive and provides additional information. Therefore both analyses are presented in this summary. Phase: III Study Period: Study initiation date: 06 May 2004 Study end date final efficacy analysis: 24 October 2008 Study end date (Month 48): 26 November 2009 Study Design: Double-blind, randomized (1:1), controlled, multi-centre and multi-country study with 2 parallel groups. Centers: 135 centers in 14 countries: Australia, Belgium, Brazil, Canada, Finland, Germany, Italy, Mexico, Philippines, Spain, Taiwan, Thailand, UK and USA. Indication: Active immunization of girls and women from 10 years of age onwards for the prevention of persistent HPV infections and related clinical outcomes (cytological abnormalities and pre-cancerous lesions) caused by oncogenic HPV types 16 and 18. Treatment: The treatment groups were as follows: HPV Group: subjects received 3 doses of HPV vaccine. HAV Group: subjects received 3 doses of HAV vaccine. All vaccines were administered intramuscularly into the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule. Visits 1, 2, 3, 4, 5, 6, 7, 8, 9 & 10 corresponded to Months 0, 1, 6, 7, 12, 18, 24, 30, 36 & 48 in the schedule. Objectives: To demonstrate efficacy of the candidate vaccine compared with control in the prevention of histopathologically-confirmed CIN2+* associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by polymerase chain reaction [PCR]). This objective was assessed post Dose 3 in adolescent and young adult women who were negative for HPV DNA (by PCR) at Months 0 and 6 for the corresponding HPV type, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). The principal analysis was performed on subjects who were seronegative (by ELISA) prior to vaccination for the corresponding HPV type present in the sample. *CIN2+ was defined as CIN2, CIN3, AIS and invasive cervical cancer. Primary Outcome/Efficacy Variable: Histopathologically-confirmed CIN2+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen by (by PCR), overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA). Secondary Outcome/Efficacy Variable(s): Efficacy: Persistent infection (12-month definition) with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA). Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type (by PCR) at all available time points over approximately a 12-month interval (evaluations were planned at

2 approximately 6-month intervals). Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA). Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type (by PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Persistent infection (6-month definition) with the following oncogenic HPV types (or combination of types): HPV- 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 (by PCR). Histopathologically-confirmed CIN2+ associated with the oncogenic HPV types (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) (or combination of types) detected within the lesional component of the cervical tissue specimen (by PCR). Histopathologically-confirmed CIN1+ associated with HPV-16 or HPV-18 detected within the lesional component of the cervical tissue specimen (by PCR), overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA). CIN1+ was defined as CIN1, CIN2, CIN3, AIS and invasive cervical cancer. Histopathologically-confirmed CIN1+ associated with the oncogenic HPV types (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) detected within the lesional component of the cervical tissue specimen (by PCR). Immunogenicity: HPV-16 and HPV-18 ELISA titers and seroconversion* at Months 6, 7, 12, 24, 36 and 48 (in the immunogenicity subset), overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus. Antibody titers and seroconversion for V5/J4 monoclonal antibody inhibition testing and viral neutralization were assessed in a selected subset of subjects. * Seroconversion was defined as the appearance of antibodies (i.e. titer greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. HPV-16 and HPV-18 ELISA titers and seroconversion assessed in vaccine recipients with breakthrough HPV-16 and/or HPV-18 infections and HPV-16 and/or HPV-18 associated neoplasias, compared with selected non-cases (vaccine recipients without persistent infection or neoplasia matched for age, ethnicity and clinic site). Antibody titers and seroconversion for V5/J4 monoclonal antibody inhibition testing and/or viral neutralization were also assessed on these samples. These analyses were restricted to subjects who are seronegative for the corresponding HPV type prior to vaccination**. **According to the protocol, subjects with breakthrough infection or neoplasia and a matched set of subjects without breakthrough infection or neoplasia were to be tested for anti-hpv-16 and anti-hpv-18 antibodies by ELISA, pseudovirion based neutralizing assay (PBNA) and/or V5/J4 monoclonal antibody inhibition assay at Months 7 and 24. At the end-of-study analysis, serum samples from subjects with breakthrough CIN2+ in Total Vaccinated Cohort-1 were evaluated by anti-hpv- 16 and anti-hpv-18 ELISA, PBNA and V5/J4 assays at pre-vaccination, Month 7 and Month 24. No matched set of subjects without breakthrough CIN2+ was evaluated. GMTs and seroconversion rates for anti-hpv-16 and anti-hpv-18 antibodies by ELISA in subjects with breakthrough persistent infections (6-month and 12-month definition) were compared to those in a matched set of subjects without breakthrough persistent infections. These data were not available at the moment this CTRS was written. This CTRS will be updated when data are available. Safety: Occurrence, intensity, relationship to vaccination and resulting school or work absenteeism (as applicable) of any solicited local or solicited general symptoms within 7 days (Day 0-6) after each vaccination dose and stratified by initial (Month 0) HPV-16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA) in a subset of subjects from select study sites (safety diary card subset: N = 4000, at least 1000 per region). Occurrence, intensity, relationship to vaccination and resulting school or work absenteeism*** (as applicable) of any unsolicited symptoms within 30 days (Day 0-29) after any vaccination and stratified by initial (Month 0) HPV- 16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA) in a subset of subjects from select study sites (safety diary card subset: N = 4000, at least 1000 per region) Occurrence of serious adverse events (SAEs) throughout the entire study period (Month 0 to 48) and stratified by initial (Month 0) HPV-16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA) in all subjects Occurrence of New Onset of Chronic Diseases (NOCDs) (e.g. diabetes mellitus, autoimmune diseases) throughout the entire study (Month 0 to 48) in all subjects and stratified by initial (Month 0) HPV-16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA) Occurrence of medically significant conditions throughout the entire study period (Month 0 to 48) and stratified by initial (Month 0) HPV-16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA) in all subjects. Medically significant conditions were defined as: adverse events (AEs) prompting emergency room or physician

3 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 include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury. Outcome of all pregnancies throughout the entire study period (Month 0 to 48), overall and stratified by initial (Month 0) HPV-16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA) *** Because the collection of information regarding AEs resulting in school or work absenteeism was incomplete, an analysis could not be performed. Statistical Methods: The analyses were performed on the Total Vaccinated Cohort, the Safety Subset of the Total Vaccinated Cohort, the According-To-Protocol (ATP) cohort for efficacy, the ATP cohort for immunogenicity and the Total Vaccinated Cohort for efficacy 1 (TVC-1). - The Total Vaccinated Cohort included all vaccinated subjects for whom data were available. - 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 criteria during the study) for whom efficacy data were available and who had a normal or low-grade cytology (i.e. negative or Atypical Squamous Cells of Undetermined Significance (ASC-US) or Low-grade Squamous Intraepithelial Lesion (LSIL)) at Month 0. - The Safety Subset (safety diary card subset) of the Total Vaccinated Cohort included vaccinated subjects from a subset of selected study sites who were to complete safety diary cards (safety diary card subset: N 4000, at least 1000 per region (Asia/Pacific, Europe, Latin America, North America) to record solicited (Day 0-6) and unsolicited symptoms (Day 0-29) following each vaccine dose. - The ATP cohort for immunogenicity included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom data concerning immunogenicity outcome variables were available. - The TVC-1 included all vaccinated subjects (i.e., who received at least one dose) for whom data concerning efficacy outcome measures were available and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0. In addition, subjects had to be negative for HPV DNA (by PCR) at Month 0 for the corresponding HPV type considered in the analysis (i.e. HPV type associated with the efficacy outcome), except for the outcomes evaluated in HPV DNA positive women at Month 0. In an additional analysis, the association with HPV types was based not only on the detection of HPV DNA in the lesion, but also considered the presence of HPV types in the 2 immediately preceding cytology samples in case more than one HPV type was found in the lesion. For this analysis, the following rules were applied: If more than one HPV type was found in a lesion, the presence of HPV types in the two immediately preceding cytology samples was evaluated: - The HPV type present in both the lesion and in at least one of the two immediately preceding cytology samples was considered to be associated with that lesion. - In case none of the HPV types present in the lesion were found in any of the two immediately preceding cytology samples, then the HPV types present in the lesion were considered to be associated with that lesion (as per original analysis). If only a single HPV type was found in a lesion, then this type was considered to be associated with the lesion (as per original analysis). This analysis is referred to as the HPV type assignment algorithm (TAA) Analysis of efficacy: The primary analysis was performed on the ATP cohort for efficacy. Incidence and vaccine efficacy against CIN2+, persistent infection (6-month definition), CIN1+ and persistent infection (12-month definition), associated with HPV-16 and/or HPV-18, overall and stratified according to initial (Month 0) HPV-16 or 18 serostatus (by ELISA), were calculated with their confidence intervals (CIs). Vaccine efficacy () was calculated using conditional exact method and the follow-up time of the subjects within each group. The was defined as follows: = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/t(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed in years in each group. For each group, incidence and against persistent infection (6-month definition), CIN1+ and CIN2+ (incidence only), associated with oncogenic HPV types were calculated with their CIs.

4 Analysis of immunogenicity: The analyses were performed on the ATP cohort for immunogenicity, the Total Vaccinated Cohort and the TVC-1. For each treatment group, at each time point that a blood sample result was available, seropositivity* rates for HPV-16 and HPV-18 with exact 95% confidence intervals (CI) and geometric mean titers (GMTs) with 95% CI were tabulated according to the initial serostatus at Day 0. *For anti-hpv-16 antibody, seropositivity was defined as antibody titer 8 EL.U/mL; for anti-hpv-18 antibody, seropositivity was defined as seropositivity 7 EL.U/Ml. Anti-HPV-16 and anti-hpv-18 PBNA and antibody titers and seroconversion for V5/J4 monoclonal antibody inhibition testing and viral neutralization were assessed in a selected subset of subjects. Anti-HPV-16 and anti-hpv-18 ELISA, PBNA and V5/J4 monoclonal antibody inhibition titers at Month 0, Month 7 and Month 24 were listed in vaccine recipients with breakthrough HPV-16 and/or HPV-18 associated neoplasias. This analysis was restricted to subjects who were HPV DNA negative for the corresponding HPV type prior to vaccination. Analysis of safety: All analyses were performed by vaccinated group. Additionally, analyses of solicited local and general symptoms and unsolicited symptoms were done on seronegative and DNA negative subjects for both HPV-16 and HPV-18 at baseline, on seropositive or DNA positive subjects for either HPV-16 or HPV-18 at baseline and on DNA positive subjects for either HPV- 16 or HPV-18 at baseline. The analysis was performed on the Total Vaccinated Cohort or on the Safety Subset of the Total Vaccinated Cohort. The Total Vaccinated Cohort for the analysis of solicited symptoms included the subset of subjects from selected study sites (safety diary card subset) who completed and returned a safety diary card. For each group in the safety diary card subset, the percentage of subjects with solicited local symptoms (any, Grade 3 and resulting in absenteeism from school or work) and general symptoms (any, Grade 3, related and resulting in absenteeism from school or work) reported during the 7-day (Day 0-6) follow-up period after each vaccination was tabulated stratified by initial (Month 0) HPV-16/18 DNA status (by PCR) and according to HPV-16 or 18 serostatus (by ELISA). The Total Vaccinated Cohort for the analysis of unsolicited symptoms included the safety diary card subset for solicited (Days 0-6) and unsolicited (Days 0-29) symptoms after vaccination, and all subjects for SAEs, NOCD and medically significant conditions during the entire study period. The percentage of subjects with unsolicited AEs reported during the 30- day (Day 0-29) follow-up period after each vaccination was tabulated per group, according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. The same tabulation was performed for Grade 3 unsolicited AEs and for unsolicited AEs with a relationship to vaccination. The occurrence of SAEs throughout the study period was summarized per group and in subgroups by baseline seropositivity and/or DNA positivity status, according to the MedDRA preferred terms. The occurrence of NOCDs and medically significant conditions throughout the study period was tabulated per group and in subgroups by baseline seropositivity and/or DNA positivity status, according to the MedDRA preferred terms. Pregnancy outcomes were recorded during the entire study period per group and in subgroups by baseline seropositivity and/or DNA positivity status. Study Population: Healthy women, aged 15 to 25 years at the time of first vaccination, free of obvious health problems as established by medical history and clinical examination before entering into the study. If of childbearing potential, they had a negative urine pregnancy test, were abstinent or using adequate contraceptive precautions for 30 days prior to the first vaccination and agreeing to continue such precautions for 2 months after completion of the vaccination series. Subjects did not have more than 6 lifetime sexual partners prior to enrolment and had to have intact cervix (e.g. no history of cauterization or surgical treatment involving damage to the transformation zone of the cervix). Subjects had received no previous vaccination against HPV, hepatitis A), had no history of hepatitis A disease and had not had any colposcopy to evaluate an abnormal cervical cytology. Written informed consent (or an assent in the case of subjects below the age of consent) was obtained from each subject and also from a legally acceptable representative (LAR) in the case of subjects below the age of consent prior to the performance of any study-specific procedure. Number of subjects HPV Group HAV Group Planned, N Randomized, N (Total Vaccinated Cohort) Completed up to Month 48, n (%) 7798 (83.7) 7811 (83.8) Total Number Subjects Withdrawn, n (%) 1521 (16.3) 1514 (16.2) Withdrawn due to Adverse Events, n (%) 17 (0.2)* 20 (0.2) Withdrawn due to Lack of Efficacy, n (%) Not Applicable Not Applicable Withdrawn for other reasons, n (%) 1505 (16.1) 1494 (16.0) Demographics HPV Group HAV Group N (Total Vaccinated Cohort)

5 Females: Males 9319: : 0 Mean Age, years (SD) 20.0 (3.10) 20.0 (3.12) White/Caucasian, n (%) 5120 (54.9) 5098 (54.7) For one subject (in HPV group), the reason for dropped-out was classified as Other but the detailed description was Death. This should have been classified as SAE in the CRF. Still, it is included here in the number of subjects withdrawn due to an SAE. Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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) (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline using conditional exact method (ATP cohort for efficacy, using the HPV type assignment algorithm - Final analysis) HPV-16/18 HPV

6 HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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) (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (Type Assignment Algorithm) (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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)

7 (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy, using the HPV type assignment algorithm - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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) (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Primary Efficacy Results: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (Type Assignment Algorithm) (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group

8 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% 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 seronegative subjects at baseline using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group; 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) (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% 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 seronegative subjects at baseline, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group Subjects have 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 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% 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, regardless of initial serostatus, using

9 conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N = number of subjects included in each group with 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) n = number of subjects reporting at least one event in each group T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed in years in each group (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% 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, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group Subjects have 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 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N = number of subjects included in each group 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)

10 n = number of subjects reporting at least one event in each group T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed in years in each group (%) = Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline using conditional exact method (ATP cohort for efficacy, using the HPV type assignment algorithm - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV 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) (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (Type Assignment Algorithm) (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV

11 HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N = number of subjects included in each group 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) n = number of subjects reporting at least one event in each group T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed in years in each group (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or

12 HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy, using the HPV type assignment algorithm - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV 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) T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed in years in each group (%) = Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (Type Assignment Algorithm) (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% 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 (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group; 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)

13 (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% 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 (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group Subjects have 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 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% 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, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16/18 HPV HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group Subjects have 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) (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% 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, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16/18 HPV

14 HAV HPV-16 HPV HAV HPV-18 HPV HAV N=number of subjects included in each group Subjects have 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 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (6-month definition) with oncogenic HPV types (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16 HPV HAV HPV-18 HPV HAV HPV-31 HPV HAV HPV-33 HPV HAV HPV-35 HPV HAV HPV-39 HPV HAV HPV-45 HPV HAV HPV-51 HPV HAV HPV-52 HPV HAV HPV-56 HPV HAV HPV-58 HPV HAV HPV-59 HPV HAV HPV-66 HPV HAV HPV-68 HPV HAV HRW-HPV HPV HAV HR-HPV HPV HAV N=number of subjects included in each group Subjects have at least 5 months of follow-up after Month 12

15 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) 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against persistent infection (6-month definition) with oncogenic HPV types (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis) HPV-16 HPV HAV HPV-18 HPV HAV HPV-31 HPV HAV HPV-33 HPV HAV HPV-35 HPV HAV HPV-39 HPV HAV HPV-45 HPV HAV HPV-51 HPV HAV HPV-52 HPV HAV HPV-56 HPV HAV HPV-58 HPV HAV HPV-59 HPV HAV HPV-66 HPV HAV HPV-68 HPV HAV HRW-HPV HPV HAV HR-HPV HPV HAV N=number of subjects included in each group Subjects have 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 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 HRW-HPV = All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18

16 HR-HPV = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 (%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with oncogenic HPV types (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy - Final analysis) HPV-16 HPV HAV HPV-18 HPV HAV HPV-31 HPV HAV HPV-33 HPV HAV HPV-35 HPV HAV HPV-39 HPV HAV HPV-45 HPV HAV HPV-51 HPV HAV HPV-52 HPV HAV HPV-56 HPV HAV HPV-58 HPV HAV HPV-59 HPV HAV HPV-66 HPV HAV HPV-68 HPV HAV HRW-HPV HPV HAV HR-HPV HPV HAV 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) 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 (%)=Vaccine Efficacy (conditional exact method) LL,UL=96.1% Lower and Upper confidence limits Secondary Outcome Variable (s): Incidence rates and vaccine efficacy against CIN1+ associated with oncogenic HPV types (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method (ATP cohort for efficacy Month 48 analysis)