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.: 580299/009 (HPV-009) Title: A double blind, controlled, randomized, phase III study of the efficacy of an HPV16/18 VLP vaccine in the prevention of advanced cervical intraepithelial neoplasia (CIN2, CIN3, adenocarcinoma in situ [AIS] and invasive cervical cancer) associated with HPV16 or HPV18 cervical infection in healthy young adult women in Costa Rica. HPV16/18 VLP (HPV): GlaxoSmithKline (GSK) Biologicals Human Papilloma Virus 16 and 18 virus-like particle based candidate vaccine. Rationale: The aim of this study was to evaluate the prophylactic efficacy of HPV vaccine against the development of incident, histopathologically confirmed cervical intraepithelial neoplasia (CIN) associated with HPV16 or HPV18 cervical infections, using the licensed GSK hepatitis A vaccine as an active control. Havrix (HAV): GSK Biologicals Hepatitis A inactivated virus vaccine. Phase: III Study Period: From 28 June 2004 to 17 December 2010 Study Design: A double blind, self-contained, active-control, randomised (1:1), single-centre study, with 2 parallel groups. Centres: 1 centre in Costa Rica Indication: Primary immunisation of healthy women between 18-25 years of age against HPV16 or HPV18 cervical infection. Treatment: The treatment groups were as follows. HPV Group: Subjects received 3 doses of HPV vaccine at study Months 0, 1 and 6. Control Group: Subjects received 3 doses of HAV vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm. Objectives: To demonstrate the efficacy of the candidate vaccine compared with control in the prevention of histopathologically confirmed CIN2+* associated with an HPV16 or HPV18 cervical infection post Dose 3 (from Month 6 to Month 48), in young adult women negative for HPV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) at Months 0 and 6 for the corresponding HPV type. *CIN2+ is defined as CIN grade 2 (CIN2), CIN grade 3 (CIN3), adenocarcinoma in situ (AIS) or invasive cervical cancer Primary Outcome/Efficacy Variable: Histopathologically confirmed CIN2+ cases associated with HPV16 or HPV18 infection detected by PCR in the preceding cervical cytology specimen in previously negative subjects for HPV DNA by PCR at Months 0 and 6 for the corresponding HPV type. Note: Preceding cervical cytology was defined as the last cervical cytology specimen collected before the histopathology specimen was obtained. Secondary Outcome/Efficacy Variable(s): Efficacy Time to occurrence of incident cervical infection with HPV16 or HPV18 detected by PCR. Histopathologically confirmed CIN2+ cases associated with infection by any oncogenic HPV type (including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), detected by PCR in the preceding cervical cytology specimen in previously negative subjects for HPV DNA (by PCR) at Months 0 and 6 for the corresponding HPV type. Histopathologically confirmed CIN2+ cases associated with HPV16 or HPV18 infection detected by PCR within the lesional component of the cervical tissue specimen in previously negative subjects for HPV DNA (by PCR) at Months 0 and 6 and seronegative by ELISA at Month 0 for the corresponding HPV type. Persistent HPV16 or HPV18 cervical infection cases, defined as detection of the same HPV type (by PCR) in cervical samples from all consecutive evaluations over approximately 12 months from Month 6 to Month 48. Immunogenicity HPV16 and HPV18 ELISA and V5/J4 monoclonal antibody inhibition Enzyme Immunoassay (EIA) titres in the 600 subjects enrolled into the immunogenicity subcohort. Safety Occurrence and intensity of solicited local adverse events (AEs) and occurrence (either onset or aggravation) of solicited general AEs including urticaria within 60 minutes after each vaccination and over all vaccinations
combined. Occurrence and intensity of solicited local AEs and solicited general AEs on a 10% random subset of participants on one day from Day 3 to Day 6 after each vaccination and over all vaccinations combined. Occurrence of unsolicited AEs and SAEs throughout the entire study (Month 0 up to Month 48). Outcome of all pregnancies. HPV 66 type was not assessed because it is classified only as possibly oncogenic according to World Health Organization - International Agency for Research on Cancer (WHO-IARC) criteria. This analysis was not performed, in accordance with the Statistical Analysis Plan submitted to the FDA. Statistical Methods: The analyses were performed on the Total Vaccinated cohort (for safety), the According-To-Protocol (ATP) cohort for efficacy and the ATP cohort for immunogenicity. The Total Vaccinated cohort included all vaccinated subjects with at least 1 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 criteria during the study) for whom efficacy data were available, who received 3 doses of vaccine, who were HPV DNA (by PCR) negative for the corresponding type at enrollment and at the time when the third dose was administered (Month 6 visit) and who did not have a biopsy or treatment during the vaccination phase (i.e., prior to the Month 6 visit). The ATP cohort for immunogenicity included all evaluable subjects (i.e. meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) who received 3 doses of vaccine, who were HPV DNA (by PCR) negative for the corresponding type at enrollment and during the 48-month follow-up period, who did not have a biopsy or treatment during the vaccination phase (i.e., prior to the Month 6 visit) and for whom immunogenicity results were available. An immunogenicity subcohort was defined with a subset of 557 subjects from the 2 groups of this ATP cohort: subjects attended one extra clinic visit approximately one month (30 to 60 days) after the last dose was administered (Month 7 visit). Analysis of efficacy The analysis was carried out on the ATP cohort for efficacy. Vaccine efficacy (VE) was calculated in comparing the candidate vaccine with the control vaccine in the prevention of histopathologically confirmed CIN2+* associated with an HPV16 or HPV18 cervical infection post Dose 3 (from Month 6 to Month 48), in subjects negative for HPV DNA by PCR at Months 0 and 6 for the corresponding HPV type. VE and the 95% confidence intervals (CIs) were estimated using the conditional exact method. VE was defined as 1 minus the ratio of the attack rates in the HPV and control cohorts. The attack rate was the percentage of women in the cohort who developed the event. The incidence rates of cervical infection were compared between the 2 groups using an extension of the exact conditional test (based on a sum of binomial random variables). The time to occurrence of incident cervical infection with HPV16 or HPV18 detected by PCR was tabulated by group during the entire study period. The number of histopathologically confirmed CIN2+ cases associated with HPV16 or HPV18 infection, in previously HPV16/18 DNA negative subjects at Months 0 and 6 for the corresponding HPV type, was tabulated by group for the period post dose 3 (from Month 6 to Month 48). The same analysis was carried out for the number of histopathologically confirmed CIN2+ cases associated with any oncogenic HPV type infection in previously HPV DNA negative subjects. The number of persistent HPV16 or HPV18 cervical infection cases, i.e. defined as detection of the same HPV type (by PCR) in cervical samples from all consecutive evaluations over approximately 12 months, was tabulated from Month 6 to Month 48. Analysis of immunogenicity: The analyses were performed on the ATP cohort for immunogenicity. 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% CI as well as geometric mean titers (GMTs) with 95% CI were tabulated based on ELISA quantification results. The same tabulation was made based on V5/J4 monoclonal antibodies inhibition results. For anti-hpv-16 antibody, seropositivity (ELISA) was defined as antibody titer 8 EL.U/mL and for anti-hpv-18 antibody, as antibody titer 7 EL.U/mL. For anti-hpv-16 antibody (V5), seropositivity was defined as antibody titer 41 EL.U/mL and for anti-hpv-18 antibody (J4), as antibody titer 110 EL.U/mL. Safety The analysis of safety was based on the Total Vaccinated cohort. The incidence of solicited local and general symptoms occurring 60 minutes after each vaccination was tabulated with exact 95%CI for each treatment group. The same tabulation was performed for symptoms with intensity of Grade 3. The
occurrence and intensity of solicited local and general symptoms reported during a 4-day post-vaccination period (from Day 3 to Day 6) was also tabulated with exact 95%CI for each treatment group in a 10% random subset of participants. The percentage of subjects with at least one report of an unsolicited adverse event classified by the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term, within 30 days (Days 0-29) after vaccination, was tabulated for each treatment group. The same tabulation was performed for unsolicited AEs reported during the entire study period. SAEs were collected and summarized through the entire study period, from Month 0 up to Month 48. Occurrence of pregnancies and their outcome were reported during the entire study period. Study Population: Healthy women between and including 18-25 years of age at the time of first study vaccination, who were seronegative for HPV, with neither history of vaccination against nor infection by Hepatitis A, and who planned to reside in the Guanacaste province and surroundings for the six months following first vaccine dose. Written informed consent was obtained from the subject prior to enrolment. Number of Subjects HPV Group Control Group Planned*, N 7500 7500 Randomised, N (Total Vaccinated Cohort) 3727 3739 Completed, n (%) 3453 (92.6) 3481 (93.1) Total Number Subjects Withdrawn, n (%) 274 (7.4) 258 (6.9) Withdrawn due to Adverse Events n (%) 14 (0.4) 11 (0.3) Withdrawn due to Lack of Efficacy n (%) Not applicable Not applicable Withdrawn for other reasons n (%) 260 (7.0) 247 (6.6) Demographics HPV Group Control Group N (Total Vaccinated Cohort) 3727 3739 Females: Males 3727:0 3739:0 Mean Age, years (SD) 21.1 (2.3) 21.1 (2.3) Race, n (%) Not available Not available * Maximum approved by Institutional Review Board Primary Efficacy Results: Incidence rates and vaccine efficacy against histopathologically confirmed CIN2+ associated with HPV-16 and/or HPV-18 cervical infection using conditional exact method (ATP cohort for efficacy) Rate per 1000 VE women Event Type Group N Number n LL UL % LL UL P-value Events HPV 2635 1 0.38 0.02 1.87 89.8 39.5 99.5 0.012595 Control 2677 10 3.74 1.90 6.65... HPV16 and/or 18 Associated CIN2+ HPV16 Associated CIN2+ HPV 2464 1 0.41 0.02 2.00 88.9 32.7 99.5 0.021059 Control 2452 9 3.67 1.79 6.73... HPV18 Associated CIN2+ HPV 2567 0 0.00 0.00 1.17 100-250.7 100 0.505051 Control 2593 2 0.77 0.13 2.55... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against cervical infection associated with HPV-16 and/or HPV-18 during the entire study period using conditional exact method (ATP cohort for efficacy) Rate per 1000 women VE n LL UL % LL UL Event Type Group N Number Events HPV16 and/or 18 Cervical HPV 2635 78 29.60 23.63 36.61 79.5 74.0 84.0 Infection Control 2677 387 144.6 131.8 158.4... HPV16 Cervical Infection HPV 2464 50 20.29 15.26 26.45 80.2 73.3 85.5 Control 2452 251 102.4 90.98 115.0... HPV18 Cervical Infection HPV 2567 32 12.47 8.69 17.34 81.7 73.7 87.6
Control 2593 177 68.26 59.03 78.46... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against cervical infection associated with HPV-16 and/or HPV-18 during the first year of follow-up period using conditional exact method (ATP cohort for efficacy) Rate per 1000 women VE Event Type Group N Number n LL UL % LL UL Events HPV16 and/or 18 Cervical Infection HPV 2380 27 11.34 7.64 16.24 57.1 33.2 73.0 Control 2420 64 26.45 20.60 33.43... HPV16 Cervical Infection HPV 2242 21 9.37 5.96 14.04 43.5 3.9 67.4 Control 2232 37 16.58 11.87 22.54... HPV18 Cervical Infection HPV 2330 7 3.00 1.31 5.93 75.7 46.4 90.1 Control 2347 29 12.36 8.45 17.47... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against cervical infection associated with HPV-16 and/or HPV-18 during the second year of follow-up period using conditional exact method (ATP cohort for efficacy) Rate per 1000 VE women Event Type Group N Number n LL UL % LL UL Events HPV16 and/or 18 Cervical Infection HPV 2313 18 7.78 4.76 12.03 84.4 74.8 90.7 Control 2349 117 49.81 41.55 59.18... HPV16 Cervical Infection HPV 2170 10 4.61 2.34 8.20 87.0 75.7 93.6 Control 2176 77 35.39 28.22 43.79... HPV18 Cervical Infection HPV 2269 9 3.97 1.94 7.27 80.5 61.5 91.0 Control 2307 47 20.37 15.18 26.77... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against cervical infection associated with HPV-16 and/or HPV-18 during the third year of follow-up period using conditional exact method (ATP cohort for efficacy) Rate per 1000 women Event Type Group N Number Events VE n LL UL % LL UL
HPV16 and/or 18 Cervical Infection HPV 2232 11 4.93 2.59 8.55 87.9 78.0 93.8 Control 2166 88 40.63 32.91 49.58... HPV16 Cervical Infection HPV 2097 6 2.86 1.16 5.94 90.3 78.9 96.2 Control 2026 60 29.62 22.88 37.70... HPV18 Cervical Infection HPV 2200 6 2.73 1.11 5.66 86.4 69.7 94.7 Control 2196 44 20.04 14.77 26.56... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against cervical infection associated with HPV-16 and/or HPV-18 from the fourth year follow-up period using conditional exact method (ATP cohort for efficacy) Rate per 1000 VE women Event Type Group N Number n LL UL % LL UL Events HPV16 and/or 18 Cervical Infection HPV 2421 22 9.09 5.85 13.50 82.6 73.0 89.2 Control 2261 118 52.19 43.58 61.95... HPV16 Cervical Infection HPV 2277 13 5.71 3.18 9.50 84.1 72.1 91.5 Control 2139 77 36.00 28.71 44.54... HPV18 Cervical Infection HPV 2389 10 4.19 2.13 7.45 82.9 67.6 91.7 Control 2325 57 24.52 18.79 31.42... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against histopathologically confirmed CIN2+ associated with infection by any oncogenic HPV types, using conditional exact method (ATP cohort for efficacy) Rate per 1000 VE women Event Type Group N Number n LL UL % LL UL Events HPV16 Associated CIN2+ HPV 2464 1 0.41 0.02 2.00 88.9 32.7 99.5 Control 2452 9 3.67 1.79 6.73... HPV18 Associated CIN2+ HPV 2567 0 0.00 0.00 1.17 100-250.7 100 Control 2593 2 0.77 0.13 2.55... HPV31 Associated CIN2+ HPV 2525 1 0.40 0.02 1.95 83.2-13.8 99.3 Control 2546 6 2.36 0.96 4.89... HPV33 Associated CIN2+ HPV 2596 0 0.00 0.00 1.15 100-74.7 100 Control 2645 3 1.13 0.29 3.08... HPV35 Associated CIN2+ HPV 2593 0 0.00 0.00 1.15 100-13.1 100 Control 2631 4 1.52 0.48 3.66... HPV39 Associated CIN2+ HPV 2528 0 0.00 0.00 1.18... Control 2581 0 0.00 0.00 1.16... HPV45 Associated CIN2+ HPV 2573 1 0.39 0.02 1.92-1.9-3874.3 97.4 Control 2622 1 0.38 0.02 1.88... HPV51 Associated CIN2+ HPV 2453 1 0.41 0.02 2.01 82.7-16.8 99.3
Control 2539 6 2.36 0.96 4.91... HPV52 Associated CIN2+ HPV 2456 5 2.04 0.75 4.51 49.0-48.1 84.3 Control 2505 10 3.99 2.03 7.10... HPV56 Associated CIN2+ HPV 2524 1 0.40 0.02 1.95 79.7-46.7 99.1 Control 2564 5 1.95 0.71 4.32... HPV58 Associated CIN2+ HPV 2551 2 0.78 0.13 2.59 59.3-106.3 94.5 Control 2595 5 1.93 0.71 4.27... HPV59 Associated CIN2+ HPV 2576 3 1.16 0.30 3.17-2.4-495.8 82.4 Control 2637 3 1.14 0.29 3.09... HPV68 and/or 73* Associated HPV 2519 1 0.40 0.02 1.96 74.4-103.5 99.0 CIN2+ Control 2576 4 1.55 0.49 3.74... Non 16/18 Oncogenic HPV HPV 2643 11 4.16 2.19 7.22 59.9 20.7 80.8 Associated CIN2+ Control 2697 28 10.38 7.05 14.77... Any Oncogenic HPV Associated HPV 2643 11 4.16 2.19 7.22 66.0 34.0 83.5 CIN2+ Control 2697 33 12.24 8.58 16.94... N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95% Lower and Upper confidence limits * The assay did not distinguish between both HPV types Secondary Outcome Variable(s): Incidence rates and vaccine efficacy against persistent infection (12-month definition) associated with HPV types using conditional exact method (ATP cohort for efficacy) Rate per 1000 women Event Type Group N Number n LL UL % LL UL Events Persistent HPV16 and/or 18 Infection HPV 2635 10 3.80 1.90 6.82 90.2 81.8 95.2 Control 2677 104 38.85 31.90 46.83... Persistent HPV16 Infection HPV 2464 10 4.06 2.03 7.29 86.0 73.4 93.2 Control 2452 71 28.96 22.75 36.31... Persistent HPV18 Infection HPV 2567 0 0.00 0.00 1.20 100 91.2 100 Control 2593 37 14.27 10.15 19.51... Persistent incident HPV-16 and /or HPV-18 cervical infection had to fulfil the following criteria: first detection after the 6-month visit, 2 same type HPV positive (by PCR) test results 10+ months apart, and no intervening HPV negative tests for the corresponding type. N = number of subjects included in each group For single type: Subjects DNA negative at Month 0 and Month 6 for the corresponding HPV type For combined types: Subjects DNA negative at Month 0 and Month 6 for at least one HPV type (subjects are in the analysis of at least one single type) n=number of subjects reporting at least one event in each group Subjects with an event are DNA negative at Month 0 and Month 6 for the corresponding HPV type rate=incidence rate of subjects reporting at least one event VE(%)=Vaccine Efficacy (conditional exact method) LL,UL=95.4% Lower and Upper confidence limits (95.4% limits were used due to alpha adjustment) Secondary Outcome Variable(s): Seropositivity rates (ELISA) and GMTs for anti-hpv-16 antibody in the immunogenicity subcohort (ATP cohort for immunogenicity) 8 EL.U/mL GMT 95% CI 95% CI Group Timing N n % LL UL value LL UL Control PRE 156 46 29.5 22.7 37.0 8.2 6.7 10.0 PI(M1) 157 45 28.7 22.0 36.1 7.9 6.5 9.6 VE
PII(M6) 156 49 31.4 24.5 39.0 8.4 6.9 10.3 PIII(M7) 157 49 31.2 24.3 38.8 8.5 6.9 10.3 PIII(M12) 146 43 29.5 22.5 37.2 8.3 6.7 10.4 PIII(M18) 17 6 35.3 15.7 59.5 10.4 4.8 22.7 PIII(M24) 137 47 34.3 26.7 42.6 8.6 6.9 10.7 PIII(M30) 15 7 46.7 23.2 71.3 11.9 5.1 28.0 PIII(M36) 132 54 40.9 32.8 49.5 9.0 7.4 11.0 PIII(M42) 18 4 22.2 7.5 45.3 6.1 4.0 9.4 PIII(M48) 131 56 42.7 34.5 51.3 9.5 7.7 11.7 HPV PRE 194 46 23.7 18.1 30.1 6.7 5.7 7.8 PI(M1) 196 195 99.5 97.5 100 646.6 549.3 761.1 PII(M6) 195 195 100 98.5 100 771.5 668.3 890.7 PIII(M7) 195 195 100 98.5 100 3261 2959 3595 PIII(M12) 182 181 99.5 97.3 100 2090 1822 2398 PIII(M18) 25 25 100 88.7 100 1045 776.0 1408 PIII(M24) 175 175 100 98.3 100 1486 1293 1709 PIII(M30) 19 19 100 85.4 100 1070 747.5 1532 PIII(M36) 163 162 99.4 97.0 100 1256 1080 1461 PIII(M42) 22 22 100 87.3 100 1259 879.4 1802 PIII(M48) 172 172 100 98.3 100 1155 1009 1322 GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range 95% CI = 95% confidence interval. LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination PI(M1) = Post dose 1 at Month 1 PII(M6) = Post dose 2 at Month 6 PIII(M7) = Post dose 3 at Month 7 PIII(M12) = Post dose 3 at Month 12 PIII(M18) = Post dose 3 at Month 18 PIII(M24) = Post dose 3 at Month 24 PIII(M30) = Post dose 3 at Month 30 PIII(M36) = Post dose 3 at Month 36 PIII(M42) = Post dose 3 at Month 42 PIII(M48) = Post dose 3 at Month 48 Secondary Outcome Variable(s): Seropositivity rates (ELISA) and GMTs for anti-hpv-18 antibody in the immunogenicity subcohort (ATP cohort for immunogenicity) 7 EL.U/mL GMT 95% CI 95% CI Group Timing N n % LL UL value LL UL Control PRE 173 44 25.4 19.4 32.3 6.2 5.2 7.4 PI(M1) 170 45 26.5 20.3 33.5 6.4 5.4 7.6 PII(M6) 175 51 29.1 22.8 36.2 6.7 5.6 7.9 PIII(M7) 175 50 28.6 22.2 35.6 6.8 5.7 8.1 PIII(M12) 166 47 28.3 21.9 35.5 7.0 5.7 8.5 PIII(M18) 20 6 30.0 13.2 52.3 6.7 3.8 12.1 PIII(M24) 150 47 31.3 24.3 39.1 6.9 5.6 8.4 PIII(M30) 19 6 31.6 13.9 54.5 6.4 3.8 10.5 PIII(M36) 145 35 24.1 17.7 31.6 6.0 5.0 7.2 PIII(M42) 19 5 26.3 10.3 49.1 5.5 3.6 8.4 PIII(M48) 149 45 30.2 23.2 37.9 6.6 5.5 8.0 HPV PRE 200 50 25.0 19.4 31.4 5.4 4.8 6.1 PI(M1) 203 202 99.5 97.6 100 372.7 322.8 430.3 PII(M6) 203 203 100 98.5 100 532.2 467.5 605.9 PIII(M7) 202 202 100 98.5 100 3276 3001 3576 PIII(M12) 190 189 99.5 97.4 100 1082 942.0 1242 PIII(M18) 28 28 100 89.9 100 502.4 339.1 744.5
PIII(M24) 178 178 100 98.3 100 633.0 551.5 726.6 PIII(M30) 17 17 100 83.8 100 403.8 257.8 632.5 PIII(M36) 168 167 99.4 97.1 100 519.7 449.3 601.1 PIII(M42) 25 25 100 88.7 100 582.4 422.9 801.9 PIII(M48) 179 179 100 98.3 100 470.1 411.2 537.4 GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range 95% CI = 95% confidence interval. LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination PI(M1) = Post dose 1 at Month 1 PII(M6) = Post dose 2 at Month 6 PIII(M7) = Post dose 3 at Month 7 PIII(M12) = Post dose 3 at Month 12 PIII(M18) = Post dose 3 at Month 18 PIII(M24) = Post dose 3 at Month 24 PIII(M30) = Post dose 3 at Month 30 PIII(M36) = Post dose 3 at Month 36 PIII(M42) = Post dose 3 at Month 42 PIII(M48) = Post dose 3 at Month 48 Secondary Outcome Variable(s): Seropositivity rates (V5) and GMTs for anti-hpv-16 antibody in the immunogenicity subcohort (ATP cohort for immunogenicity) 41 EL.U/mL GMT 95% CI 95% CI Group Timing N n % LL UL value LL UL Control PRE 158 5 3.2 1.2 6.9 21.4 20.6 22.3 PI(M1) 155 6 3.9 1.6 7.9 21.5 20.7 22.3 PII(M6) 156 5 3.2 1.2 7.0 21.5 20.6 22.4 PIII(M7) 158 6 3.8 1.6 7.7 21.4 20.6 22.3 PIII(M12) 146 7 4.8 2.1 9.3 22.6 20.8 24.5 PIII(M18) 17 0 0.0 0.0 16.2 20.5.. PIII(M24) 138 5 3.6 1.3 7.8 21.4 20.6 22.3 PIII(M30) 15 0 0.0 0.0 18.1 20.5.. PIII(M36) 132 1 0.8 0.0 3.7 20.8 20.2 21.3 PIII(M42) 18 0 0.0 0.0 15.3 20.5.. PIII(M48) 133 3 2.3 0.6 6.0 21.0 20.4 21.7 HPV PRE 196 4 2.0 0.7 4.8 21.1 20.5 21.8 PI(M1) 182 104 57.1 49.9 64.2 58.5 48.3 70.8 PII(M6) 189 148 78.3 72.0 83.7 80.9 70.3 93.1 PIII(M7) 193 193 100 98.5 100 1047 926.3 1183 PIII(M12) 175 170 97.1 93.8 98.9 291.4 253.7 334.8 PIII(M18) 24 22 91.7 75.1 98.6 116.6 83.2 163.3 PIII(M24) 169 165 97.6 94.4 99.2 184.6 163.0 209.1 PIII(M30) 18 17 94.4 75.5 99.7 112.4 78.7 160.6 PIII(M36) 162 153 94.4 90.1 97.3 139.7 122.5 159.5 PIII(M42) 22 21 95.5 79.6 99.8 126.9 89.9 179.1 PIII(M48) 168 155 92.3 87.4 95.6 131.8 115.5 150.5 GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range 95% CI = 95% confidence interval. LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination PI(M1) = Post dose 1 at Month 1 PII(M6) = Post dose 2 at Month 6 PIII(M7) = Post dose 3 at Month 7 PIII(M12) = Post dose 3 at Month 12 PIII(M18) = Post dose 3 at Month 18
PIII(M24) = Post dose 3 at Month 24 PIII(M30) = Post dose 3 at Month 30 PIII(M36) = Post dose 3 at Month 36 PIII(M42) = Post dose 3 at Month 42 PIII(M48) = Post dose 3 at Month 48 Secondary Outcome Variable(s): Seropositivity rates (J4) and GMTs for anti-hpv-18 antibody in the immunogenicity subcohort (ATP cohort for immunogenicity) 110 EL.U/mL GMT 95% CI 95% CI Group Timing N n % LL UL value LL UL Control PRE 176 2 1.1 0.2 3.7 55.7 54.7 56.7 PI(M1) 173 1 0.6 0.0 2.8 55.3 54.7 55.8 PII(M6) 175 1 0.6 0.0 2.8 55.4 54.6 56.3 PIII(M7) 176 0 0.0 0.0 1.7 55.0.. PIII(M12) 166 3 1.8 0.5 4.8 56.7 54.7 58.8 PIII(M18) 20 0 0.0 0.0 13.9 55.0.. PIII(M24) 154 0 0.0 0.0 1.9 55.0.. PIII(M30) 19 0 0.0 0.0 14.6 55.0.. PIII(M36) 145 0 0.0 0.0 2.0 55.0.. PIII(M42) 19 0 0.0 0.0 14.6 55.0.. PIII(M48) 150 2 1.3 0.2 4.3 56.7 54.0 59.6 HPV PRE 203 0 0.0 0.0 1.5 55.0.. PI(M1) 194 78 40.2 33.5 47.2 99.1 88.0 111.5 PII(M6) 195 99 50.8 43.8 57.7 111.4 100.2 123.9 PIII(M7) 198 197 99.5 97.5 100 823.6 737.7 919.5 PIII(M12) 182 148 81.3 75.2 86.5 231.1 203.2 262.7 PIII(M18) 28 16 57.1 38.6 74.3 121.8 89.5 165.8 PIII(M24) 170 105 61.8 54.3 68.8 140.8 123.8 160.2 PIII(M30) 17 8 47.1 24.8 70.3 89.5 67.6 118.7 PIII(M36) 167 83 49.7 42.2 57.3 107.9 96.0 121.2 PIII(M42) 25 14 56.0 36.4 74.3 103.3 80.3 132.9 PIII(M48) 179 82 45.8 38.6 53.1 96.9 87.7 107.0 GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range 95% CI = 95% confidence interval. LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination PI(M1) = Post dose 1 at Month 1 PII(M6) = Post dose 2 at Month 6 PIII(M7) = Post dose 3 at Month 7 PIII(M12) = Post dose 3 at Month 12 PIII(M18) = Post dose 3 at Month 18 PIII(M24) = Post dose 3 at Month 24 PIII(M30) = Post dose 3 at Month 30 PIII(M36) = Post dose 3 at Month 36 PIII(M42) = Post dose 3 at Month 42 PIII(M48) = Post dose 3 at Month 48 Secondary Outcome Variable(s): Occurrence of solicited local symptoms reported within 60 minutes after vaccination following each dose and across doses (Total Vaccinated cohort) HPV Group Control Group Sympto m Intensit y 95 % CI 95 % CI N n % LL UL N n % LL UL Dose 1 Pain Any 3728 917 24.6 23.2 26.0 3739 840 22.5 21.2 23.8 Grade 3 3728 5 0.1 0.0 0.3 3739 3 0.1 0.0 0.2
Redness Any 3728 375 10.1 9.1 11.1 3739 340 9.1 8.2 10.1 > 50 mm 3728 0 0.0 0.0 0.1 3739 1 0.0 0.0 0.1 Swelling Any 3728 120 3.2 2.7 3.8 3739 107 2.9 2.4 3.4 > 50 mm 3728 0 0.0 0.0 0.1 3739 0 0.0 0.0 0.1 Dose 2 Pain Any 3348 671 20.0 18.7 21.4 3388 742 21.9 20.5 23.3 Grade 3 3348 13 0.4 0.2 0.6 3388 10 0.3 0.2 0.5 Redness Any 3348 284 8.5 7.6 9.5 3388 260 7.7 6.8 8.6 > 50 mm 3348 0 0.0 0.0 0.1 3388 0 0.0 0.0 0.1 Swelling Any 3348 67 2.0 1.6 2.5 3388 76 2.2 1.8 2.8 > 50 mm 3348 0 0.0 0.0 0.1 3388 0 0.0 0.0 0.1 Dose 3 Pain Any 3072 651 21.2 19.8 22.7 3100 612 19.7 18.4 21.2 Grade 3 3072 7 0.2 0.1 0.5 3100 8 0.3 0.1 0.5 Redness Any 3072 160 5.2 4.5 6.0 3100 130 4.2 3.5 4.9 > 50 mm 3072 0 0.0 0.0 0.1 3100 1 0.0 0.0 0.2 Swelling Any 3072 37 1.2 0.9 1.6 3100 33 1.1 0.7 1.5 > 50 mm 3072 0 0.0 0.0 0.1 3100 1 0.0 0.0 0.2 Across doses Pain Any 3730 1627 43.6 42.0 45.2 3740 1610 43.0 41.5 44.6 Grade 3 3730 25 0.7 0.4 1.0 3740 20 0.5 0.3 0.8 Redness Any 3730 544 14.6 13.5 15.8 3740 501 13.4 12.3 14.5 > 50 mm 3730 0 0.0 0.0 0.1 3740 2 0.1 0.0 0.2 Swelling Any 3730 207 5.5 4.9 6.3 3740 201 5.4 4.7 6.1 > 50 mm 3730 0 0.0 0.0 0.1 3740 1 0.0 0.0 0.1 N = number of subjects with at least one administered vaccine dose documented n/% = number/percentage of subjects reporting at least once the symptom 95%CI = exact 95% confidence interval; LL = lower Limit, UL = Upper Limit Any = incidence of a particular symptom regardless of intensity grade Grade 3 pain = pain that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy. Secondary Outcome Variable(s): Occurrence of solicited general symptoms reported within 60 minutes after vaccination following each dose and across doses (Total Vaccinated cohort) HPV Group Control Group 95 % CI 95 % CI Symptom Intensity/ N n % LL UL N n % LL UL Relationshi p Dose 1 Fatigue Any 3728 257 6.9 6.1 7.8 3739 237 6.3 5.6 7.2 Grade 3 3728 2 0.1 0.0 0.2 3739 1 0.0 0.0 0.1 Myalgia Any 3728 140 3.8 3.2 4.4 3739 114 3.0 2.5 3.6 Grade 3 3728 0 0.0 0.0 0.1 3739 0 0.0 0.0 0.1 Arthralgia Any 3728 20 0.5 0.3 0.8 3739 25 0.7 0.4 1.0 Grade 3 3728 0 0.0 0.0 0.1 3739 0 0.0 0.0 0.1 Gastrointestina l Any 3728 96 2.6 2.1 3.1 3739 83 2.2 1.8 2.7 Grade 3 3728 0 0.0 0.0 0.1 3739 0 0.0 0.0 0.1 Headache Any 3728 374 10.0 9.1 11.0 3739 384 10.3 9.3 11.3 Grade 3 3728 1 0.0 0.0 0.1 3739 0 0.0 0.0 0.1 Rash Any 3728 6 0.2 0.1 0.3 3739 8 0.2 0.1 0.4 Grade 3 3728 0 0.0 0.0 0.1 3739 0 0.0 0.0 0.1 Urticaria Any 3728 7 0.2 0.1 0.4 3739 12 0.3 0.2 0.5 Grade 3 3728 0 0.0 0.0 0.1 3739 0 0.0 0.0 0.1
Fever/(oral) 37.5 C 3727 256 6.9 6.1 7.7 3737 255 6.8 6.1 7.7 > 39.0 C 3727 0 0.0 0.0 0.1 3737 0 0.0 0.0 0.1 Dose 2 Fatigue Any 3348 188 5.6 4.9 6.4 3388 192 5.7 4.9 6.5 Grade 3 3348 1 0.0 0.0 0.1 3388 4 0.1 0.0 0.3 Myalgia Any 3348 66 2.0 1.5 2.5 3388 85 2.5 2.0 3.1 Grade 3 3348 0 0.0 0.0 0.1 3388 1 0.0 0.0 0.1 Arthralgia Any 3348 16 0.5 0.3 0.8 3388 22 0.6 0.4 1.0 Grade 3 3348 0 0.0 0.0 0.1 3388 1 0.0 0.0 0.1 Gastrointestina l Any 3348 68 2.0 1.6 2.6 3388 44 1.3 1.0 1.7 Grade 3 3348 0 0.0 0.0 0.1 3388 0 0.0 0.0 0.1 Headache Any 3348 288 8.6 7.7 9.6 3388 264 7.8 6.9 8.7 Grade 3 3348 1 0.0 0.0 0.1 3388 0 0.0 0.0 0.1 Rash Any 3348 3 0.1 0.0 0.2 3388 7 0.2 0.1 0.4 Grade 3 3348 0 0.0 0.0 0.1 3388 0 0.0 0.0 0.1 Urticaria Any 3348 5 0.1 0.1 0.3 3388 4 0.1 0.0 0.3 Grade 3 3348 0 0.0 0.0 0.1 3388 0 0.0 0.0 0.1 Fever/(oral) 37.5 C 3348 155 4.6 4.0 5.4 3386 158 4.7 4.0 5.4 > 39.0 C 3348 0 0.0 0.0 0.1 3386 0 0.0 0.0 0.1 Dose 3 Fatigue Any 3072 174 5.7 4.9 6.5 3100 170 5.5 4.7 6.3 Grade 3 3072 3 0.1 0.0 0.3 3100 0 0.0 0.0 0.1 Myalgia Any 3072 75 2.4 1.9 3.0 3100 56 1.8 1.4 2.3 Grade 3 3072 0 0.0 0.0 0.1 3100 0 0.0 0.0 0.1 Arthralgia Any 3072 25 0.8 0.5 1.2 3100 19 0.6 0.4 0.9 Grade 3 3072 0 0.0 0.0 0.1 3100 0 0.0 0.0 0.1 Gastrointestina l Any 3072 47 1.5 1.1 2.0 3100 54 1.7 1.3 2.2 Grade 3 3072 0 0.0 0.0 0.1 3100 0 0.0 0.0 0.1 Headache Any 3072 246 8.0 7.1 9.0 3100 243 7.8 6.9 8.8 Grade 3 3072 0 0.0 0.0 0.1 3100 0 0.0 0.0 0.1 Rash Any 3072 6 0.2 0.1 0.4 3100 2 0.1 0.0 0.2 Grade 3 3072 0 0.0 0.0 0.1 3100 0 0.0 0.0 0.1 Urticaria Any 3072 7 0.2 0.1 0.5 3100 6 0.2 0.1 0.4 Grade 3 3072 0 0.0 0.0 0.1 3100 0 0.0 0.0 0.1 Fever/(oral) 37.5 C 3072 121 3.9 3.3 4.7 3099 138 4.5 3.8 5.2 > 39.0 C 3072 0 0.0 0.0 0.1 3099 0 0.0 0.0 0.1 Across doses Fatigue Any 3730 512 13.7 12.7 14.9 3740 502 13.4 12.4 14.6 Grade 3 3730 6 0.2 0.1 0.3 3740 5 0.1 0.0 0.3 Myalgia Any 3730 257 6.9 6.1 7.7 3740 232 6.2 5.5 7.0 Grade 3 3730 0 0.0 0.0 0.1 3740 1 0.0 0.0 0.1 Arthralgia Any 3730 58 1.6 1.2 2.0 3740 64 1.7 1.3 2.2 Grade 3 3730 0 0.0 0.0 0.1 3740 1 0.0 0.0 0.1 Gastrointestina l Any 3730 191 5.1 4.5 5.9 3740 171 4.6 3.9 5.3 Grade 3 3730 0 0.0 0.0 0.1 3740 0 0.0 0.0 0.1 Headache Any 3730 714 19.1 17.9 20.4 3740 718 19.2 18.0 20.5 Grade 3 3730 2 0.1 0.0 0.2 3740 0 0.0 0.0 0.1 Rash Any 3730 15 0.4 0.2 0.6 3740 17 0.5 0.3 0.7
Grade 3 3730 0 0.0 0.0 0.1 3740 0 0.0 0.0 0.1 Urticaria Any 3730 19 0.5 0.3 0.8 3740 21 0.6 0.4 0.8 Grade 3 3730 0 0.0 0.0 0.1 3740 0 0.0 0.0 0.1 Fever/(oral) 37.5 C 3730 472 12.7 11.6 13.8 3740 477 12.8 11.7 13.9 > 39.0 C 3730 0 0.0 0.0 0.1 3740 0 0.0 0.0 0.1 N = number of subjects with at least one administered vaccine dose documented n/% = number/percentage of subjects reporting at least once the symptom 95%CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Any = incidence of a particular symptom regardless of intensity grade or relationship to vaccination Grade 3 fatigue, myalgia, arthralgia, gastrointestinal, headache, rash = symptoms that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy. Grade 3 urticaria = occurred on at least 4 body areas. Secondary Outcome Variable(s): Occurrence of solicited local symptoms reported from Day 3 to Day 6 post-vaccination following each dose and across doses, in the subset (Total Vaccinated cohort) HPV Group Control Group 95 % CI 95 % CI Sympto m Intensit y N n % LL UL N n % LL UL Dose 1 Pain Any 375 123 32.8 28.2 37.7 366 39 10.7 7.8 14.1 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Redness Any 375 4 1.1 0.3 2.6 366 1 0.3 0.0 1.3 > 50 mm 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Swelling Any 375 10 2.7 1.4 4.7 366 1 0.3 0.0 1.3 > 50 mm 375 3 0.8 0.2 2.2 366 0 0.0 0.0 0.8 Dose 2 Pain Any 330 95 28.8 24.1 33.9 321 31 9.7 6.8 13.3 Grade 3 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Redness Any 330 1 0.3 0.0 1.5 321 0 0.0 0.0 0.9 > 50 mm 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Swelling Any 330 10 3.0 1.5 5.3 321 0 0.0 0.0 0.9 > 50 mm 330 4 1.2 0.4 2.9 321 0 0.0 0.0 0.9 Dose 3 Pain Any 301 72 23.9 19.4 29.0 300 17 5.7 3.4 8.7 Grade 3 301 0 0.0 0.0 1.0 300 0 0.0 0.0 1.0 Redness Any 301 1 0.3 0.0 1.6 300 0 0.0 0.0 1.0 > 50 mm 301 1 0.3 0.0 1.6 300 0 0.0 0.0 1.0 Swelling Any 301 5 1.7 0.6 3.6 300 0 0.0 0.0 1.0 > 50 mm 301 1 0.3 0.0 1.6 300 0 0.0 0.0 1.0 Across doses Pain Any 380 202 53.2 48.1 58.1 376 74 19.7 15.9 23.9 Grade 3 380 0 0.0 0.0 0.8 376 0 0.0 0.0 0.8 Redness Any 380 6 1.6 0.6 3.3 376 1 0.3 0.0 1.3 > 50 mm 380 1 0.3 0.0 1.3 376 0 0.0 0.0 0.8 Swelling Any 380 23 6.1 4.0 8.8 376 1 0.3 0.0 1.3 > 50 mm 380 7 1.8 0.8 3.6 376 0 0.0 0.0 0.8
N = number of subjects with at least one administered vaccine dose documented n/% = number/percentage of subjects reporting at least once the symptom 95%CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Any = incidence of a particular symptom regardless of intensity grade Grade 3 pain = pain that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy. Secondary Outcome Variable(s): Occurrence of solicited general symptoms reported from Day 3 to Day 6 postvaccination following each dose and across doses, in the subset (Total Vaccinated cohort) HPV Group Control Group 95 % CI 95 % CI Symptom Intensity/ N n % LL UL N n % LL UL Relationshi p Dose 1 Fatigue Any 375 139 37.1 32.3 42.0 366 128 35.0 30.2 40.0 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Myalgia Any 375 168 44.8 39.8 49.9 366 125 34.2 29.4 39.1 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Arthralgia Any 375 18 4.8 3.0 7.3 366 17 4.6 2.8 7.2 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Gastrointestina l Any 375 89 23.7 19.6 28.2 366 72 19.7 15.8 24.0 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Headache Any 375 159 42.4 37.5 47.5 366 156 42.6 37.6 47.7 Grade 3 375 1 0.3 0.0 1.3 366 0 0.0 0.0 0.8 Rash Any 375 14 3.7 2.1 6.0 366 11 3.0 1.6 5.2 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Urticaria Any 375 1 0.3 0.0 1.3 366 1 0.3 0.0 1.3 Grade 3 375 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Fever/(oral) 37.5 C 374 22 5.9 3.8 8.6 366 22 6.0 3.9 8.8 > 39.0 C 374 0 0.0 0.0 0.8 366 0 0.0 0.0 0.8 Dose 2 Fatigue Any 330 102 30.9 26.1 36.1 321 83 25.9 21.3 30.9 Grade 3 330 1 0.3 0.0 1.5 321 0 0.0 0.0 0.9 Myalgia Any 330 119 36.1 31.0 41.4 321 91 28.3 23.6 33.5 Grade 3 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Arthralgia Any 330 19 5.8 3.6 8.7 321 6 1.9 0.8 3.8 Grade 3 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Gastrointestina l Any 330 67 20.3 16.2 24.9 321 46 14.3 10.8 18.5 Grade 3 330 0 0.0 0.0 0.9 321 1 0.3 0.0 1.5 Headache Any 330 139 42.1 36.9 47.5 321 127 39.6 34.3 45.0 Grade 3 330 0 0.0 0.0 0.9 321 2 0.6 0.1 2.0 Rash Any 330 10 3.0 1.5 5.3 321 11 3.4 1.8 5.9 Grade 3 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Urticaria Any 330 1 0.3 0.0 1.5 321 0 0.0 0.0 0.9 Grade 3 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Fever/(oral) 37.5 C 330 12 3.6 2.0 6.1 321 12 3.7 2.0 6.3 > 39.0 C 330 0 0.0 0.0 0.9 321 0 0.0 0.0 0.9 Dose 3 Fatigue Any 301 95 31.6 26.5 37.0 300 74 24.7 20.0 29.8 Grade 3 301 1 0.3 0.0 1.6 300 0 0.0 0.0 1.0
Myalgia Any 301 109 36.2 30.9 41.8 300 91 30.3 25.3 35.7 Grade 3 301 1 0.3 0.0 1.6 300 0 0.0 0.0 1.0 Arthralgia Any 301 14 4.7 2.7 7.5 300 12 4.0 2.2 6.7 Grade 3 301 0 0.0 0.0 1.0 300 0 0.0 0.0 1.0 Gastrointestina l Any 301 61 20.3 16.0 25.1 300 38 12.7 9.3 16.8 Grade 3 301 0 0.0 0.0 1.0 300 0 0.0 0.0 1.0 Headache Any 301 126 41.9 36.4 47.5 300 102 34.0 28.8 39.5 Grade 3 301 0 0.0 0.0 1.0 300 0 0.0 0.0 1.0 Rash Any 301 11 3.7 1.9 6.3 300 6 2.0 0.8 4.1 Grade 3 301 0 0.0 0.0 1.0 300 0 0.0 0.0 1.0 Urticaria Any 301 1 0.3 0.0 1.6 300 0 0.0 0.0 1.0 Grade 3 301 0 0.0 0.0 1.0 300 0 0.0 0.0 1.0 Fever/(oral) 37.5 C 301 10 3.3 1.7 5.8 299 9 3.0 1.5 5.5 > 39.0 C 301 0 0.0 0.0 1.0 299 0 0.0 0.0 1.0 Across doses Fatigue Any 380 214 56.3 51.3 61.2 376 189 50.3 45.2 55.3 Grade 3 380 2 0.5 0.1 1.7 376 0 0.0 0.0 0.8 Myalgia Any 380 250 65.8 60.9 70.4 376 211 56.1 51.1 61.1 Grade 3 380 1 0.3 0.0 1.3 376 0 0.0 0.0 0.8 Arthralgia Any 380 44 11.6 8.6 15.1 376 32 8.5 6.0 11.7 Grade 3 380 0 0.0 0.0 0.8 376 0 0.0 0.0 0.8 Gastrointestina l Any 380 157 41.3 36.4 46.3 376 119 31.6 27.1 36.5 Grade 3 380 0 0.0 0.0 0.8 376 1 0.3 0.0 1.3 Headache Any 380 247 65.0 60.1 69.7 376 242 64.4 59.4 69.1 Grade 3 380 1 0.3 0.0 1.3 376 2 0.5 0.1 1.7 Rash Any 380 31 8.2 5.7 11.2 376 26 6.9 4.7 9.8 Grade 3 380 0 0.0 0.0 0.8 376 0 0.0 0.0 0.8 Urticaria Any 380 3 0.8 0.2 2.1 376 1 0.3 0.0 1.3 Grade 3 380 0 0.0 0.0 0.8 376 0 0.0 0.0 0.8 Fever/(oral) 37.5 C 380 43 11.3 8.4 14.8 376 37 9.8 7.1 13.2 > 39.0 C 380 0 0.0 0.0 0.8 376 0 0.0 0.0 0.8 N = number of subjects with at least one administered vaccine dose documented n/% = number/percentage of subjects reporting at least once the symptom 95%CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit Any = incidence of a particular symptom regardless of intensity grade or relationship to vaccination Grade 3 fatigue, myalgia, arthralgia, gastrointestinal, headache, rash = symptoms that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy. Grade 3 urticaria = occurred on at least 4 body areas. Secondary Outcome Variable(s): Occurrence of pregnancies and their outcome reported during the entire study period (Total Vaccinated cohort) HPV Group N= 2123 Control Group N= 2129 Outcome n % n % Pregnancy loss 317 14.9 294 13.8 Pregnancy resolved alive 1756 82.7 1766 82.9 Unresolved pregnancy 50 2.4 69 3.2 N = number of pregnancies n (%) = number (percentage) of cases in a given category. Safety Results: Number (%) of subjects with unsolicited adverse events reported within 30 days after vaccination (Total Vaccinated cohort). Most frequent adverse events -On-Therapy HPV Group Control Group
(occurring within Days 0-29 following vaccination) N =3727 N =3739 Subjects with any AE(s), n (%) 1638 (43.9) 1536 (41.1) Influenza 263 (7.1) 293 (7.8) Myalgia 355 (9.5) 166 (4.4) Headache 218 (5.8) 214 (5.7) Pain in extremity 174 (4.7) 80 (2.1) Menstruation irregular 123 (3.3) 112 (3.0) Dizziness 99 (2.7) 84 (2.2) Pyrexia 110 (3.0) 60 (1.6) Malaise 92 (2.5) 76 (2.0) Pruritus 71 (1.9) 76 (2.0) Vomiting 69 (1.9) 67 (1.8) Counting rule applied: As there were more than 30 subjects per treatment group and 3 groups, only the 10 most frequent events in each treatment group are to be listed. Safety Results: Number (%) of subjects with unsolicited adverse events reported during the entire study period (Total Vaccinated cohort). Most frequent adverse events (occurring during entire study period) HPV Group N =3727 Control Group N =3739 Subjects with any AE(s), n (%) 3228 (86.6) 3254 (87.0) Menstruation irregular 1021 (27.4) 1011 (27.0) Influenza 903 (24.2) 950 (25.4) Vaginal infection 709 (19.0) 763 (20.4) Vulvovaginal candidiasis 714 (19.2) 678 (18.1) Urinary tract infection 555 (14.9) 565 (15.1) Upper respiratory tract infection 324 ( 8.7) 327 ( 8.7) Headache 324 ( 8.7) 315 ( 8.4) Myalgia 386 (10.4) 189 ( 5.1) Gastrointestinal inflammation 263 ( 7.1) 249 ( 6.7) Dengue fever 174 ( 4.7) 190 ( 5.1) Counting rule applied: As there were more than 30 subjects per treatment group and 3 groups, only the 10 most frequent events in each treatment group are to be listed. Safety Results: Number (%) of subjects with Serious Adverse Events (SAEs) during the entire study period (from Month 0 up to Month 48) (Total Vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] SAEs HPV Group N =3727 Control Group N =3739 Subjects with any SAE(s), n (%) [n assessed by the investigator as related*] 912 (24.5) [53 ] 891 (23.8) [39 ] Abortion spontaneous incomplete 134 ( 3.6) [17] 108 ( 2.9) [7] False labour 66 ( 1.8) [4] 88 ( 2.4) [2] Abortion spontaneous complete 64 ( 1.7) [10] 64 ( 1.7) [13] Abortion missed 59 ( 1.6) [7] 63 ( 1.7) [4] Foetal distress syndrome 57 ( 1.5) [1] 64 ( 1.7) [0] Caesarean section 56 ( 1.5) [0] 59 ( 1.6) [0] Uterine hypotonus 54 ( 1.4) [0] 54 ( 1.4) [0] Gestational hypertension 39 ( 1.0) [0] 53 ( 1.4) [0] Dengue fever 38 ( 1.0) [0] 48 ( 1.3) [0] Abortion threatened 42 ( 1.1) [5] 37 ( 1.0) [0] Cephalo-pelvic disproportion 33 ( 0.9) [0] 45 ( 1.2) [0] Breech presentation 40 ( 1.1) [0] 33 ( 0.9) [0] Urinary tract infection 25 ( 0.7) [0] 24 ( 0.6) [0] Anaemia of pregnancy 24 ( 0.6) [0] 22 ( 0.6) [0] Cholecystitis 26 ( 0.7) [0] 19 ( 0.5) [0] Pre-eclampsia 18 ( 0.5) [0] 23 ( 0.6) [1] Failed induction of labour 19 ( 0.5) [0] 20 ( 0.5) [0] Complication of pregnancy 18 ( 0.5) [0] 19 ( 0.5) [0] Intentional self-injury 20 ( 0.5) [0] 17 ( 0.5) [0]
Appendicitis 17 ( 0.5) [0] 18 ( 0.5) [1] Intra-uterine death 16 ( 0.4) [2] 18 ( 0.5) [1] Foetal growth restriction 18 ( 0.5) [0] 14 ( 0.4) [0] Cholelithiasis 22 ( 0.6) [0] 9 ( 0.2) [0] Premature rupture of membranes 11 ( 0.3) [0] 19 ( 0.5) [1] Obstructed labour 13 ( 0.3) [0] 15 ( 0.4) [0] Abnormal product of conception 14 ( 0.4) [0] 11 ( 0.3) [0] Postoperative wound infection 12 ( 0.3) [0] 12 ( 0.3) [0] Ectopic pregnancy 9 ( 0.2) [0] 14 ( 0.4) [0] Postpartum haemorrhage 13 ( 0.3) [0] 7 ( 0.2) [0] Postpartum sepsis 12 ( 0.3) [0] 8 ( 0.2) [0] Oligohydramnios 11 ( 0.3) [0] 8 ( 0.2) [0] Benign ovarian tumour 11 ( 0.3) [0] 7 ( 0.2) [0] Gastrointestinal disorder 9 ( 0.2) [0] 9 ( 0.2) [0] Premature separation of placenta 5 ( 0.1) [0] 10 ( 0.3) [1] Hyperemesis gravidarum 6 ( 0.2) [0] 8 ( 0.2) [1] Multiple injuries 3 ( 0.1) [0] 10 ( 0.3) [0] Gestational diabetes 5 ( 0.1) [0] 6 ( 0.2) [0] Hypertension 5 ( 0.1) [0] 6 ( 0.2) [0] Ovarian cyst 5 ( 0.1) [0] 6 ( 0.2) [0] Pancreatitis acute 6 ( 0.2) [0] 5 ( 0.1) [0] Multiple pregnancy 8 ( 0.2) [0] 2 ( 0.1) [0] Placenta praevia haemorrhage 6 ( 0.2) [0] 4 ( 0.1) [0] Subcutaneous abscess 5 ( 0.1) [0] 5 ( 0.1) [0] Uterine haemorrhage 5 ( 0.1) [0] 5 ( 0.1) [0] Abdominal pain 6 ( 0.2) [0] 3 ( 0.1) [0] Foetal disorder 7 ( 0.2) [0] 2 ( 0.1) [0] Depression 5 ( 0.1) [0] 3 ( 0.1) [0] Infectious peritonitis 6 ( 0.2) [0] 2 ( 0.1) [0] Large for dates baby 4 ( 0.1) [0] 4 ( 0.1) [0] Mental disorder 5 ( 0.1) [0] 3 ( 0.1) [0] Injury 2 ( 0.1) [0] 5 ( 0.1) [0] Menometrorrhagia 5 ( 0.1) [1] 2 ( 0.1) [0] Postoperative wound complication 4 ( 0.1) [0] 3 ( 0.1) [0] Premature delivery 5 ( 0.1) [0] 2 ( 0.1) [0] Respiratory disorder 5 ( 0.1) [0] 2 ( 0.1) [0] Vaginal haemorrhage 3 ( 0.1) [0] 4 ( 0.1) [0] Pelvic inflammatory disease 3 ( 0.1) [0] 3 ( 0.1) [0] Premature labour 2 ( 0.1) [0 ] 4 ( 0.1) [2] Pyrexia 5 ( 0.1) [0] 1 ( 0.0) [0] Transverse presentation 3 ( 0.1) [0] 3 ( 0.1) [0] Abortion incomplete 4 ( 0.1) [1] 1 ( 0.0) [1] Cardiovascular disorder 5 ( 0.1) [0] 0 (0.0) [0] Cellulitis 1 ( 0.0) [0] 4 ( 0.1) [0] Concussion 2 ( 0.1) [0] 3 ( 0.1) [0] Essential hypertension 4 ( 0.1) [0] 1 ( 0.0) [0] Irritable bowel syndrome 1 ( 0.0) [0] 4 ( 0.1) [0] Salpingitis 3 ( 0.1) [0] 2 ( 0.1) [0] Staphylococcal infection 3 ( 0.1) [0] 2 ( 0.1) [0] Umbilical cord abnormality 3 ( 0.1) [0] 2 ( 0.1) [0] Breast inflammation 2 ( 0.1) [0] 2 ( 0.1) [0] Bronchopneumonia 1 ( 0.0) [0] 3 ( 0.1) [0] Eclampsia 1 ( 0.0) [0] 3 ( 0.1) [0] Endometriosis 2 ( 0.1) [0] 2 ( 0.1) [0] Lower limb fracture 2 ( 0.1) [0] 2 ( 0.1) [0] Open wound 3 ( 0.1) [0] 1 ( 0.0) [0]
Pelvic pain 1 ( 0.0) [0] 3 ( 0.1) [0] Perineal pain 1 ( 0.0) [0] 3 ( 0.1) [0] Retained placenta or membranes 4 ( 0.1) [0] 0 (0.0) [0] Thyroid cancer 1 ( 0.0) [0] 3 ( 0.1) [0] Type 2 diabetes mellitus 3 ( 0.1) [0] 1 ( 0.0) [0] Viral infection 1 ( 0.0) [0] 3 ( 0.1) [0] Abortion complicated 3 ( 0.1) [2] 0 (0.0) [0] Amniotic cavity infection 1 ( 0.0) [0] 2 ( 0.1) [0] Bartholin s abscess 2 ( 0.1) [0] 1 ( 0.0) [0] Bronchitis 2 ( 0.1) [0] 1 ( 0.0) [0] Calculus urinary 1 ( 0.0) [0] 2 ( 0.1) [0] Circulatory collapse 2 ( 0.1) [0] 1 ( 0.0) [0] Colitis ulcerative 2 ( 0.1) [1] 1 ( 0.0) [0] Foetal malpresentation 0 (0.0) [0] 3 ( 0.1) [0] Genital disorder female 1 ( 0.0) [0] 2 ( 0.1) [0] Humerus fracture 3 ( 0.1) [0] 0 (0.0) [0] Hyperthyroidism 2 ( 0.1) [1] 1 ( 0.0) [0] Liver disorder 0 (0.0) [0] 3 ( 0.1) [0] Lymphadenitis 2 ( 0.1) [0] 1 ( 0.0) [0] Menstruation irregular 1 ( 0.0) [0] 2 ( 0.1) [0] Migraine 2 ( 0.1) [0] 1 ( 0.0) [0] Ovarian cancer 2 ( 0.1) [0] 1 ( 0.0) [0] Physical assault 3 ( 0.1) [0] 0 (0.0) [0] Placenta praevia 2 ( 0.1) [0] 1 ( 0.0) [0] Sexually transmitted disease 1 ( 0.0) [0] 2 ( 0.1) [0] Toxicity to various agents 2 ( 0.1) [0] 1 ( 0.0) [0] Tubulointerstitial nephritis 2 ( 0.1) [0] 1 ( 0.0) [0] Uterine leiomyoma 2 ( 0.1) [0] 1 ( 0.0) [0] Anaphylactic shock 0 (0.0) [0] 2 ( 0.1) [2] Appendix disorder 2 ( 0.1) [0] 0 (0.0) [0] Asthma 2 ( 0.1) [0] 0 (0.0) [0] Bartholin s cyst 1 ( 0.0) [0] 1 ( 0.0) [0] Benign hydatidiform mole 1 ( 0.0) [0] 1 ( 0.0) [0] Blood disorder 1 ( 0.0) [0] 1 ( 0.0) [0] Cervix disorder 2 ( 0.1) [0] 0 (0.0) [0] Constipation 1 ( 0.0) [0] 1 ( 0.0) [0] Convulsion 1 ( 0.0) [0] 1 ( 0.0) [0] Gastrointestinal inflammation 1 ( 0.0) [0] 1 ( 0.0) [0] HIV infection 1 ( 0.0) [0] 1 ( 0.0) [0] Lumbar vertebral fracture 1 ( 0.0) [0] 1 ( 0.0) [0] Multiple fractures 2 ( 0.1) [0] 0 (0.0) [0] Nephrolithiasis 2 ( 0.1) [0] 0 (0.0) [0] Nervous system disorder 0 (0.0) [0] 2 ( 0.1) [0] Otitis externa 2 ( 0.1) [0] 0 (0.0) [0] Parametritis 1 ( 0.0) [0] 1 ( 0.0) [0] Phlebitis 0 (0.0) [0] 2 ( 0.1) [0] Pneumonia 2 ( 0.1) [0] 0 (0.0) [0] Polyhydramnios 1 ( 0.0) [0] 1 ( 0.0) [0] Post procedural complication 0 (0.0) [0] 2 ( 0.1) [0] Post-traumatic stress disorder 1 ( 0.0) [0] 1 ( 0.0) [0] Proteinuria 2 ( 0.1) [0] 0 (0.0) [0] Rheumatoid arthritis 1 ( 0.0) [1] 1 ( 0.0) [0] Road traffic accident 1 ( 0.0) [0] 1 ( 0.0) [0] Status asthmaticus 2 ( 0.1) [0] 0 (0.0) [0] Systemic lupus erythematosus 2 ( 0.1) [0] 0 (0.0) [0] Tension headache 1 ( 0.0) [0] 1 ( 0.0) [0]