109616 hpv-023 ext 001 y7 , 109624 hpv-023 ext 001 … · hpv-023 (ext 001 y7, y8 and y9 evaluates...

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Study No.: 109616 (HPV-023 EXT 001 Y7), 109624 (HPV-023 EXT 001 Y8) Title: Follow-up study to evaluate the long-term efficacy of a HPV vaccine (580299) in healthy young adult women in Brazil. HPV vaccine (580299) (HPV): GlaxoSmithKline (GSK) Biologicals’ vaccine against human papillomaviruses 16 and 18. Rationale: The aim of this multi-center study conducted in Brazil was to evaluate the long-term efficacy of HPV vaccine, administered in primary study HPV-001 (580299/001), in healthy young adult women. After the primary vaccination phase HPV-001 (580299/001), a long-term follow-up [North America and Brazil] was performed in HPV-007 (580299/007). HPV-023 (EXT 001 Y7, Y8 and Y9 evaluates the vaccine efficacy, the persistence of vaccine-induced immune responses and the safety of the HPV vaccine for an additional 36 months in a sub-cohort [subjects enrolled in Brazil], which will result in a mean follow-up period of approximately nine years following first vaccination in study HPV-001. This CTRS presents the results of Year-7 and Year 8 Interim analysis (IA). Results on Year 9 [final analysis] (109625) will be disclosed when they become available. Phase: IIb Study Period: 109616: 29 November 2007 to 11 July 2008 (Year 7) 109624: 15 September 2008 to 11 July 2009 (Year 8) Study Design: Double-blind, randomized, placebo-controlled, multi-center study with 2 parallel groups. Centers: 5 centers in Brazil 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 in the primary study. Treatment: The study groups were as follows: • HPV Group: received HPV vaccine at 0, 1 and 6 months during the primary study 580299/001. • Placebo Group: received a placebo at 0, 1 and 6 months during the primary study 580299/001. No vaccines were administered during this long-term follow-up study. Objectives: To evaluate the long-term vaccine efficacy in the prevention of incident cervical infections with HPV-16 and/or HPV-18 (by polymerase chain reaction [PCR]) in women who were previously uninfected with HPV-16 or HPV-18. Primary Outcome/Efficacy Variable: • Incident cervical infection with HPV-16 and/or HPV-18. Incident cervical HPV infection was defined as the first detection of an HPV type in a subject previously negative for that HPV type. Secondary Outcome/Efficacy Variables: • Incident cervical infection with any/each oncogenic HPV type*. • Persistent cervical infection (6-month definition) with HPV-16 and/or HPV-18. Persistent cervical HPV infection (6-month definition) was defined as detection of the same HPV type in cervical specimens at 2 consecutive evaluations over a minimum of 5 months • Persistent cervical infection (6-month definition) with any/each oncogenic HPV type*. • Persistent cervical infection (12-month definition) with HPV-16 and/or HPV-18. Persistent cervical HPV infection (12-month definition) was defined as detection of the same HPV type in cervical specimens at all consecutive evaluations over a minimum of 10 months. • Persistent cervical infection (12-month definition) with any/each oncogenic HPV type*. • Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ or CIN2+ associated with HPV-16 or HPV-18

detected within the lesional component of the cervical tissue specimen. CIN1+ is defined as CIN1, CIN2, CIN3, adenocarcinoma in situ (AIS) and invasive cervical cancer. CIN2+ is defined as CIN2, CIN3, AIS and invasive cervical cancer. • Histopathologically-confirmed CIN1+ or CIN2+ associated with any/each oncogenic HPV type* detected within the

lesional component of the cervical tissue specimen. • Abnormal cytology (Atypical squamous cells of undetermined significance [ASC-US], Low-grade squamous

intraepithelial lesion [LSIL], High-grade squamous intraepithelial lesion [HSIL], Atypical glandular cells [AGC], Atypical squamous cells, cannot exclude HSIL [ASC-H]) associated with an HPV-16 and/or HPV-18 cervical infection

• Abnormal cytology [ASC-US, LSIL, HSIL, AGC, ASC-H] associated with any/each oncogenic HPV type* cervical infection.

*any/each oncogenic HPV type: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 • HPV-16 and HPV-18 ELISA titers in all study subjects, and neutralizing antibodies in a subset of subjects**. • Occurrence of serious adverse events (SAEs), new onset chronic diseases (NOCDs, e.g. autoimmune disorders,

asthma, type I diabetes, allergies etc.), and medically significant conditions, i.e. adverse events (AEs) prompting either emergency room (ER) or physician visits that are not related to common diseases, or SAEs that are not related to common diseases, throughout the entire study period. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, vaginitis, vulvitis, menstrual cycle abnormalities, and injury**.

** These outcome measures were considered as Secondary Outcome/ other outcome variables. Statistical Methods: The analyses were performed on the Total cohort, According-To-Protocol (ATP) cohort for efficacy and ATP cohort for immunogenicity. - The Total cohort included all enrolled subjects who came at first visit and received at least one vaccine dose (HPV or placebo) - The ATP cohort for analysis of efficacy included all subjects for whom differential treatment effect on efficacy was likely (i.e. those meeting all eligibility criteria in studies 580299/001, 580299/007, 109616 and 109624), complying with the procedures defined in the 109616 and 109624 study protocol, and for whom efficacy data were available. - The ATP cohort for analysis of the immunogenicity included all evaluable subjects - i.e. those meeting all eligibility criteria in studies 580299/001, 580299/007, 109616 and 109624, complying with the procedures defined in the protocol, and fulfilling requirements for analysis - for whom immunogenicity data were available. This included subjects for whom assay results were available for antibodies against at least one study vaccine antigen component at least one blood-sampling time point. Efficacy analysis The analysis was based on the ATP cohort for efficacy and on the Total Cohort. Inferential analysis Vaccine Efficacy (VE) for all outcome variables were calculated on HPV-023 efficacy data using the conditional exact method. This method computed an exact confidence interval (CI) around the rate ratio (ratio of the event rates in the vaccinated versus control group) and took into account the follow-up time of the subjects within each group. The follow-up time for each subject started at the day of first visit in HPV-023 study and ended at the time of the event (start of the persistent infection or at the histopathological time point) or at the latest visit for which data were available (before the data lock point at the interim analyses) for subjects who did not yet completed the study at the time of the analysis or for subjects who withdrew from the study and did not have an event. The incidence rates of cervical infection were compared between the 2 groups using the Fisher exact test. The null hypothesis (the expected incidence rate during the considered period being similar in both groups) was rejected if the Fisher exact p-value was <0.001. VE was defined as 1 minus the rate ratio (ratio of the event rates in the vaccinated versus placebo group). A combined (pooled) analysis of efficacy data of HPV-001, HPV-007 and HPV-023 was also performed. The same methods as described above were used for this analysis with the exception that p-values were not calculated; for each outcome variables, the point estimates of the vaccine efficacy (with 95% CI) were provided. Subjects with an outcome measure (virological, cytological or histopathological) associated with an HPV type in the preceeding studies (HPV-001/007) were censored from analyses related to the same endpoint in HPV-023. Due to the limitations of HPV-023 (i.e. limited sample size, limited length of follow-up, higher number of subjects at risk in the vaccine group than in the control group) the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data. Immunogenicity analysis The analysis was performed on the ATP cohort for immunogenicity. For each treatment group, at each time interval for which result was available, seropositivity rates for both HPV-16 and HPV-18 ELISA titers and/or neutralizing antibodies (calculated on a subset of subjects*) with exact 95% CI. Geometric mean titers (GMTs) with 95% CI were also calculated. Seropositivity was defined as anti-HPV-16 titer ≥ 8 EL.U/mL and anti-HPV-18 titer ≥ 7 EL.U/mL by ELISA. * Approximately 60 subjects were tested for HPV-16//18 neutralizing antibodies. This subset was to include at least 50 subjects from the HPV Group and approximately 10 from the Placebo Group. Safety analysis The occurrences of AEs (Medically significant conditions i.e. AEs prompting ER visits or physician visits that were not related to common diseases medically significant conditions or SAEs that were not related to common diseases, NOCDs, new onset autoimmune disease [NOADs]) were tabulated during the follow-up period up to year 8 according to Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. The occurrence of SAEs during the follow-up period up to

year 8 was tabulated according to MedDRA preferred terms. Please note that the study is currently ongoing and therefore still blinded. The treatment information for some events is therefore not provided in the result section to preserve the study blind. Study Population: Healthy young adult women who participated in study HPV-007 (580299/007) in Brazil, whom the investigator (or designee) could contact and who were eligible. Prior to the performance of any study-specific procedures, written informed consent was obtained from each subject. Year 7 Number of Subjects: HPV Group Placebo Group Planned, N Not applicable* Not applicable* Entered, N (Total cohort) 222 211 Completed (at Year 7), n (%) 220 (99.1) 208 (98.6) Total Number Subjects Withdrawn, n (%) 2 (0.9) 3 (1.4) Withdrawn due to AEs, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not applicable Not applicable Withdrawn for other reasons n (%) 2 (0.9) 3 (1.4) Demographics HPV Group Placebo Group N (Total cohort) 222 211 Mean Age, years (SD) 26.5 (3.2) 26.4 (2.9) White/Caucasian, n (%) 125 (56.6) 125 (59.2) *Of the 448 subjects initially enrolled in study HPV-007 in Brazil, all subjects whom the investigator (or designee) could contact and who were eligible were invited to participate. Year 8 Number of Subjects: HPV Group Placebo Group Planned, N Not applicable Not applicable Entered, N (Total cohort) 223* 213* Completed (at Year 8), n (%) 222 (99.6) 211 (99.1) Total Number Subjects Withdrawn, n (%) 1 (0.4) 2 (0.9) Withdrawn due to AEs, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not applicable Not applicable Withdrawn for other reasons n (%) 1 (0.4) 2 (0.9) * Out of the five subjects withdrawn at Year 7, three subjects came back during Year 8 and are therefore not longer considered as withdrawn subjects. Demographics data were not re-calculated at Year 8. Primary Efficacy Results: Incidence rates and vaccine efficacy against incident infection with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (ATP cohort for efficacy)

Person-year rate VE Study Event

Type Group N n T(year) n/T

(Per 100) LL UL % LL UL P-value

HPV-023*

HPV-16/18

HPV 176 0 335.59 0.0 0.0 1.1 100.0 25.6 100.0 0.0109 Placebo 122 5 228.66 2.2 0.7 5.1 - - - -

HPV-16 HPV 178 0 339.59 0.0 0.0 1.1 100.0 20.0 100.0 0.0137 Placebo 133 5 249.01 2.0 0.7 4.7 - - - -

HPV-18 HPV 176 0 335.59 0.0 0.0 1.1 100.0 -18.9 100.0 0.0370 Placebo 139 4 263.44 1.5 0.4 3.9 - - - -

Pooled HPV-16/18

HPV 193 3 1042.72 0.3 0.1 0.8 95.1 84.6 99.0 Placebo 175 46 789.75 5.8 4.3 7.8 - - -

HPV-16 HPV 193 1 1050.17 0.1 0.0 0.5 97.7 86.1 99.9 Placebo 175 34 832.07 4.1 2.8 5.7 - - -

HPV-18 HPV 193 2 1044.77 0.2 0.0 0.7 93.7 74.6 99.3 Placebo 175 25 828.15 3.0 2.0 4.5 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 N = number of subjects included in each group n = number of subjects reporting at least one event in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects are DNA (Deoxyribonucleic acid) negative for the 14 oncogenic HPV types and have a normal cytology at baseline

in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) P-value = P-value from Fisher Exact Test * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against incident infection with oncogenic HPV types (by PCR) using Conditional exact method (ATP cohort for efficacy)



(Per 100)

LL UL % LL UL

HPV-023* HPV-HR HPV 154 32 267.60 12.0 8.2 16.9 32.0 -11.3 58.8 Placebo 133 39 221.71 17.6 12.5 24.0 - - -

HPV-HRW

HPV 154 32 267.60 12.0 8.2 16.9 23.2 -27.2 53.8 Placebo 135 36 231.25 15.6 10.9 21.6 - - -

Pooled HPV-HR HPV 179 87 789.79 11.0 8.8 13.6 20.5 -7.9 41.4 Placebo 158 91 656.99 13.9 11.2 17.0 - - -

HPV-HRW

HPV 179 87 789.79 11.0 8.8 13.6 8.2 -25.6 32.8 Placebo 158 83 691.91 12.0 9.6 14.9 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 N = number of subjects included in each group n = number of subjects reporting at least one event in each group. For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method)

* the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data- please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against incident infection with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (ATP cohort for efficacy)



(Per 100) LL UL % LL UL

HPV-023* HPV-31 HPV 195 1 372.36 0.3 0.0 1.5 83.1 -51.4 99.6 Placebo 168 5 315.40 1.6 0.5 3.7 - - -

HPV-33 HPV 195 0 372.44 0.0 0.0 1.0 100.0 -3379.3 100.0 Placebo 175 1 332.27 0.3 0.0 1.7 - - -

HPV-35 HPV 195 4 368.51 1.1 0.3 2.8 27.3 -237.6 85.6 Placebo 177 5 334.69 1.5 0.5 3.5 - - -

HPV-39 HPV 189 4 359.04 1.1 0.3 2.9 -72.0 -1801.2 75.4 Placebo 162 2 308.73 0.6 0.1 2.3 - - -

HPV-45 HPV 201 3 380.27 0.8 0.2 2.3 48.2 -166.4 92.0 Placebo 174 5 328.54 1.5 0.5 3.6 - - -

HPV-51 HPV 166 4 314.69 1.3 0.3 3.3 63.7 -25.9 91.7 Placebo 152 10 285.74 3.5 1.7 6.4 - - -

HPV-52 HPV 170 15 312.32 4.8 2.7 7.9 -51.7 -293.2 37.8 Placebo 152 9 284.31 3.2 1.4 6.0 - - -

HPV-56 HPV 181 2 346.42 0.6 0.1 2.1 53.9 -221.8 95.8 Placebo 168 4 319.51 1.3 0.3 3.2 - - -

HPV-58 HPV 189 4 360.75 1.1 0.3 2.8 -81.6 -1907.6 74.0 Placebo 173 2 327.57 0.6 0.1 2.2 - - -

HPV-59 HPV 193 2 366.80 0.5 0.1 2.0 -87.0 -10932.6 90.3 Placebo 180 1 342.97 0.3 0.0 1.6 - - -

HPV-66 HPV 176 3 332.04 0.9 0.2 2.6 65.2 -45.0 94.1 Placebo 164 8 308.08 2.6 1.1 5.1 - - -

HPV-68 HPV 186 6 350.52 1.7 0.6 3.7 11.4 -231.4 76.3 Placebo 166 6 310.57 1.9 0.7 4.2 - - -

Pooled HPV-31 HPV 226 10 1175.66 0.9 0.4 1.6 54.1 -3.9 80.9 Placebo 201 19 1026.31 1.9 1.1 2.9 - - -

HPV-33 HPV 226 9 1159.39 0.8 0.4 1.5 33.4 -72.1 75.2 Placebo 204 12 1028.93 1.2 0.6 2.0 - - -

HPV-35 HPV 225 11 1148.75 1.0 0.5 1.7 34.4 -52.9 72.7 Placebo 204 15 1027.67 1.5 0.8 2.4 - - -

HPV-39 HPV 227 20 1131.64 1.8 1.1 2.7 33.6 -23.7 64.8 Placebo 202 26 977.40 2.7 1.7 3.9 - - -

HPV-45 HPV 226 6 1171.83 0.5 0.2 1.1 70.7 22.9 90.5 Placebo 205 18 1030.58 1.7 1.0 2.8 - - -

HPV-51 HPV 223 42 1041.11 4.0 2.9 5.5 10.0 -41.0 42.6 Placebo 204 43 958.95 4.5 3.2 6.0 - - -

HPV-52 HPV 223 46 1038.70 4.4 3.2 5.9 -9.5 -73.7 30.5 Placebo 197 37 915.18 4.0 2.8 5.6 - - -

HPV-56 HPV 224 24 1094.06 2.2 1.4 3.3 10.8 -62.8 51.2 Placebo 206 25 1016.96 2.5 1.6 3.6 - - -

HPV-58 HPV 224 16 1130.01 1.4 0.8 2.3 10.1 -92.1 57.9 Placebo 204 16 1016.42 1.6 0.9 2.6 - - -

HPV-59 HPV 227 13 1143.32 1.1 0.6 1.9 -49.1 -315.1 42.7 Placebo 206 8 1049.24 0.8 0.3 1.5 - - -

HPV-66 HPV 220 28 1062.18 2.6 1.8 3.8 5.0 -67.5 46.0 Placebo 197 27 972.95 2.8 1.8 4.0 - - -

HPV-68 HPV 223 21 1114.55 1.9 1.2 2.9 35.4 -17.3 65.0 Placebo 204 29 994.86 2.9 2.0 4.2 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 N = number of subjects included in each group n = number of subjects reporting at least one event in each group. For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method)

* the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against persistent infection (6-month) with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (ATP cohort for efficacy)




HPV-023* HPV-16/18 HPV 178 0 339.59 0.0 0.0 1.1 . . . Placebo 144 0 272.70 0.0 0.0 1.4 - - -

HPV-16 HPV 178 0 339.59 0.0 0.0 1.1 . . . Placebo 149 0 282.41 0.0 0.0 1.3 - - -

HPV-18 HPV 178 0 339.59 0.0 0.0 1.1 . . . Placebo 151 0 286.28 0.0 0.0 1.3 - - -

Pooled HPV-16/18 HPV 193 0 1052.22 0.0 0.0 0.4 100.0 79.8 100.0 Placebo 175 17 876.48 1.9 1.1 3.1 - - -

HPV-16 HPV 193 0 1052.22 0.0 0.0 0.4 100.0 69.3 100.0 Placebo 175 12 897.97 1.3 0.7 2.3 - - -

HPV-18 HPV 193 0 1052.22 0.0 0.0 0.4 100.0 50.4 100.0 Placebo 175 8 890.19 0.9 0.4 1.8 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 N = number of subjects included in each group n = number of subjects reporting at least one event in each group. For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method)

* the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against persistent infection (6-month) with oncogenic HPV types (by PCR) using Conditional exact method (ATP cohort for efficacy)





HPV-HRW HPV 162 15 292.77 5.1 2.9 8.5 22.8 -64.2 64.1 Placebo 143 17 255.99 6.6 3.9 10.6 - - -



Pooled = Combined (pooled) analysis of HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 N = number of subjects included in each group n = number of subjects reporting at least one event in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval

VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against persistent infection (6-month) with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (ATP cohort for efficacy)





HPV-33 HPV 199 1 379.09 0.3 0.0 1.5 8.9 -7053.3 98.8 Placebo 182 1 345.45 0.3 0.0 1.6 - - -

HPV-35 HPV 200 2 379.44 0.5 0.1 1.9 40.3 -421.4 95.0 Placebo 180 3 339.96 0.9 0.2 2.6 - - -

HPV-39 HPV 199 2 378.86 0.5 0.1 1.9 13.1 -1099.5 93.7 Placebo 174 2 329.39 0.6 0.1 2.2 - - -

HPV-45 HPV 203 4 382.92 1.0 0.3 2.7 -264.7 -17859.9 63.9 Placebo 184 1 349.11 0.3 0.0 1.6 - - -

HPV-51 HPV 191 3 360.84 0.8 0.2 2.4 8.7 -581.4 87.8 Placebo 174 3 329.34 0.9 0.2 2.7 - - -

HPV-52 HPV 185 4 347.92 1.1 0.3 2.9 10.4 -380.9 83.3 Placebo 166 4 311.66 1.3 0.3 3.3 - - -

HPV-56 HPV 196 1 375.48 0.3 0.0 1.5 54.0 -784.0 99.2 Placebo 182 2 345.57 0.6 0.1 2.1 - - -

HPV-58 HPV 195 3 371.92 0.8 0.2 2.4 8.2 -585.2 87.7 Placebo 181 3 341.33 0.9 0.2 2.6 - - -

HPV-59 HPV 202 0 385.66 0.0 0.0 1.0 . . . Placebo 184 0 350.78 0.0 0.0 1.1 - - -

HPV-66 HPV 191 1 363.09 0.3 0.0 1.5 55.5 -754.4 99.2 Placebo 171 2 322.99 0.6 0.1 2.2 - - -

HPV-68 HPV 199 2 378.94 0.5 0.1 1.9 9.6 -1146.7 93.4 Placebo 181 2 342.45 0.6 0.1 2.1 - - -


HPV-33 HPV 226 6 1183.85 0.5 0.2 1.1 -36.7 -558.7 67.6 Placebo 204 4 1079.04 0.4 0.1 0.9 - - -

HPV-35 HPV 225 4 1185.34 0.3 0.1 0.9 59.7 -44.2 90.9 Placebo 204 9 1073.51 0.8 0.4 1.6 - - -

HPV-39 HPV 227 8 1182.73 0.7 0.3 1.3 36.1 -74.4 77.7 Placebo 202 11 1038.78 1.1 0.5 1.9 - - -

HPV-45 HPV 226 5 1195.82 0.4 0.1 1.0 -52.1 -879.5 70.4 Placebo 205 3 1091.40 0.3 0.1 0.8 - - -

HPV-51 HPV 223 15 1144.21 1.3 0.7 2.2 8.3 -101.2 58.2 Placebo 204 15 1048.77 1.4 0.8 2.4 - - -

HPV-52 HPV 223 21 1121.58 1.9 1.2 2.9 -2.6 -104.2 48.0 Placebo 197 18 986.11 1.8 1.1 2.9 - - -

HPV-56 HPV 224 9 1167.72 0.8 0.4 1.5 24.2 -101.2 72.2 Placebo 206 11 1081.61 1.0 0.5 1.8 - - -

HPV-58 HPV 224 10 1164.91 0.9 0.4 1.6 8.3 -145.5 65.8 Placebo 204 10 1068.08 0.9 0.4 1.7 - - -

HPV-59 HPV 227 2 1196.62 0.2 0.0 0.6 39.1 -431.2 94.9 Placebo 206 3 1092.25 0.3 0.1 0.8 - - -

HPV-66 HPV 220 10 1140.58 0.9 0.4 1.6 24.9 -89.7 70.9 Placebo 197 12 1028.08 1.2 0.6 2.0 - - -

HPV-68 HPV 223 5 1174.58 0.4 0.1 1.0 42.6 -98.8 85.2 Placebo 204 8 1077.91 0.7 0.3 1.5 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 N = number of subjects included in each group n = number of subjects reporting at least one event in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis , interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method)

* the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against persistent infection (12-month) with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (ATP cohort for efficacy)





HPV-16 HPV 178 0 339.59 0.0 0.0 1.1 . . . Placebo 154 0 292.05 0.0 0.0 1.3 - - -

HPV-18 HPV 178 0 339.59 0.0 0.0 1.1 . . . Placebo 156 0 296.07 0.0 0.0 1.2 - - -


HPV-16 HPV 193 0 1052.22 0.0 0.0 0.4 100.0 39.3 100.0 Placebo 175 7 920.99 0.8 0.3 1.6 - - -

HPV-18 HPV 193 0 1052.22 0.0 0.0 0.4 100.0 -111.8 100.0 Placebo 175 3 920.73 0.3 0.1 1.0 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 N = number of subjects included in each group n = number of subjects reporting at least one event in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method)

* the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis Secondary Outcome Variables: Incidence rates and vaccine efficacy against persistent infection (12-month) with oncogenic HPV types (by PCR) using Conditional exact method (ATP cohort for efficacy)




HPV-023* HPV-HR HPV 163 8 302.01 2.6 1.1 5.2 -134.0 -1269.2 43.8 Placebo 142 3 264.96 1.1 0.2 3.3 - - -

HPV-HRW HPV 163 8 302.01 2.6 1.1 5.2 -135.7 -1279.6 43.4 Placebo 143 3 266.98 1.1 0.2 3.3 - - -


HPV-HRW HPV 179 32 899.64 3.6 2.4 5.0 -23.3 -120.7 30.1 Placebo 158 23 797.33 2.9 1.8 4.3 - - -

Pooled = Combined (pooled) analysis of HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 N = number of subjects included in each group n = number of subjects reporting at least one event in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against persistent infection (12-month) with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (ATP cohort for efficacy)





HPV-33 HPV 202 1 385.03 0.3 0.0 1.4 . . 97.7 Placebo 184 0 350.25 0.0 0.0 1.1 - - -

HPV-35 HPV 200 0 382.13 0.0 0.0 1.0 100.0 -3482.3 100.0 Placebo 185 1 351.00 0.3 0.0 1.6 - - -

HPV-39 HPV 200 2 380.76 0.5 0.1 1.9 -78.9 -10455.5 90.7 Placebo 179 1 340.62 0.3 0.0 1.6 - - -

HPV-45 HPV 204 3 385.57 0.8 0.2 2.3 -174.6 -14317.4 77.9 Placebo 186 1 352.96 0.3 0.0 1.6 - - -

HPV-51 HPV 198 1 376.79 0.3 0.0 1.5 8.5 -7084.1 98.8 Placebo 182 1 344.84 0.3 0.0 1.6 - - -

HPV-52 HPV 191 3 361.17 0.8 0.2 2.4 -170.8 -14118.3 78.3 Placebo 172 1 326.06 0.3 0.0 1.7 - - -

HPV-56 HPV 200 0 383.82 0.0 0.0 1.0 . . . Placebo 185 0 352.08 0.0 0.0 1.0 - - -

HPV-58 HPV 199 0 381.21 0.0 0.0 1.0 100.0 -3441.5 100.0 Placebo 183 1 346.17 0.3 0.0 1.6 - - -

HPV-59 HPV 203 0 387.58 0.0 0.0 1.0 . . . Placebo 186 0 354.29 0.0 0.0 1.0 - - -

HPV-66 HPV 195 0 372.33 0.0 0.0 1.0 100.0 -3412.9 100.0 Placebo 177 1 335.37 0.3 0.0 1.7 - - -

HPV-68 HPV 200 1 382.15 0.3 0.0 1.5 . . 97.7

Placebo 184 0 349.81 0.0 0.0 1.1 - - - Pooled HPV-31 HPV 226 4 1198.98 0.3 0.1 0.9 -19.6 -716.6 79.8

Placebo 201 3 1075.66 0.3 0.1 0.8 - - - HPV-33 HPV 226 2 1196.17 0.2 0.0 0.6 -82.8 -10682.3 90.5

Placebo 204 1 1093.06 0.1 0.0 0.5 - - - HPV-35 HPV 225 2 1189.02 0.2 0.0 0.6 38.7 -435.0 94.9

Placebo 204 3 1092.96 0.3 0.1 0.8 - - - HPV-39 HPV 227 6 1190.88 0.5 0.2 1.1 -7.6 -345.7 72.6

Placebo 202 5 1067.80 0.5 0.2 1.1 - - - HPV-45 HPV 226 3 1202.39 0.2 0.1 0.7 -175.0 -14334.4 77.9

Placebo 205 1 1102.01 0.1 0.0 0.5 - - - HPV-51 HPV 223 6 1177.26 0.5 0.2 1.1 8.3 -242.8 75.5

Placebo 204 6 1078.98 0.6 0.2 1.2 - - - HPV-52 HPV 223 15 1138.34 1.3 0.7 2.2 -49.5 -287.4 38.7

Placebo 197 9 1021.00 0.9 0.4 1.7 - - - HPV-56 HPV 224 2 1190.21 0.2 0.0 0.6 7.3 -1178.8 93.3

Placebo 206 2 1103.24 0.2 0.0 0.7 - - - HPV-58 HPV 224 2 1184.55 0.2 0.0 0.6 63.4 -123.4 96.5

Placebo 204 5 1083.01 0.5 0.1 1.1 - - - HPV-59 HPV 227 2 1197.61 0.2 0.0 0.6 -84.6 -10790.9 90.4

Placebo 206 1 1105.39 0.1 0.0 0.5 - - - HPV-66 HPV 220 5 1156.21 0.4 0.1 1.0 -13.6 -472.5 75.5

Placebo 197 4 1050.81 0.4 0.1 1.0 - - - HPV-68 HPV 223 2 1182.43 0.2 0.0 0.6 7.6 -1175.2 93.3

Placebo 204 2 1092.95 0.2 0.0 0.7 - - - Pooled = Combined (pooled) analysis of HPV-001/007/023 N = number of subjects included in each group n = number of subjects reporting at least one event in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. Subjects with an event are DNA negative for the corresponding HPV type at Month 6 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 6 in HPV-001 for pooled HPV-001/007/023 analysis , interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against CIN1+ associated with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (Total cohort)





HPV-16 HPV 199 0 380.39 0.0 0.0 1.0 . . . Placebo 183 0 348.16 0.0 0.0 1.1 - - -

HPV-18 HPV 199 0 380.39 0.0 0.0 1.0 . . . Placebo 186 0 353.91 0.0 0.0 1.0 - - -


HPV-16 HPV 219 0 1284.26 0.0 0.0 0.3 100.0 20.3 100.0 Placebo 212 6 1205.82 0.5 0.2 1.1 - - -

HPV-18 HPV 219 0 1284.26 0.0 0.0 0.3 100.0 -3563.6 100.0 Placebo 212 1 1206.43 0.1 0.0 0.5 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against CIN1+ associated with oncogenic HPV types (by PCR) using Conditional exact method (Total cohort)






Pooled HPV-HR HPV 219 6 1274.85 0.5 0.2 1.0 68.5 17.2 89.8 Placebo 212 18 1204.30 1.5 0.9 2.4 - - -


Pooled = Combined (pooled) analysis of studies HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against CIN1+ associated with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (Total cohort)


Type Group N n T(year) n/T (Per

100) LL UL % LL UL

HPV-023* HPV-31 HPV 221 0 422.46 0.0 0.0 0.9 . . . Placebo 207 0 393.35 0.0 0.0 0.9 - - -

HPV-33 HPV 220 0 420.26 0.0 0.0 0.9 . . . Placebo 207 0 393.37 0.0 0.0 0.9 - - -

HPV-35 HPV 219 0 418.23 0.0 0.0 0.9 . . . Placebo 206 0 392.28 0.0 0.0 0.9 - - -

HPV-39 HPV 222 0 424.36 0.0 0.0 0.9 . . . Placebo 209 0 397.17 0.0 0.0 0.9 - - -

HPV-45 HPV 221 0 422.35 0.0 0.0 0.9 . . . Placebo 208 0 395.34 0.0 0.0 0.9 - - -

HPV-51 HPV 215 0 411.50 0.0 0.0 0.9 . . . Placebo 206 0 392.27 0.0 0.0 0.9 - - -

HPV-52 HPV 218 0 416.65 0.0 0.0 0.9 100.0 -3513.2 100.0 Placebo 204 1 386.01 0.3 0.0 1.4 - - -

HPV-56 HPV 219 0 418.85 0.0 0.0 0.9 100.0 -3598.6 100.0 Placebo 209 1 397.22 0.3 0.0 1.4 - - -

HPV-58 HPV 221 0 422.46 0.0 0.0 0.9 . . . Placebo 206 0 391.43 0.0 0.0 0.9 - - -

HPV-59 HPV 220 0 420.36 0.0 0.0 0.9 . . . Placebo 208 0 395.70 0.0 0.0 0.9 - - -

HPV-66 HPV 219 0 418.56 0.0 0.0 0.9 . . . Placebo 203 0 385.63 0.0 0.0 1.0 - - -

HPV-68 HPV 221 0 422.44 0.0 0.0 0.9 . . . Placebo 209 0 397.16 0.0 0.0 0.9 - - -


HPV-33 HPV 251 2 1433.60 0.1 0.0 0.5 5.6 -1202.0 93.2 Placebo 238 2 1352.97 0.1 0.0 0.5 - - -

HPV-35 HPV 251 3 1431.24 0.2 0.0 0.6 -41.4 -1593.2 83.8 Placebo 236 2 1349.40 0.1 0.0 0.5 - - -

HPV-39 HPV 251 0 1444.51 0.0 0.0 0.3 . . . Placebo 237 0 1361.50 0.0 0.0 0.3 - - -

HPV-45 HPV 249 0 1436.60 0.0 0.0 0.3 . . . Placebo 236 0 1353.88 0.0 0.0 0.3 - - -

HPV-51 HPV 245 3 1405.34 0.2 0.0 0.6 -43.9 -1622.3 83.5 Placebo 237 2 1347.73 0.1 0.0 0.5 - - -

HPV-52 HPV 247 1 1419.55 0.1 0.0 0.4 81.2 -68.4 99.6 Placebo 237 5 1337.52 0.4 0.1 0.9 - - -

HPV-56 HPV 247 0 1426.05 0.0 0.0 0.3 100.0 -3621.0 100.0 Placebo 237 1 1360.60 0.1 0.0 0.4 - - -

HPV-58 HPV 250 0 1438.19 0.0 0.0 0.3 100.0 -398.9 100.0 Placebo 237 2 1347.64 0.1 0.0 0.5 - - -

HPV-59 HPV 249 1 1432.34 0.1 0.0 0.4 . . 97.6 Placebo 237 0 1356.19 0.0 0.0 0.3 - - -

HPV-66 HPV 248 1 1423.13 0.1 0.0 0.4 53.3 -797.6 99.2 Placebo 234 2 1330.01 0.2 0.0 0.5 - - -

HPV-68 HPV 251 1 1441.10 0.1 0.0 0.4 . . 97.6 Placebo 237 0 1359.53 0.0 0.0 0.3 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group

Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against CIN2+ associated with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (Total cohort)





HPV-16 HPV 199 0 380.39 0.0 0.0 1.0 . . . Placebo 185 0 351.98 0.0 0.0 1.0 - - -

HPV-18 HPV 199 0 380.39 0.0 0.0 1.0 . . . Placebo 186 0 353.91 0.0 0.0 1.0 - - -

Pooled HPV-16/18 HPV 219 0 1284.26 0.0 0.0 0.3 100.0 -128.0 100.0 Placebo 212 3 1210.23 0.2 0.1 0.7 - - -

HPV-16 HPV 219 0 1284.26 0.0 0.0 0.3 100.0 -403.1 100.0 Placebo 212 2 1213.52 0.2 0.0 0.6 - - -

HPV-18 HPV 219 0 1284.26 0.0 0.0 0.3 100.0 -3584.1 100.0 Placebo 212 1 1213.16 0.1 0.0 0.5 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against CIN2+ associated with oncogenic HPV types (by PCR) using Conditional exact method (Total cohort)




HPV-023* HPV-HR HPV 199 0 380.39 0.0 0.0 1.0 . . . Placebo 187 0 355.82 0.0 0.0 1.0 - - -

HPV-HRW HPV 199 0 380.39 0.0 0.0 1.0 . . . Placebo 187 0 355.82 0.0 0.0 1.0 - - -



Pooled = Combined (pooled) analysis of studies HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and

68 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against CIN2+ associated with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (Total cohort)



100) LL UL % LL UL

HPV-023* HPV-31 HPV 221 0 422.46 0.0 0.0 0.9 . . . Placebo 208 0 395.25 0.0 0.0 0.9 - - -

HPV-33 HPV 220 0 420.26 0.0 0.0 0.9 . . . Placebo 208 0 395.36 0.0 0.0 0.9 - - -

HPV-35 HPV 220 0 420.36 0.0 0.0 0.9 . . . Placebo 206 0 392.28 0.0 0.0 0.9 - - -

HPV-39 HPV 222 0 424.36 0.0 0.0 0.9 . . . Placebo 209 0 397.17 0.0 0.0 0.9 - - -

HPV-45 HPV 221 0 422.35 0.0 0.0 0.9 . . . Placebo 208 0 395.34 0.0 0.0 0.9 - - -

HPV-51 HPV 217 0 415.29 0.0 0.0 0.9 . . . Placebo 207 0 394.31 0.0 0.0 0.9 - - -

HPV-52 HPV 218 0 416.65 0.0 0.0 0.9 100.0 -3550.5 100.0 Placebo 206 1 390.00 0.3 0.0 1.4 - - -

HPV-56 HPV 219 0 418.85 0.0 0.0 0.9 . . . Placebo 209 0 397.22 0.0 0.0 0.9 - - -

HPV-58 HPV 221 0 422.46 0.0 0.0 0.9 . . . Placebo 207 0 393.31 0.0 0.0 0.9 - - -

HPV-59 HPV 220 0 420.36 0.0 0.0 0.9 . . . Placebo 208 0 395.70 0.0 0.0 0.9 - - -

HPV-66 HPV 220 0 420.46 0.0 0.0 0.9 . . . Placebo 205 0 389.59 0.0 0.0 0.9 - - -

HPV-68 HPV 221 0 422.44 0.0 0.0 0.9 . . . Placebo 209 0 397.16 0.0 0.0 0.9 - - -

Pooled HPV-31 HPV 249 0 1436.69 0.0 0.0 0.3 . . . Placebo 237 0 1360.46 0.0 0.0 0.3 - - -

HPV-33 HPV 251 2 1433.60 0.1 0.0 0.5 -90.1 -11112.7 90.1 Placebo 238 1 1362.31 0.1 0.0 0.4 - - -

HPV-35 HPV 251 2 1435.97 0.1 0.0 0.5 5.7 -1201.0 93.2 Placebo 236 2 1354.21 0.1 0.0 0.5 - - -

HPV-39 HPV 251 0 1444.51 0.0 0.0 0.3 . . . Placebo 237 0 1366.31 0.0 0.0 0.3 - - -

HPV-45 HPV 249 0 1436.60 0.0 0.0 0.3 . . . Placebo 236 0 1358.69 0.0 0.0 0.3 - - -

HPV-51 HPV 245 1 1412.19 0.1 0.0 0.4 3.9 -7445.1 98.8 Placebo 237 1 1357.41 0.1 0.0 0.4 - - -

HPV-52 HPV 247 1 1419.55 0.1 0.0 0.4 68.3 -294.7 99.4

Placebo 237 3 1349.76 0.2 0.0 0.6 - - - HPV-56 HPV 247 0 1426.05 0.0 0.0 0.3 . . .

Placebo 237 0 1365.41 0.0 0.0 0.3 - - - HPV-58 HPV 250 0 1438.19 0.0 0.0 0.3 100.0 -3578.0 100.0

Placebo 237 1 1356.31 0.1 0.0 0.4 - - - HPV-59 HPV 249 1 1432.34 0.1 0.0 0.4 . . 97.6

Placebo 237 0 1361.00 0.0 0.0 0.3 - - - HPV-66 HPV 248 0 1427.40 0.0 0.0 0.3 . . .

Placebo 234 0 1341.69 0.0 0.0 0.3 - - - HPV-68 HPV 251 1 1441.10 0.1 0.0 0.4 . . 97.6

Placebo 237 0 1364.33 0.0 0.0 0.3 - - - Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against cytological abnormalities (greater than or equal to ASC-US) associated with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (Total cohort)




HPV-023* HPV-16/18 HPV 198 0 378.41 0.0 0.0 1.0 100.0 -3131.1 100.0 Placebo 165 1 313.50 0.3 0.0 1.8 - - -

HPV-16 HPV 198 0 378.41 0.0 0.0 1.0 . . . Placebo 171 0 325.19 0.0 0.0 1.1 - - -

HPV-18 HPV 199 0 380.39 0.0 0.0 1.0 100.0 -3348.8 100.0 Placebo 177 1 336.39 0.3 0.0 1.7 - - -


HPV-16 HPV 224 1 1385.58 0.1 0.0 0.4 95.5 71.8 99.9 Placebo 219 20 1251.69 1.6 1.0 2.5 - - -

HPV-18 HPV 224 0 1387.08 0.0 0.0 0.3 100.0 67.7 100.0 Placebo 219 12 1244.30 1.0 0.5 1.7 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against cytological abnormalities (greater than or

equal to ASC-US) associated with oncogenic HPV types (by PCR) using Conditional exact method (Total cohort) Person-year rate VE Study Event







Pooled = Combined (pooled) analysis of studies HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against cytological abnormalities (greater than or equal to ASC-US) associated with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (Total cohort)



100) LL UL % LL UL

HPV-023* HPV-31 HPV 217 0 415.67 0.0 0.0 0.9 100.0 0.9 100.0 Placebo 200 5 377.59 1.3 0.4 3.1 - - -

HPV-33 HPV 218 0 416.44 0.0 0.0 0.9 100.0 -3493.3 100.0 Placebo 202 1 383.69 0.3 0.0 1.5 - - -

HPV-35 HPV 217 1 414.35 0.2 0.0 1.3 7.4 -7167.9 98.8 Placebo 202 1 383.64 0.3 0.0 1.5 - - -

HPV-39 HPV 217 1 415.77 0.2 0.0 1.3 10.1 -6960.7 98.9 Placebo 197 1 373.98 0.3 0.0 1.5 - - -

HPV-45 HPV 220 2 419.48 0.5 0.1 1.7 . . 82.6 Placebo 204 0 387.52 0.0 0.0 1.0 - - -

HPV-51 HPV 202 1 386.41 0.3 0.0 1.4 68.1 -296.8 99.4 Placebo 194 3 369.34 0.8 0.2 2.4 - - -

HPV-52 HPV 205 3 389.92 0.8 0.2 2.2 11.6 -560.3 88.2 Placebo 183 3 344.84 0.9 0.2 2.5 - - -

HPV-56 HPV 207 1 397.36 0.3 0.0 1.4 3.4 -7485.3 98.8 Placebo 202 1 383.98 0.3 0.0 1.5 - - -

HPV-58 HPV 213 0 407.72 0.0 0.0 0.9 100.0 -123.7 100.0 Placebo 199 3 376.86 0.8 0.2 2.3 - - -

HPV-59 HPV 216 0 412.35 0.0 0.0 0.9 100.0 -3597.2 100.0 Placebo 206 1 390.91 0.3 0.0 1.4 - - -

HPV-66 HPV 214 2 407.12 0.5 0.1 1.8 -80.2 -10533.2 90.6

Placebo 194 1 366.88 0.3 0.0 1.5 - - - HPV-68 HPV 217 2 413.63 0.5 0.1 1.7 -85.4 -10840.5 90.3

Placebo 202 1 383.52 0.3 0.0 1.5 - - - Pooled HPV-31 HPV 256 4 1540.14 0.3 0.1 0.7 71.4 7.4 93.2

Placebo 245 13 1431.67 0.9 0.5 1.6 - - - HPV-33 HPV 258 5 1542.33 0.3 0.1 0.8 42.3 -99.9 85.2

Placebo 245 8 1422.77 0.6 0.2 1.1 - - - HPV-35 HPV 258 7 1536.03 0.5 0.2 0.9 18.8 -156.1 74.9

Placebo 244 8 1424.70 0.6 0.2 1.1 - - - HPV-39 HPV 258 7 1536.01 0.5 0.2 0.9 54.3 -20.9 84.4

Placebo 245 14 1402.66 1.0 0.5 1.7 - - - HPV-45 HPV 254 3 1544.30 0.2 0.0 0.6 30.8 -309.2 89.9

Placebo 244 4 1425.59 0.3 0.1 0.7 - - - HPV-51 HPV 252 18 1467.95 1.2 0.7 1.9 -0.9 -108.3 50.9

Placebo 245 17 1398.48 1.2 0.7 1.9 - - - HPV-52 HPV 253 18 1481.11 1.2 0.7 1.9 47.7 3.5 72.4

Placebo 245 31 1334.81 2.3 1.6 3.3 - - - HPV-56 HPV 254 14 1483.25 0.9 0.5 1.6 -49.2 -290.7 39.9

Placebo 245 9 1422.56 0.6 0.3 1.2 - - - HPV-58 HPV 257 8 1520.34 0.5 0.2 1.0 43.1 -48.0 79.6

Placebo 245 13 1405.06 0.9 0.5 1.6 - - - HPV-59 HPV 256 5 1527.70 0.3 0.1 0.8 -56.4 -907.0 69.6

Placebo 245 3 1433.45 0.2 0.0 0.6 - - - HPV-66 HPV 255 10 1513.50 0.7 0.3 1.2 29.7 -73.4 72.4

Placebo 242 13 1382.34 0.9 0.5 1.6 - - - HPV-68 HPV 258 7 1535.49 0.5 0.2 0.9 28.0 -117.1 77.2

Placebo 245 9 1420.48 0.6 0.3 1.2 - - - Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis , interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against cytological abnormalities (greater than or equal to LSIL) associated with HPV-16 and/or HPV-18 (by PCR) using Conditional exact method (Total cohort)




HPV-023* HPV-16/18 HPV 198 0 378.41 0.0 0.0 1.0 100.0 -3309.9 100.0 Placebo 174 1 330.86 0.3 0.0 1.7 - - -

HPV-16 HPV 198 0 378.41 0.0 0.0 1.0 . . . Placebo 177 0 336.84 0.0 0.0 1.1 - - -

HPV-18 HPV 199 0 380.39 0.0 0.0 1.0 100.0 -3467.2 100.0 Placebo 183 1 347.93 0.3 0.0 1.6 - - -


HPV-16 HPV 224 1 1385.58 0.1 0.0 0.4 92.9 52.8 99.8 Placebo 219 13 1276.88 1.0 0.5 1.7 - - -

HPV-18 HPV 224 0 1387.08 0.0 0.0 0.3 100.0 -0.9 100.0 Placebo 219 5 1282.53 0.4 0.1 0.9 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group. Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against cytological abnormalities (greater than or equal to LSIL) associated with oncogenic HPV types (by PCR) using Conditional exact method (Total cohort)







HPV-HRW HPV 224 30 1344.60 2.2 1.5 3.2 47.2 15.9 67.5 Placebo 219 53 1253.26 4.2 3.2 5.5 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 HPV-HR = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 HPV-HRW = High-risk (oncogenic) HPV types without HPV-16 or HPV-18: HPV-31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects are DNA negative for the 14 oncogenic HPV types and have a normal cytology at baseline in HPV-001. Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis; interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval

VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Incidence rates and vaccine efficacy against cytological abnormalities (greater than or equal to LSIL) associated with individual oncogenic non-vaccine HPV type (by PCR) using Conditional exact method (Total cohort)



100) LL UL % LL UL


HPV-33 HPV 219 0 418.36 0.0 0.0 0.9 100.0 -3530.6 100.0 Placebo 205 1 389.46 0.3 0.0 1.4 - - -

HPV-35 HPV 217 0 414.35 0.0 0.0 0.9 . . . Placebo 204 0 388.92 0.0 0.0 0.9 - - -

HPV-39 HPV 219 1 419.59 0.2 0.0 1.3 9.7 -6985.1 98.9 Placebo 200 1 378.72 0.3 0.0 1.5 - - -

HPV-45 HPV 220 2 419.48 0.5 0.1 1.7 . . 82.6 Placebo 205 0 389.46 0.0 0.0 0.9 - - -

HPV-51 HPV 211 1 402.99 0.2 0.0 1.4 69.0 -286.5 99.4 Placebo 197 3 375.19 0.8 0.2 2.3 - - -

HPV-52 HPV 210 2 400.91 0.5 0.1 1.8 40.1 -423.2 95.0 Placebo 191 3 360.45 0.8 0.2 2.4 - - -

HPV-56 HPV 211 1 404.16 0.2 0.0 1.4 . . 97.6 Placebo 202 0 384.08 0.0 0.0 1.0 - - -

HPV-58 HPV 216 0 413.51 0.0 0.0 0.9 100.0 -397.2 100.0 Placebo 203 2 386.12 0.5 0.1 1.9 - - -

HPV-59 HPV 219 0 418.13 0.0 0.0 0.9 100.0 -3564.0 100.0 Placebo 207 1 392.82 0.3 0.0 1.4 - - -

HPV-66 HPV 217 0 414.56 0.0 0.0 0.9 100.0 -3369.3 100.0 Placebo 195 1 368.78 0.3 0.0 1.5 - - -

HPV-68 HPV 219 2 417.54 0.5 0.1 1.7 -87.5 -10959.4 90.2 Placebo 206 1 391.35 0.3 0.0 1.4 - - -


HPV-33 HPV 258 4 1547.18 0.3 0.1 0.7 25.3 -247.2 85.2 Placebo 245 5 1445.28 0.3 0.1 0.8 - - -

HPV-35 HPV 258 5 1539.33 0.3 0.1 0.8 6.4 -306.5 78.5 Placebo 244 5 1440.11 0.3 0.1 0.8 - - -

HPV-39 HPV 258 4 1548.84 0.3 0.1 0.7 66.6 -12.8 92.2 Placebo 245 11 1424.02 0.8 0.4 1.4 - - -

HPV-45 HPV 254 3 1546.20 0.2 0.0 0.6 6.9 -594.8 87.5 Placebo 244 3 1438.92 0.2 0.0 0.6 - - -

HPV-51 HPV 252 9 1505.80 0.6 0.3 1.1 39.5 -50.0 76.9 Placebo 245 14 1416.22 1.0 0.5 1.7 - - -

HPV-52 HPV 253 11 1503.08 0.7 0.4 1.3 51.8 -4.5 79.0 Placebo 245 21 1382.49 1.5 0.9 2.3 - - -

HPV-56 HPV 254 10 1504.41 0.7 0.3 1.2 -18.9 -246.7 57.8 Placebo 245 8 1430.92 0.6 0.2 1.1 - - -

HPV-58 HPV 257 5 1534.24 0.3 0.1 0.8 33.2 -144.5 83.3 Placebo 245 7 1434.59 0.5 0.2 1.0 - - -

HPV-59 HPV 256 2 1545.13 0.1 0.0 0.5 6.4 -1191.1 93.2 Placebo 245 2 1446.01 0.1 0.0 0.5 - - -

HPV-66 HPV 255 4 1526.58 0.3 0.1 0.7 69.6 -0.3 92.9 Placebo 242 12 1392.17 0.9 0.4 1.5 - - -

HPV-68 HPV 258 5 1543.29 0.3 0.1 0.8 6.6 -306.0 78.5 Placebo 245 5 1441.92 0.3 0.1 0.8 - - -

Pooled = Combined (pooled) analysis of studies HPV-001/007/023 N = number of subjects included in each group For study HPV-023: Subjects with an event who did not report the same event in HPV-001/HPV-007. n = number of subjects reporting at least one event in each group Subjects with an event are DNA negative for the corresponding HPV type at Month 0 in HPV-001. T(year) = sum of follow-up period expressed in year censored at the first occurrence of event in each group Follow-up period starts at Month 0 in HPV-001 for pooled HPV-001/007/023 analysis , interval periods between end of HPV-001 and beginning of HPV-007 and between end of HPV-007 and beginning of HPV-023 are censored. n/T = person-year rate in each group LL, UL = Lower and Upper limits of the 95% confidence interval VE(%) = Vaccine Efficacy (Conditional exact method) * the focus for efficacy outcome measure is on the combined (pooled) analysis of HPV-001/007/023 data - please refer to Statistical Methods, section Efficacy Analysis. Secondary Outcome Variables: Seropositivity rates and GMTs for HPV-16 antibodies measured by ELISA (ATP cohort for immunogenicity)

≥≥≥≥ 8 EL.U/mL GMT 95% CI 95% CI

Group Study Timing N n % LL UL value LL UL HPV HPV-001 PRE 176 11 6.3 3.2 10.9 4.3 4.1 4.5

PIII(M7) 179 179 100 98.0 100 3874.0 3355.3 4472.8 PIII(M12) 176 176 100 97.9 100 1052.6 900.7 1230.2 PIII(M18) 177 176 99.4 96.9 100 641.0 545.4 753.4

HPV-007 [M33-M38] 117 117 100 96.9 100 455.4 369.7 561.0 [M39-M44] 63 63 100 94.3 100 513.2 403.2 653.3 [M45-M50] 137 137 100 97.3 100 370.6 307.5 446.6 [M51-M56] 39 39 100 91.0 100 603.3 435.5 835.8 [M57-M62] 129 129 100 97.2 100 399.3 329.1 484.4 [M63-M68] 50 50 100 92.9 100 505.4 380.9 670.8 [M69-M74] 131 130 99.2 95.8 100 360.7 293.1 443.9 [M75-M76] 49 49 100 92.7 100 453.2 348.8 588.8

HPV-023 [M77-M82] 69 69 100 94.8 100 374.9 291.8 481.8 [M83-M88] 111 111 100 96.7 100 383.4 312.9 469.9 [M89-M94] 94 94 100 96.2 100 346.3 270.3 443.6 [M95-M101] 87 87 100 95.8 100 435.1 347.5 544.9

Placebo HPV-001 PRE 1 0 0.0 0.0 97.5 4.0 - - PIII(M7) 1 0 0.0 0.0 97.5 4.0 - - PIII(M12) 1 0 0.0 0.0 97.5 4.0 - - PIII(M18) 1 0 0.0 0.0 97.5 4.0 - -

HPV-007 [M33-M38] 83 12 14.5 7.7 23.9 5.3 4.4 6.3 [M39-M44] 39 5 12.8 4.3 27.4 4.7 4.1 5.4 [M45-M50] 94 13 13.8 7.6 22.5 5.0 4.4 5.7 [M51-M56] 28 4 14.3 4.0 32.7 4.9 4.0 6.0 [M57-M62] 88 23 26.1 17.3 36.6 6.1 5.1 7.3 [M63-M68] 31 5 16.1 5.5 33.7 4.9 4.1 5.8 [M69-M74] 88 9 10.2 4.8 18.5 4.9 4.3 5.6 [M75-M76] 33 4 12.1 3.4 28.2 4.6 4.0 5.4

HPV-023 [M77-M82] 54 9 16.7 7.9 29.3 5.4 4.4 6.6 [M83-M88] 68 11 16.2 8.4 27.1 5.1 4.4 6.0 [M89-M94] 67 10 14.9 7.4 25.7 5.4 4.4 6.7 [M95-M101] 56 10 17.9 8.9 30.4 5.4 4.4 6.6

GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit

PRE = Pre-vaccination in study HPV-001 PIII(Mxx) = Post-Dose III (Month xx) in study HPV-001 [Myy-Mzz] = Post-Dose III (yy<=Month<=zz) in study HPV-007/HPV-023 Secondary Outcome Variables: Seropositivity rates and GMTs for HPV-18 antibodies measured by ELISA (ATP cohort for immunogenicity)

≥≥≥≥ 7 EL.U/mL GMT 95% CI 95% CI


PIII(M7) 178 178 100 97.9 100 3011.4 2647.1 3425.8 PIII(M12) 176 176 100 97.9 100 811.8 708.5 930.1 PIII(M18) 177 176 99.4 96.9 100 484.0 417.1 561.6

HPV-007 [M33-M38] 117 117 100 96.9 100 342.9 282.3 416.6 [M39-M44] 63 63 100 94.3 100 349.2 270.8 450.4 [M45-M50] 137 137 100 97.3 100 267.2 223.5 319.6 [M51-M56] 39 39 100 91.0 100 361.5 268.7 486.3 [M57-M62] 129 129 100 97.2 100 276.8 230.3 332.8 [M63-M68] 50 50 100 92.9 100 288.2 225.8 367.8 [M69-M74] 131 130 99.2 95.8 100 261.7 214.8 318.8 [M75-M76] 49 49 100 92.7 100 273.8 211.7 354.2

HPV-023 [M77-M82] 69 69 100 94.8 100 252.8 196.9 324.7 [M83-M88] 111 111 100 96.7 100 251.0 208.7 301.8 [M89-M94] 94 94 100 96.2 100 234.6 188.8 291.5 [M95-M101] 87 87 100 95.8 100 246.5 197.6 307.5

Placebo HPV-001 PRE 1 0 0.0 0.0 97.5 3.5 - - PIII(M7) 1 0 0.0 0.0 97.5 3.5 - - PIII(M12) 1 0 0.0 0.0 97.5 3.5 - - PIII(M18) 1 0 0.0 0.0 97.5 3.5 - -


HPV-023 [M77-M82] 54 7 13.0 5.4 24.9 4.3 3.7 5.1 [M83-M88] 68 14 20.6 11.7 32.1 5.0 4.1 6.1 [M89-M94] 67 8 11.9 5.3 22.2 4.4 3.7 5.2 [M95-M101] 56 9 16.1 7.6 28.3 4.6 3.7 5.6

GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination in study HPV-001 PIII(Mxx) = Post-Dose III (Month xx) in study HPV-001 [Myy-Mzz] = Post-Dose III (yy<=Month<=zz) in study HPV-007/HPV-023 Secondary Outcome Variables: Seropositivity rates and GMTs for HPV-16 neutralizing antibodies measured by pseudovirion-based neutralization assay (PBNA) (ATP cohort for immunogenicity; subset)

≥≥≥≥ 40 ED50 GMT 95% CI 95% CI


PIII(M7) 45 45 100 92.1 100 25926.3 18355.0 36620.6 PIII(M18) 44 44 100 92.0 100 4244.2 2989.4 6025.7

HPV-007 [M33-M38] 25 25 100 86.3 100 2788.2 1750.2 4442.0 [M39-M44] 20 19 95.0 75.1 99.9 3703.0 1568.9 8739.9 [M45-M50] 30 30 100 88.4 100 3027.6 1969.5 4654.1 [M51-M56] 13 13 100 75.3 100 7918.8 2717.8 23072.6 [M57-M62] 28 28 100 87.7 100 2914.4 1833.5 4632.3 [M63-M68] 16 16 100 79.4 100 4048.7 1869.7 8767.2 [M69-M74] 29 29 100 88.1 100 2304.1 1504.7 3528.0 [M75-M76] 16 16 100 79.4 100 4416.1 2295.7 8494.8

HPV-023 [M77-M82] 15 15 100 78.2 100 1616.1 592.7 4407.0 [M83-M88] 30 30 100 88.4 100 1990.7 1228.5 3225.8 [M89-M94] 18 18 100 81.5 100 1385.0 740.6 2590.0 [M95-M101] 27 27 100 87.2 100 1611.6 934.1 2780.3

Placebo HPV-001 PRE 12 0 0.0 0.0 26.5 20.0 20.0 20.0 PIII(M7) 12 1 8.3 0.2 38.5 25.0 15.3 40.9 PIII(M18) 11 0 0.0 0.0 28.5 20.0 20.0 20.0


HPV-023 [M77-M82] 4 0 0.0 0.0 60.2 20.0 20.0 20.0 [M83-M88] 8 0 0.0 0.0 36.9 20.0 20.0 20.0 [M89-M94] 6 0 0.0 0.0 45.9 20.0 20.0 20.0 [M95-M101] 6 0 0.0 0.0 45.9 20.0 20.0 20.0

GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination in study HPV-001 PIII(Mxx) = Post-Dose III (Month xx) in study HPV-001 [Myy-Mzz] = Post-Dose III (yy<=Month<=zz) in study HPV-007/HPV-023 Secondary Outcome Variables: Seropositivity rates and GMTs for HPV-18 neutralizing antibodies measured by pseudovirion-based neutralization assay (PBNA) (ATP cohort for immunogenicity; subset)

≥≥≥≥ 40 ED50 GMT 95% CI 95% CI


PIII(M7) 45 45 100 92.1 100 16893.0 11688.2 24415.4 PIII(M18) 44 44 100 92.0 100 1597.4 1099.8 2320.1

HPV-007 [M33-M38] 25 25 100 86.3 100 1066.7 624.4 1822.5 [M39-M44] 20 19 95.0 75.1 99.9 711.5 358.4 1412.5 [M45-M50] 30 29 96.7 82.8 99.9 736.3 444.4 1220.0 [M51-M56] 13 13 100 75.3 100 518.3 219.9 1221.9 [M57-M62] 28 28 100 87.7 100 807.7 468.2 1393.5 [M63-M68] 16 16 100 79.4 100 553.6 302.2 1014.2 [M69-M74] 29 29 100 88.1 100 811.9 502.2 1312.7 [M75-M76] 16 16 100 79.4 100 540.8 291.8 1002.4

HPV-023 [M77-M82] 15 15 100 78.2 100 845.4 361.6 1976.7 [M83-M88] 30 29 96.7 82.8 99.9 751.6 466.3 1211.5 [M89-M94] 18 18 100 81.5 100 1185.3 656.1 2141.1 [M95-M101] 27 27 100 87.2 100 578.2 352.9 947.1

Placebo HPV-001 PRE 12 0 0.0 0.0 26.5 20.0 20.0 20.0 PIII(M7) 12 0 0.0 0.0 26.5 20.0 20.0 20.0 PIII(M18) 11 0 0.0 0.0 28.5 20.0 20.0 20.0


HPV-023 [M77-M82] 4 0 0.0 0.0 60.2 20.0 20.0 20.0 [M83-M88] 8 0 0.0 0.0 36.9 20.0 20.0 20.0 [M89-M94] 6 0 0.0 0.0 45.9 20.0 20.0 20.0 [M95-M101] 6 0 0.0 0.0 45.9 20.0 20.0 20.0

GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination in study HPV-001 PIII(Mxx) = Post-Dose III (Month xx) in study HPV-001 [Myy-Mzz] = Post-Dose III (yy<=Month<=zz) in study HPV-007/HPV-023

Secondary Outcome Variable(s): Number (%) of subjects with NOCD, during the follow-up period in HPV-023 up to Year 7 (Total cohort) NOCDs HPV Group

N = 222 Placebo Group

N = 211 Subjects with any NOCD, n (%) 0 (0.0) 0 (0.0) Secondary Outcome Variable(s): Number (%) of subjects with NOCD*, during the follow-up period in HPV-023 up to Year 8 (Total cohort) NOCDs HPV Group


N = 213 Subjects with any NOCD, n (%) 5 (2.2) 2 (0.9) * NOCDs which were not unblinded at the subject level at the time of the analysis are not presented in this document Secondary Outcome Variable(s): Number (%) of subjects with NOAD, during the follow-up period in HPV-023 up to Year 7 (Total cohort) NOADs HPV Group


N = 211 Subjects with any NOAD, n (%) 0 (0.0) 0 (0.0) Secondary Outcome Variable(s): Number (%) of subjects with NOAD*, during the follow-up period in HPV-023 up to Year 8 (Total cohort) NOADs HPV Group


N = 213 Subjects with any NOAD, n (%) *2* *2* *NOADs reported in one group and none in the other group. Those cases remain blinded as the study is ongoing Secondary Outcome Variable(s): Number (%) of subjects with medically significant conditions* during the follow-up period in HPV-023 up to Year 7 (Total cohort) Most frequent medically significant condition- on-Therapy (occurring during the entire study period)

HPV Group N = 222

Placebo Group N = 211

Subjects with any Adverse Event, n (%) 18 (8.1) 13 (6.2) Gastritis 1 (0.5) 1 (0.5) Bipolar disorder 1 (0.5) 1 (0.5) Depression 2 (0.9) 1 (0.5)

Hypertension 1 (0.5) 1 (0.5) *Medically significant conditions which were not unblinded at the subject level at the time of the analysis are not presented in this document Secondary Outcome Variable(s): Number (%) of subjects with medically significant conditions* during the follow-up period in HPV-023 up to Year 8 (Total cohort) Most frequent medically significant condition- on-Therapy (occurring during the entire study period)

HPV Group N = 223

Placebo Group N = 213

Subjects with any Adverse Event, n (%) 40 (17.9) 24 (11.3) Gastritis 4 (1.8) 1 (0.5) Depression 3 (1.3) 1 (0.5) Hypertension 3 (1.3) 1 (0.5) Abortion missed 2 (0.9) 2 (0.9) Bipolar disorder 1 (0.4) 1 (0.5) Blood pressure increased 1 (0.4) 1 (0.5) Panic disorder 1 (0.4) 1 (0.5) *Medically significant conditions which were not unblinded at the subject level at the time of the analysis are not presented in this document Safety results: Number (%) of subjects with SAEs during the follow-up period in HPV-023 up to Y7 (Total cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs* HPV Group


N = 211 Subjects with any SAE(s), n (%) [n assessed by investigator as related]

4 (1.8)[0] 5 (2.4)[0]

Peptic ulcer *1*[0] *1*[0] Ovarian cancer *1*[0] *1*[0] Myelitis *1*[0] *1*[0] Abortion missed *1*[0] *1*[0] Ectopic pregnancy *1*[0] *1*[0] Pre-eclampsia *1*[0] *1*[0] Bipolar disorder *1*[0] *1*[0] Nephrolithiasis *1*[0] *1*[0] Varicose vein *1*[0] *1*[0] Fatal SAEs HPV Group


N = 211 Subjects with fatal SAE(s), n (%) [n assessed by investigator as related]

0 (0.0) [0] 0 (0.0) [0]

*SAE reported in one group and none in the other group. Those cases remain blinded as the study is ongoing Safety results: Number (%) of subjects with SAEs during the follow-up period in HPV-023 up to Y8 (Total cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs* HPV Group


N = 213 Subjects with any SAE(s), n (%) [n assessed by investigator as related]

10 (4.5)[0] 7 (3.3)[0]

Peptic ulcer *1*[0] *1*[0] Appendicitis *1*[0] *1*[0] Ovarian cancer *1*[0] *1*[0] Intracranial pressure increased *1*[0] *1*[0] Myelitis *1*[0] *1*[0] Abortion missed 2 (0.9)[0] 2 (0.9)[0] Abortion spontaneous incomplete *1*[0] *1*[0] Ectopic pregnancy *1*[0] *1*[0] Intra-ulterine death *1*[0] *1*[0] Pre-eclampsia *1*[0] *1*[0] Bipolar disorder *1*[0] *1*[0] Suicide attempt *1*[0] *1*[0]

Nephrolithiasis *1*[0] *1*[0] Varicose vein *1*[0] *1*[0] Fatal SAEs HPV Group


N = 213 Subjects with fatal SAE(s), n (%) [n assessed by investigator as related]

0 (0.0) [0] 0 (0.0) [0]

*SAE reported in one group and none in the other group. Those cases remain blinded as the study is ongoing

Conclusion: Five new cases of incident infection with HPV-16/18 were diagnosed during the two years of follow-up in study HPV-023, all in the Placebo Group. For the combined (pooled) HPV-001/007/023 analysis, the observed vaccine efficacy against HPV-16 and/or HPV-18 incident infection up to 8 years post first vaccination was 95.1%. At least one SAE was reported by 10 (4.5%) subjects of the HPV Group and 7 (3.3%) subjects of the Placebo Group, up to Year 8; none were considered by the investigators as related to the study vaccination. No fatal SAEs were reported up to Year 8. Please refer also to the publications below.

Publications: De Carvalho N et al. Immunogenicity and safety of HPV-16/18 AS04-adjuvanted vaccine up to 7.3y – Abstract presented at the 25th International Papillomavirus Conference (IPC) and Clinical Workshop. Malmö, Sweden, 8-14 May 2009. De Carvalho N et al. Sustained levels of total and neutralising antibodies and favourable long term safety with the HPC-16/18 AS04-adjuvanted vaccine (CervarixTM): follow-up to 7.3 years. Abstract presented at FIGO 2009 - 19th World Congress of Gynecology & Obstetrics. Cape Town, South Africa, 4-9 October 2009. De Carvalho N et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine (CervarixTM): follow-up to 7.3 years. Abstract presented at the 16th International Meeting of European Society of Gynaecological Oncology (ESGO). Belgrade, Serbia, 11-14 October 2009. De Carvalho N et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years. Abstract presented at the 4th Biennial Meeting of Asia Oceania Research Organisation in Genital Infections and Neoplasia (AOGIN). New Delhi, India, 26-28 March 2010. Roteli-Martins C et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine: Follow-up to 8.4 years. Abstract presented at the 28th Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID). Nice, France, 4-8 May 2010. De Carvalho N et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years. Abstract presented at 58th Annual Clinical Meeting of American College of Obstetricians and Gynecologists (ACOG). San Fransisco, USA, 15-19 May 2010. Date updated: 21 June 2010

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