Efficacy, immunogenicity and safety of the AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years: End-of-study results from a phase II/III, randomised, controlled trial.

BACKGROUND: Cervical cancer is a major public health concern in China. We report the end-of-study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04-human papillomavirus (HPV)-16/18 vaccine in Chinese women aged 18-25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported. METHODS: Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of AS04-HPV-16/18 vaccine or Al(OH)3 (control) at Months 0-1-6. Vaccine efficacy against HPV-16/18 infection and cervical intraepithelial neoplasia (CIN), cross-protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according-to-protocol efficacy (ATP-E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC-E; vaccine N = 2987; control N = 2985) and TVC-naïve (vaccine N = 1660; control N = 1587). RESULTS: In initially HPV-16/18 seronegative/DNA-negative women, vaccine efficacy against HPV-16/18-associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP-E, 88.7% (95% CI: 18.5, 99.7) in the TVC-E, and 100% (95% CI: 17.9, 100) in the TVC-naïve. Cross-protective efficacy against incident infection with HPV-31, HPV-33 and HPV-45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP-E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and anti-HPV-18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group. CONCLUSIONS: This is the first large-scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV-16/18-associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China. TRIAL REGISTRATION: NCT00779766.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9-14 years: Results to month 36 from a randomized trial.

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9-14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9-14 years. CLINICAL TRIAL REGISTRATION: NCT0146235.

Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15-55 years of age.

Women remain at risk of human papillomavirus (HPV) infection for most of their lives. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. We investigated the 10-year immune response and long-term safety profile of the HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18 vaccine) in females aged between 15 and 55 years at first vaccination. Females who received primary vaccination with three doses of AS04-HPV-16/18 vaccine in the primary phase-III study (NCT00196937) were invited to attend annual evaluations for long-term immunogenicity and safety. Anti-HPV-16/18 antibodies in serum and cervico-vaginal secretions (CVS) were measured using enzyme-linked immunosorbent assay (ELISA). Serious adverse events (SAEs) were recorded throughout the follow-up period. Seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. It was found that 99.2% of 15-25-year olds remained seropositive for anti-HPV-18 compared to 93.7% and 83.8% of 26-45-year olds and 45-55-year olds, respectively. Geometric mean titers (GMT) remained above natural infection levels in all age groups. Anti-HPV-16 and anti-HPV-18 titers were at least 5.3-fold and 3.1-fold higher than titers observed after natural infection, respectively, and were predicted to persist above natural infection levels for ≥30 years in all age groups. At Year 10, anti-HPV-16/18 antibody titers in subjects aged 15-25 years remained above plateau levels observed in previous studies. Correlation coefficients for antibody titers in serum and CVS were 0.64 (anti-HPV-16) and 0.38 (anti-HPV-18). This study concluded that vaccinated females aged 15-55 years elicited sustained immunogenicity with an acceptable safety profile up to 10 years after primary vaccination, suggesting long-term protection against HPV.

Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial.

We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of <2 years, and immunogenicity until 7 months post-dose 1. Here, we report efficacy and safety results from an event-triggered analysis with ~3 years longer follow-up, and immunogenicity until M24. Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV-16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18-associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6-month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV-16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile.

Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study.

BACKGROUND: Although the risk of human papillomavirus (HPV) infection is greatest in young women, women older than 25 years remain at risk. We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up. METHODS: In this phase 3, double-blind, randomised controlled trial, healthy women older than 25 years were enrolled (age stratified: 26-35 years, 36-45 years, and ≥46 years). Up to 15% in each age stratum had a history of HPV infection or disease. Women were randomly assigned (1:1) to receive HPV 16/18 vaccine or aluminium hydroxide control, with an internet-based system. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater (CIN1+) associated with HPV 16/18. We did analyses in the according-to-protocol cohort for efficacy and total vaccinated cohort. Data for the combined primary endpoint in the according-to-protocol cohort for efficacy were considered significant when the lower limit of the 96·2% CI around the point estimate was greater than 30%. For all other endpoints and cohorts, data were considered significant when the lower limit of the 96·2% CI was greater than 0%. This study is registered with ClinicalTrials.gov, number NCT00294047. FINDINGS: The first participant was enrolled on Feb 16, 2006, and the last study visit took place on Jan 29, 2014. 4407 women were in the according-to-protocol cohort for efficacy (n=2209 vaccine, n=2198 control) and 5747 women in the total vaccinated cohort (n=2877 vaccine, n=2870 control). At month 84, in women seronegative for the corresponding HPV type in the according-to-protocol cohort for efficacy, vaccine efficacy against 6-month persistent infection or CIN1+ associated with HPV 16/18 was significant in all age groups combined (90·5%, 96·2% CI 78·6-96·5). Vaccine efficacy against HPV 16/18-related cytological abnormalities (atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) and CIN1+ was also significant. We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 (65·8%, 96·2% CI 24·9-85·8) and HPV 45 (70·7%, 96·2% CI 34·2-88·4). In the total vaccinated cohort, vaccine efficacy against CIN1+ irrespective of HPV was significant (22·9%, 96·2% CI 4·8-37·7). Serious adverse events related to vaccination occurred in five (0·2%) of 2877 women in the vaccine group and eight (0·3%) of 2870 women in the control group. INTERPRETATION: In women older than 25 years, the HPV 16/18 vaccine continues to protect against infections, cytological abnormalities, and lesions associated with HPV 16/18 and CIN1+ irrespective of HPV type, and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up. FUNDING: GlaxoSmithKline Biologicals SA.

Randomized Open Trial Comparing 2-Dose Regimens of the Human Papillomavirus 16/18 AS04-Adjuvanted Vaccine in Girls Aged 9-14 Years Versus a 3-Dose Regimen in Women Aged 15-25 Years.

BACKGROUND: This randomized, open trial compared regimens including 2 doses (2D) of human papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine in girls aged 9-14 years with one including 3 doses (3D) in women aged 15-25 years. METHODS: Girls aged 9-14 years were randomized to receive 2D at months 0 and 6 (M0,6; (n = 550) or months 0 and 12 (M0,12; n = 415), and women aged 15-25 years received 3D at months 0, 1, and 6 (n = 482). End points included noninferiority of HPV-16/18 antibodies by enzyme-linked immunosorbent assay for 2D (M0,6) versus 3D (primary), 2D (M0,12) versus 3D, and 2D (M0,6) versus 2D (M0,12); neutralizing antibodies; cell-mediated immunity; reactogenicity; and safety. Limits of noninferiority were predefined as <5% difference in seroconversion rate and <2-fold difference in geometric mean antibody titer ratio. RESULTS: One month after the last dose, both 2D regimens in girls aged 9-14 years were noninferior to 3D in women aged 15-25 years and 2D (M0,12) was noninferior to 2D (M0,6). Geometric mean antibody titer ratios (3D/2D) for HPV-16 and HPV-18 were 1.09 (95% confidence interval, .97-1.22) and 0.85 (.76-.95) for 2D (M0,6) versus 3D and 0.89 (.79-1.01) and 0.75 (.67-.85) for 2D (M0,12) versus 3D. The safety profile was clinically acceptable in all groups. CONCLUSIONS: The 2D regimens for the HPV-16/18 AS04-adjuvanted vaccine in girls aged 9-14 years (M0,6 or M0,12) elicited HPV-16/18 immune responses that were noninferior to 3D in women aged 15-25 years. CLINICAL TRIALS REGISTRATION: NCT01381575.

Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a two-dose schedule in adolescent girls: Five-year clinical data and modeling predictions from a randomized study.

In this randomized, partially-blind study ( clinicaltrials.gov ; NCT00541970), the licensed formulation of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (20 µg each of HPV-16/18 antigens) was found highly immunogenic up to 4 y after first vaccination, whether administered as a 2-dose (2D) schedule in girls 9-14 y or 3-dose (3D) schedule in women 15-25 y. This end-of-study analysis extends immunogenicity and safety data until Month (M) 60, and presents antibody persistence predictions estimated by piecewise and modified power law models. Healthy females (age stratified: 9-14, 15-19, 20-25 y) were randomized to receive 2D at M0,6 (N = 240 ) or 3D at M0,1,6 (N = 239). Here, results are reported for girls 9-14 y (2D) and women 15-25 y (3D). Seropositivity rates, geometric mean titers (by enzyme-linked immunosorbent assay) and geometric mean titer ratios (GMRs; 3D/2D; post-hoc exploratory analysis) were calculated. All subjects seronegative pre-vaccination in the according-to-protocol immunogenicity cohort were seropositive for anti-HPV-16 and -18 at M60. Antibody responses elicited by the 2D and 3D schedules were comparable at M60, with GMRs close to 1 (anti-HPV-16: 1.13 [95% confidence interval: 0.82-1.54]; anti-HPV-18: 1.06 [0.74-1.51]). Statistical modeling predicted that in 95% of subjects, antibodies induced by 2D and 3D schedules could persist above natural infection levels for ≥ 21 y post-vaccination. The vaccine had a clinically acceptable safety profile in both groups. In conclusion, a 2D M0,6 schedule of the HPV-16/18 AS04-adjuvanted vaccine was immunogenic for up to 5 y in 9-14 y-old girls. Statistical modeling predicted that 2D-induced antibodies could persist for longer than 20 y.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9-14 years: Results to month 12 from a randomized trial.

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9-14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49-1.91] for anti-HPV-16 and 4.52 [3.97-5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54-1.93] for anti-HPV-16 and 3.22 [2.82-3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9-14 years).

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women.

In this open, extended follow-up study (NCT00929526, Clinicaltrials.gov), we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy, immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20-25 years. In the initial randomized, double-blind study (NCT00316693), 1040 women received the study vaccine or hepatitis A control vaccine; 752 women were included in the follow-up study. In women from the according-to-protocol efficacy cohort (ATP-E), who were initially seronegative for the HPV type analyzed, no cervical intraepithelial neoplasia (CIN) grade 1 or greater (CIN1+) cases associated with HPV-16/18 were reported in the HPV group, while in the control group, 5 cases were identified in extended follow-up analyses (vaccine efficacy [VE] 100% [95% CI: -3.7-100]) and 8 cases in combined initial and follow-up studies analyses (VE 100% [42.2-100]). In the ATP-E, VE against CIN1+ and CIN2+ associated with high-risk HPV types reached 66.4% (21.6-87.1) and 83.0% (22.1-98.2) in extended follow-up analyses, and 63.4% (28.8-82.3) and 77.3% (30.4-94.4) in analyses of combined studies, respectively. During the 4-year period, protection against CIN1+ and CIN2+, irrespective of the HPV type, was 56.7% (32.8-72.6) and 54.9% (20.5-75.3) in women receiving ≥1 vaccine dose, regardless of baseline serostatus (total vaccinated cohort [TVC]) and 61.0% (11.8-84.2) and 73.9% (1.1-95.3) in women naïve to HPV infection at baseline (TVC-naïve), respectively. The high VE observed in Japanese women, accompanied by a sustained immune response and a clinically acceptable safety profile, support findings of large, international trials.

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years.

Immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in healthy Chinese females aged 9-45 years in 2 phase IIIB, randomized, controlled trials. Girls aged 9-17 years (ClinicalTrials.gov, NCT00996125) received vaccine (n = 374) or control (n = 376) and women aged 26-45 years (NCT01277042) received vaccine (n = 606) or control (n = 606) at months 0, 1, and 6. The primary objective was to show non-inferiority of anti-HPV-16 and -18 immune responses in initially seronegative subjects at month 7, compared with Chinese women aged 18-25 years enrolled in a separate phase II/III trial (NCT00779766). Secondary objectives were to describe the anti-HPV-16 and -18 immune response, reactogenicity and safety. At month 7, immune responses were non-inferior for girls (9-17 years) vs. young women (18-25 years): the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio (women/girls) was below the limit of 2 for both anti-HPV-16 (0.37 [95% CI: 0.32, 0.43]) and anti-HPV-18 (0.42 [0.36, 0.49]). Immune responses at month 7 were also non-inferior for 26-45 year-old women vs. 18-25 year-old women: the upper limit of the 95% CI for the difference in seroconversion (18-25 minus 26-45) was below the limit of 5% for both anti-HPV-16 (0.00% [-1.53, 1.10]) and anti-HPV-18 (0.21% [-1.36, 1.68]). GMTs were 2- to 3-fold higher in girls (9-17 years) as compared with young women (18-25 years). The HPV-16/18 AS04-adjuvanted vaccine had an acceptable safety profile when administered to healthy Chinese females aged 9-45 years.

Long-term immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in 10- to 14-year-old girls: open 6-year follow-up of an initial observer-blinded, randomized trial.

BACKGROUND: Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine were evaluated up to 6 years postvaccination (month 72) in preteen/adolescent girls. METHODS: Participants, who had received 3 HPV-16/18 AS04-adjuvanted vaccine doses at 10-14 years of age in an initial controlled, observer-blinded, randomized study (NCT00196924) and participated in the open 3-year follow-up (NCT00316706), were invited to continue the follow-up for up to 10 years postvaccination (NCT00877877). Anti-HPV-16 and -18 antibody titers were measured by enzyme-linked immunosorbent assays at yearly visits and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) and pregnancy information were recorded. RESULTS: In the according-to-protocol immunogenicity cohort, all participants (N = 505) with data available remained seropositive for anti-HPV-16 and -18 antibodies at month 72. In initially seronegative participants, anti-HPV-16 and -18 antibody geometric mean titers were 65.8- and 33.0-fold higher than those associated with natural infection (NCT00122681) and 5.0- and 2.5-fold higher than those measured at month 69-74 in a study demonstrating vaccine efficacy in women aged 15-25 years (NCT00120848). Exploratory antibody modeling, based on the 6-year data, predicted that vaccine-induced population anti-HPV-16 and -18 antibody geometric mean titers would remain above those associated with natural infection for at least 20 years postvaccination. The HPV-16/18 AS04-adjuvanted vaccine safety profile was clinically acceptable. CONCLUSIONS: In preteen/adolescent girls, the HPV-16/18 AS04-adjuvanted vaccine induced high anti-HPV-16 and -18 antibody levels up to 6 years postvaccination, which were predicted to remain above those induced by natural infection for at least 20 years.

Immune response to the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose or 3-dose schedule up to 4 years after vaccination: results from a randomized study.

This randomized, partially-blind study (ClinicalTrials.gov registration number NCT00541970) evaluated the immunogenicity and safety of 2-dose (2D) schedules of the HPV-16/18 AS04-adjuvanted vaccine. Results to month (M) 24 have been reported previously and we now report data to M48 focusing on the licensed vaccine formulation (20 µg each of HPV-16 and -18 antigens) administered at M0,6 compared with the standard 3-dose (3D) schedule (M0,1,6). Healthy females (age stratified: 9-14, 15-19, 20-25 years) were randomized to receive 2D at M0,6 (n = 240) or 3D at M0,1,6 (n = 239). In the according-to-protocol immunogenicity cohort, all initially seronegative subjects seroconverted for HPV-16 and -18 antibodies and remained seropositive up to M48. For both HPV-16 and -18, geometric mean antibody titer (GMT) ratios (3D schedule in women aged 15-25 years divided by 2D schedule in girls aged 9-14 years) at M36 and M48 were close to 1, as they were at M7 when non-inferiority was demonstrated. The kinetics of HPV-16, -18, -31, and -45 antibody responses were similar for both groups and HPV-16 and -18 GMTs were substantially higher than natural infection titers. The vaccine had a clinically acceptable safety profile in both groups. In summary, antibody responses to a 2D M0,6 schedule of the licensed vaccine formulation in girls aged 9-14 years appeared comparable to the standard 3D schedule in women aged 15-25 years up to 4 years after first vaccination. A 2D schedule could facilitate implementation of HPV vaccination programs and improve vaccine coverage and series completion rates.