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Background: Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti-HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm., Methods: Serum anti-HPV-16/18 antibodies were determined at baseline and every 12 months in baseline DNA-negative women (N = 2687 for HPV-16 and 2705 for HPV-18) by enzyme-linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6-months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7-year period. The association between the risk of type-specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models., Results: Risk of newly detected HPV-16-associated 6-month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC-US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV-16-associated incident infections (HR = 0.81 [0.56; 1.16]) and 12-month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV-18-seropositive vs -seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6-month PIs, HR = 0.31 [0.07; 1.36] for 12-month PIs, and HR = 0.61 [0.23; 1.61] for ASC-US+)., Conclusions: Naturally acquired anti-HPV-16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15- to 25-year-old women., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This study assessed long-term immunogenicity and safety following 3 doses of AS04-adjuvanted human papillomavirus (HPV)-16/18 L1 virus-like particle (VLP) vaccine in females 10-14 years old. Girls included in the immunogenicity subset in the primary controlled, observer-blinded, randomized study (NCT00196924) who received 3 doses were invited for a 10-year follow-up (NCT00316706 and NCT00877877). Serum antibody responses against HPV-16/18 (vaccine types) and HPV-31/45 (non-vaccine types) were measured by enzyme-linked immunosorbent assay (ELISA) using type-specific VLP as coating antigens. Serious adverse events (SAEs) and pregnancy information were recorded. At Month (M) 120, all subjects (N = 418, according-to-protocol immunogenicity cohort) were seropositive for anti-HPV-16/18 antibodies. Geometric mean titers (GMTs) were 1589.9 ELISA Units [EU]/mL (95% confidence interval [CI]: 1459.8-1731.6) for anti-HPV-16 and 597.2 EU/mL (95% CI: 541.7-658.5) for anti-HPV-18 in subjects seronegative at baseline for the type analyzed. Post hoc mathematical modeling predicted a durability ≥50 years for anti-HPV-16 and anti-HPV-18. For the non-vaccine humoral type response, all initially seronegative subjects had seroconverted at M7, with anti-HPV-31 GMT of 2030.5 EU/mL (95% CI: 1766.2-2334.4) and anti-HPV-45 GMT of 2300.8 EU/mL (95% CI: 2036.8-2599.0). At M120, 87.7% and 85.1% remained seropositive for anti-HPV-31 with GMT of 242.9 EU/mL (95% CI: 201.4-293.0) and anti-HPV-45 with GMT of 204.7 EU/mL (95% CI: 170.0-246.6). During the 10-year follow-up, no SAEs or abnormal pregnancy outcomes were causally related to vaccination. Three doses of the AS04-HPV-16/18 vaccine induced high and sustained antibody response against HPV-16,18,31 and 45 in girls aged 10-14 years during the 10-year follow-up, with an acceptable long-term safety profile.

Objective: Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+)., Methods: We report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials' end., Results: During the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88)., Conclusions: Ten years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects., Trial Registration Number: NCT01393470., Competing Interests: Competing interests: DA, ML, JP and JD have received grants from GSK group of companies and/or Merck & Co. Inc. through their employers (DA, Family Federation Finland; ML; University of Tampere; JP and PN University of Helsinki; JD and ML, Karolinska Institute) for HPV vaccination studies. GD was and FS is employee of GSK group of companies. FS has received shares and stock options from the GSK group of companies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We evaluated the efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in preventing HPV-related disease after surgery for cervical lesions in a post-hoc analysis of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681). Healthy women aged 15-25 years were randomized (1:1) to receive vaccine or control at months 0, 1 and 6 and followed for 4 years. Women were enrolled regardless of their baseline HPV DNA status, HPV-16/18 serostatus, or cytology, but excluded if they had previous or planned colposcopy. The primary and secondary endpoints of PATRICIA have been reported previously; the present post-hoc analysis evaluated efficacy in a subset of women who underwent an excisional procedure for cervical lesions after vaccination. The main outcome was the incidence of subsequent HPV-related cervical intraepithelial neoplasia grade 2 or greater (CIN2+) 60 days or more post-surgery. Other outcomes included the incidence of HPV-related CIN1+, and vulvar or vaginal intraepithelial neoplasia (VIN/VaIN) 60 days or more post-surgery. Of the total vaccinated cohort of 18,644 women (vaccine = 9,319; control = 9,325), 454 (vaccine = 190, control = 264) underwent an excisional procedure during the trial. Efficacy 60 days or more post-surgery for a first lesion, irrespective of HPV DNA results, was 88.2% (95% CI: 14.8, 99.7) against CIN2+ and 42.6% (-21.1, 74.1) against CIN1+. No VIN was reported and one woman in each group had VaIN2+ 60 days or more post-surgery. Women who undergo surgical therapy for cervical lesions after vaccination with the HPV-16/18 vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent CIN2+., (© 2016 UICC.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

High-risk human papillomaviruses (hrHPV) cause anogenital and oropharyngeal cancers. HPV-16/18 virus-like particle vaccine formulated with an AS04 adjuvant is very efficacious against hrHPV associated precancers but the herd effects of different vaccination scenarios are not known. Our cluster randomized trial (NCT00534638) assesses the overall and herd effects of vaccinating girls vs. girls and boys. In two school-years (2007-2008 and 2008-2009) we invited 80,272 1992-1995 born early adolescents to a CRT in 33 communities a priori stratified by low, intermediate and high HPV-16/18 seroprevalence. In 11 Arm A communities 90% of participating girls and boys were assigned to receive HPV-16/18 vaccine, in 11 Arm B communities 90% of girls were assigned to receive HPV-16/18 vaccine - boys were assigned to receive hepatitis B-virus (HBV) vaccine, and in 11 Arm C communities all were assigned to receive HBV-vaccine. Prevalence of HPV in vaccinated and unvaccinated girls is studied at age 18.5 years. Recruitment resulted in equal enrolment of four birth cohorts (born 1992-1995) comprising altogether 32,175 (40% response) early adolescents: 20,514 girls (50.5-53.0% response by arm) and 11,661 boys (21.9-31.6%% response by arm). At the age of 15 years, 79.3% of the vaccinees completed a questionnaire. Among them >98% were living at, and during the week-ends 1.3-1.6% stayed outside, the study site communities. Smoking habit and alcohol consumption were similar in the different trial arms, also mean-age of menarche (12.4 years) and 1st ejaculation (12.6 years), and sexual behaviour (among those <25%, who had had sexual debut) did not differ by arm: mean-age at the sexual debut 14.3 and 14.4 in girls and boys, and proportions of those with multiple (≥5) life-time sexual partners (6.5-7.5%) at the age of 15 years. Uniform residential, life-style and sexual behaviour characteristics indicate successful randomization/enrolment of the CRT. Our CRT will verify modelled predictions on up to 31% herd effect of vaccinating both girls and boys with moderate vaccine coverage - quantifying overall effectiveness of different strategies which will soon guide how to implement HPV vaccination., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women., Methods: In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047., Findings: The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination., Interpretation: In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45., Funding: GlaxoSmithKline Biologicals SA., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The HPV types 16/18-AS04-adjuvanted cervical cancer vaccine, Cervarix(®) (HPV-16/18-vaccine, GlaxoSmithKline, Belgium) was first approved in 2007 and is licensed in 134 countries for the prevention of persistent infection, premalignant cervical lesions and cervical cancer caused by oncogenic HPV. Benefit-risk status requires continual re-evaluation as vaccine uptake increases, as the epidemiology of the disease evolves and as new information becomes available. This paper provides an example of benefit-risk considerations and risk-management planning. Evaluation of the benefit-risk of HPV-16/18-vaccine post-licensure includes studies with a range of designs in many countries and in collaboration with national public agencies and regulatory authorities. The strategy to assess benefit versus risk will continue to evolve and adapt to the changing HPV-16/18-vaccine market.

Background: We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681)., Methods: Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15-25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463])., Results: High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242-794), 204 (95% CI, 129-480), and 480 (95% CI, 250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively., Conclusions: Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent., Methods: Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations., Results: In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74., Conclusions: The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry., (Copyright © 2011 UICC.)

Purpose: This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone., Methods: Healthy girls (9-15 years) were age-stratified (9, 10-12, and 13-15 years) and randomized to receive HPV (n = 270), HAB (n = 271), or HPV + HAB (n = 272). Vaccines were administered at months 0, 1, and 6. Immunogenicity was evaluated at months 0 and 7., Results: The hepatitis A immune response was noninferior for HPV + HAB, versus HAB, for seroconversion rates (100% in each group) and geometric mean antibody titers (GMTs) (95% CI) (4,504.2 [3,993.0-5,080.8] and 5,288.4 [4,713.3-5,933.7] mIU/mL, respectively). The hepatitis B immune response was noninferior for HPV + HAB, versus HAB, for anti-HBs seroprotection rates (98.3% and 100%); GMTs were 3,136.5 [2,436.0-4,038.4] and 5,646.5 [4,481.3-7,114.6] mIU/mL, respectively. The HPV-16/18 immune response was noninferior for HPV + HAB, versus HPV, for seroconversion rates (99.6% and 100% for both antigens) and GMTs (22,993.5 [20,093.4-26,312.0] and 26,981.9 [23,909.5-30,449.1] EL.U/mL for HPV-16; 8,671.2 [7,651.7-9,826.6] and 11,182.7 [9,924.8-12,600.1] EL.U/mL for HPV-18, respectively). No subject withdrew because of adverse events. No vaccine-related serious adverse events were reported. Immune responses and reactogenicity were similar in girls aged 9 years compared with the entire study population., Conclusions: Results support coadministration of HPV-16/18 vaccine with HAB vaccine in girls aged 9-15 years. The HPV-16/18 vaccine was immunogenic and generally well tolerated in 9-year-old girls., (Copyright © 2012 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults)., Methods: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681., Findings: Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8)., Interpretation: Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women., Funding: GlaxoSmithKline Biologicals., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults)., Methods: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681., Findings: Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination., Interpretation: PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer., Funding: GlaxoSmithKline Biologicals., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Immunization of girls against oncogenic human papillomavirus (HPV) types before sexual debut is important for cervical cancer prevention. This phase III blinded, randomized, controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine., Methods: Girls (mean age 12 years) in 12 countries received the HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine (N = 1,035) or hepatitis A virus vaccine as control (N = 1,032) at 0, 1, and 6 months. The primary objective was to compare the occurrence of serious adverse events (SAEs) between groups. HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination., Results: Up to study month 7, 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs. The difference in SAE incidence between groups was .20% (95% CI, -.78, 1.20). No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal. The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control. The incidence of unsolicited symptoms, new onset of chronic diseases, and medically significant conditions was similar between groups. All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies, respectively, in initially seronegative girls., Conclusions: The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females, the primary target of organized vaccination programs., (Copyright 2010 Society for Adolescent Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Strong and sustained HPV-16 and -18 antibody responses have been observed in previously unexposed women aged 15-25 years vaccinated with the AS04-adjuvanted HPV-16/18 L1 virus-like particle vaccine. While awaiting the extended results of ongoing trials, our objective was to predict the long-term persistence of anti-HPV-16/18 antibodies in vaccinees by applying three statistical models using immunogenicity data from vaccinated women with serum samples collected up to 6.4 years after first vaccination. Two different data lock-points (up to 5.5 years and up to 6.4 years) were used to assess the robustness of the models., Methods: Three statistical models were applied to estimate the long-term persistence of anti-HPV-16/18 antibodies in 393 women vaccinated with the AS04-adjuvanted HPV-16/18 vaccine. Individual antibody levels for each study participant at each timepoint up to 6.4 years were input to previously published power-law and modified power-law models. The power-law model estimates antibody decay over time. The modified power-law model takes into account both antibody persistence over time and immune memory. A third model, the piece-wise model, fits the data based on three different non-overlapping intervals (between Months 7 and 12, Months 12 and 21, and over 21 months), corresponding to the observed decay of vaccine-induced antibodies., Results: HPV-16 and -18 antibodies peaked at Month 7 and gradually plateaued at Months 18-24 and remained stable through 6.4 years. Mean antibody levels at the last timepoint were several fold higher than those associated with natural infection. All three models predict that HPV-16 and -18 mean antibody levels will remain well above those associated with natural infection for at least 20 years, when using data from 5.5 as well as 6.4 years' follow-up. Predictions are similar for the modified power-law model and improve with longer follow-up for both the power-law and the piece-wise models., Conclusions: Vaccination with the AS04-adjuvanted HPV-16/18 vaccine is predicted to provide long-term persistence for both HPV-16 and -18 antibodies, independent of the statistical model applied. Model predictions are based on conservative mathematical assumptions. Since the input of longer term data of up to 6.4 years showed an improved profile compared with that for data up to 5.5 years, the predictions of antibody persistence based on population means are conservative when predicting that antibody levels will remain well above levels induced by natural infection for 20 years.

Background: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis., Methods: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681., Findings: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC., Interpretation: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes., Funding: GlaxoSmithKline Biologicals.

Purpose: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix) has been shown to be well-tolerated and immunogenic in females aged 10 to 55 years, and up to 100% effective for the prevention of HPV-16/18 infection and associated precancerous cervical lesions in females aged 15 to 25 years. This study is the first to evaluate the immunogenicity and safety of the vaccine in males., Methods: Healthy males aged 10 to 18 years were randomized (2:1 ratio) to receive HPV-16/18 AS04-adjuvanted vaccine (n = 181) or hepatitis B virus (HBV) control vaccine (n = 89) at 0, 1, and 6 months, and were followed for 7 months., Results: All initially seronegative subjects in the HPV-16/18 group seroconverted for HPV-16 and 18 (ELISA) at month 2. At month 7, all subjects were seropositive, and the HPV-16 and -18 antibody levels were, respectively, four- and twofold higher than at month 2. The anti-HPV-16 and -18 antibody responses for males aged 10 to 18 years and 10 to 14 years, respectively, were higher than those reported for females aged 15 to 25 years and 10 to 14 years, respectively, in a previous study. The reactogenicity profiles of the HPV-16/18 AS04 and HBV vaccines were similar, except that pain and swelling at the injection site were more common in the HPV-16/18 group. However, vaccine-related symptoms did not affect compliance with the three-dose course, which was equally high (97%) in both groups., Conclusions: The HPV-16/18 AS04-adjuvanted vaccine is immunogenic and well tolerated in boys aged 10 to 18 years. However, further data on the potential public health benefits of vaccination of boys are required before any recommendations can be made.

Context: Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy., Objective: To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV., Design and Setting: Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica., Participants: A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results., Intervention: Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months., Main Outcome Measures: Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups., Results: There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking., Conclusion: In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections., Trial Registration: clinicaltrials.gov Identifier: NCT00128661.

Background: The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women., Methods: 18,644 women aged 15-25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint--vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18--was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681., Findings: Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14.8 (SD 4.9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90.4% (97.9% CI 53.4-99.3; p<0.0001). No clinically meaningful differences were noted in safety outcomes between the study groups., Interpretation: The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.

Human papillomaviruses (HPVs, most notably types 16 and 18) cause cervical carcinoma, the second most common cancer among women. Vaccination of adolescents against HPV16/18 might prevent large proportion of cervical and other anogenital cancers. However, because of ethical reasons this cannot be proven by clinical studies. To determine the long-term vaccine efficacy (VE) of HPV16/18 virus-like-particle (VLP) vaccine against cervical carcinoma in situ (CIS+) and invasive cervical carcinoma, the following three population-based cohorts of adolescent women have been enrolled: (1) women vaccinated with the HPV vaccine; (2) women vaccinated with hepatitis A control vaccine; and (3) unvaccinated control women. These cohorts will be passively followed for cumulative incidence of CIS+ endpoints by population-based cancer registry. Overall 24,046 16- to 17-year-old adolescent women from 18 cities in Finland were invited between May 2004 and June 2005 to participate in a phase III trial with bivalent HPV16/18 VLP vaccine. A total of 58,996 18- to 19-year-old women were invited in May 2005 to participate as unvaccinated controls. Women who reported their willingness to participate in an HPV vaccination trial had they been 1-2 years younger were eligible. Cumulative incidence (CI) of CIS+ in our cohorts over 15 years is approximately 0.45%. VE of 70% against CIS+ with 80% power requires 3357-3189 HPV16/18 vaccine recipients, 3357-3189 other vaccine recipients, and 6714-9567 unvaccinated controls. We have now enrolled 2404 HPV16/18 vaccine recipients, 2404 hepatitis A-vaccine recipients, and 5130 unvaccinated controls. This enrolment in addition to our earlier enrolment in another phase III trial guarantees enough power so that by 2020 we can ultimately provide data on the efficacy of HPV16/18 vaccination against CIS+.