Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. Prevalence of human papillomavirus infection in women in Busan, South Korea. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia: A Randomized Controlled Trial Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18. Comparison of the immunogenicity and safety of Cervarix™ and Gardasil® human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45 years Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials
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 r and omised , 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 Clinical Trials.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 BACKGROUND Although the peak incidence of human papillomavirus ( HPV ) infection occurs in most population s within 5 - 10 years of first sexual experience , all women remain at risk for acquisition of HPV infections . We tested the safety , immunogenicity , and efficacy of the quadrivalent HPV ( types 6 , 11 , 16 , 18 ) L1 virus-like-particle vaccine in women aged 24 - 45 years . METHODS Women aged 24 - 45 years with no history of genital warts or cervical disease were enrolled from community health centres , academic health centres , and primary health-care providers into an ongoing multicentre , parallel , r and omised , placebo-controlled , double-blind study . Participants were allocated by computer-generated schedule to receive quadrivalent HPV vaccine ( n=1911 ) or placebo ( n=1908 ) at day 1 , and months 2 and 6 . All study site investigators and personnel , study participants , monitors , and central laboratory personnel were blinded to treatment allocation . Co primary efficacy endpoints were 6 months ' or more duration of infection and cervical and external genital disease due to HPV 6 , 11 , 16 , 18 ; and due to HPV 16 and 18 alone . Primary efficacy analyses were done in a per- protocol population , but intention-to-treat analyses were also undertaken . This study is registered with Clinical Trials.gov , number NCT00090220 . FINDINGS 1910 women received at least one dose of vaccine and 1907 at least one dose of placebo . In the per- protocol population , efficacy against the first co primary endpoint ( disease or infection related to HPV 6 , 11 , 16 , and 18 ) was 90.5 % ( 95 % CI 73.7 - 97.5 , four of 1615 cases in the vaccine group vs 41/1607 in the placebo group ) and 83.1 % ( 50.6 - 95.8 , four of 1601 cases vs 23/1579 cases ) against the second co primary endpoint ( disease or infection related to HPV 16 and 18 alone ) . In the intention-to-treat population , efficacy against the first co primary endpoint was 30.9 % ( 95 % CI 11.1 - 46.5 , 108/1886 cases vs 154/1883 cases ) and against the second co primary endpoint was 22.6 % ( -2.9 to 41.9 , 90/1886 cases vs 115/1883 cases ) , since infection and disease were present at baseline . We recorded no vaccine-related serious adverse events . INTERPRETATION The quadrivalent HPV vaccine is efficacious in women aged 24 - 45 years not infected with the relevant HPV types at enrolment . FUNDING Merck ( USA ) Background : Previous analyses from a r and omised trial in women aged 24–45 years have shown the quadrivalent human papillomavirus ( qHPV ) vaccine to be efficacious in the prevention of infection , cervical intraepithelial neoplasia ( CIN ) , and external genital lesions ( EGLs ) related to HPV 6/11/16/18 . In this report , we present end-of- study efficacy , safety , and immunogenicity data with a median follow-up time of 4.0 years . Methods : We enrolled 3819 24–45-year-old women with no history of cervical disease or genital warts in the past 5 years . Women received quadrivalent vaccine or placebo at day 1 , and at months 2 and 6 . Ascertainment of CIN/EGL was accomplished through Pap testing , genital inspection , and cervicovaginal sampling ( every 6 months ) . The main analysis was conducted in a per- protocol efficacy population ( that received three doses , was naive to the relevant HPV types at day 1 , and remained free of infection through month 7 ) . Efficacy was also estimated in other naive and non-naive population s. Results : Vaccine efficacy against the combined incidence of persistent infection , CIN/EGL related to HPV6/11/16/18 in the per- protocol population was 88.7 % ( 95 % CI : 78.1 , 94.8 ) . Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9 % ( 95 % CI : 4.3 , 90.6 ) . At month 48 , 91.5 , 92.0 , 97.4 , and 47.9 % of vaccinated women were seropositive to HPV 6/11/16/18 , respectively . No serious vaccine-related adverse experiences were reported . Conclusions : The qHPV vaccine demonstrated high efficacy , immunogenicity , and acceptable safety in women aged 24–45 years , regardless of previous exposure to HPV vaccine type BACKGROUND A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus ( HPV ) types 6 , 11 , 16 , and 18 . METHODS In this r and omized , placebo-controlled , double-blind trial involving 5455 women between the ages of 16 and 24 years , we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1 , month 2 , and month 6 . The co primary composite end points were the incidence of genital warts , vulvar or vaginal intraepithelial neoplasia , or cancer and the incidence of cervical intraepithelial neoplasia , adenocarcinoma in situ , or cancer associated with HPV type 6 , 11 , 16 , or 18 . Data for the primary analysis were collected for a per- protocol susceptible population of women who had no virologic evidence of HPV type 6 , 11 , 16 , or 18 through 1 month after administration of the third dose . RESULTS The women were followed for an average of 3 years after administration of the first dose . In the per- protocol population , those followed for vulvar , vaginal , or perianal disease included 2261 women ( 83 % ) in the vaccine group and 2279 ( 83 % ) in the placebo group . Those followed for cervical disease included 2241 women ( 82 % ) in the vaccine group and 2258 ( 83 % ) in the placebo group . Vaccine efficacy was 100 % for each of the co primary end points . In an intention-to-treat analysis , including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV , vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34 % ( 95 % confidence interval [ CI ] , 15 to 49 ) , and the rate of cervical lesions regardless of the causal HPV type by 20 % ( 95 % CI , 8 to 31 ) . CONCLUSIONS The quadrivalent vaccine significantly reduced the incidence of  HPV-associated anogenital diseases in young women . ( Clinical Trials.gov number , NCT00092521 [ Clinical Trials.gov ] . ) To investigate the prevalence of and the risk factors for human papillomavirus ( HPV ) infection in South Korea , we interviewed and examined a r and omly selected sample of 863 sexually active women ( age range = 20 - 74 years , median 44 ) and 103 self-reported virgins from Busan . The presence of DNA of 34 different HPV types in cervical exfoliated cells was tested among sexually active women by means of a PCR-based assay .  IgG antibodies against L1 virus-like particles ( anti-VLPs ) of HPV types 16 , 18 , 31 , 33 and 58 were also evaluated by means of ELISA . The overall prevalence of HPV DNA was 10.4 % ( 95 % confidence interval , CI : 8.5 - 12.7 % ) . The most often found HPV DNA types were HPV 70 , HPV 16 and HPV 33 ; 19.8 % ( 95 % CI : 17.2 - 22.0 ) of sexually active women had antibodies against one or more HPV types . The most common anti-VLPs were against HPV 18 , 31 and 16 . Prevalences st and ardized by age on the basis of the world st and ard population were 13.0 % for HPV DNA and 17.1 % for anti-VLPs . The concordance between the 2 HPV markers at an individual level was modest , but the risk factors for detection of HPV DNA and anti-VLPs were similar : number of lifetime sexual partners ( odds ratio , OR for > /= 4 vs. 1 = 3.5 and 5.4 , respectively ) , seropositivity for herpes simplex virus-2 antibodies ( OR = 2.6 and 2.5 , respectively ) and being single or divorced . HPV DNA , but not anti-VLPs , were elevated among women whose husb and s were thought by their wives to have extra-marital affairs and those who had undergone vasectomy . Among 103 virgins , 4.9 % had anti-VLPs ( 1/73 among those aged 24 years or less ) Objectives To determine the effect of human papillomavirus ( HPV ) quadrivalent vaccine on the risk of developing subsequent disease after an excisional procedure for cervical intraepithelial neoplasia or diagnosis of genital warts , vulvar intraepithelial neoplasia , or vaginal intraepithelial neoplasia . Design Retrospective analysis of data from two international , double blind , placebo controlled , r and omised efficacy trials of quadrivalent HPV vaccine ( protocol 013 ( FUTURE I ) and protocol 015 ( FUTURE II ) ) . Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world . Participants Among 17 622 women aged 15–26 years who underwent 1:1 r and omisation to vaccine or placebo , 2054 received cervical surgery or were diagnosed with genital warts , vulvar intraepithelial neoplasia , or vaginal intraepithelial neoplasia . Intervention Three doses of quadrivalent HPV vaccine or placebo at day 1 , month 2 , and month 6 . Main outcome measures Incidence of HPV related disease from 60 days after treatment or diagnosis , expressed as the number of women with an end point per 100 person years at risk . Results A total of 587 vaccine and 763 placebo recipients underwent cervical surgery . The incidence of any subsequent HPV related disease was 6.6 and 12.2 in vaccine and placebo recipients respectively ( 46.2 % reduction ( 95 % confidence interval 22.5 % to 63.2 % ) with vaccination ) . Vaccination was associated with a significant reduction in risk of any subsequent high grade disease of the cervix by 64.9 % ( 20.1 % to 86.3 % ) . A total of 229 vaccine recipients and 475 placebo recipients were diagnosed with genital warts , vulvar intraepithelial neoplasia , or vaginal intraepithelial neoplasia , and the incidence of any subsequent HPV related disease was 20.1 and 31.0 in vaccine and placebo recipients respectively ( 35.2 % reduction ( 13.8 % to 51.8 % ) ) . Conclusions Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease , including high grade disease . Trial registration s NCT00092521 and Human papillomavirus ( HPV ) infection causes cervical cancer and genital warts . Young women ( 1106 ) were r and omized to receive one of three formulations of a quadrivalent HPV ( Types 6/11/16/18 ) L1 virus-like particle ( VLP ) vaccine or one of two placebo formulations . The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects . All three formulations were highly immunogenic . At Month 2 ( postdose 1 ) , among women with vaccine-type antibodies at baseline , vaccine-induced anti-HPV responses were approximately 12- to 26-fold higher than those observed in baseline-naïve women , suggesting an anamnestic response . Following an initial , similar sized decline , anti-HPV responses plateaued and remained stable through end-of- study ( 3.0 years ) . No vaccine-related serious adverse experiences were reported OBJECTIVE : Human papillomavirus ( HPV ) virus-like particle ( VLP ) vaccines have demonstrated effectiveness in preventing persistent HPV infections . Whether protection lasts longer than 18 months and , thus , impacts rates of cervical intraepithelial neoplasia ( CIN ) 2–3 has not yet been established . We present results from an HPV16 L1 VLP vaccine trial through 48 months . METHODS : A total of 2,391 women , aged 16–23 years , participated in a r and omized , double-blind , placebo-controlled trial . Either 40 & mgr;g HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1 , month 2 , and month 6 . Genital sample s for HPV16 DNA and Pap tests were obtained at day 1 , month 7 , and then 6-monthly through month 48 . Colposcopy and cervical biopsies were performed if clinical ly indicated and at study exit . Serum HPV16 antibody titer was measured by radioimmunoassay . RESULTS : Among 750 placebo recipients in the per protocol population , 12 women developed  HPV16-related CIN2–3 ( 6 CIN2 and 6 CIN3 ) . Among 755 vaccine recipients , there were no cases ( vaccine efficacy 100 % , 95 % confidence interval [ CI ] 65–100 % ) . There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients ( vaccine efficacy 94 % , 95 % CI 88–98 % ) . After immunization , HPV16 serum antibody geometric mean titers peaked at month 7 ( 1,519 milli-Merck units [mMU]/mL ) , declined through month 18 ( 202 mMU/mL ) , and remained relatively stable between month 30 and month 48 ( 128–150 mMU/mL ) . CONCLUSION : The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2–3 for at least 3.5 years after immunization . Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer . LEVEL OF EVIDENCE : CONTEXT Viruslike particle human papillomavirus ( HPV ) vaccines were design ed 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 r and omized 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 r and omly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 c and i date 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 clinical trials.gov Identifier : NCT00128661 BACKGROUND Human papillomavirus types 16 ( HPV-16 ) and 18 ( HPV-18 ) cause approximately 70 % of cervical cancers worldwide . A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6 , 11 , 16 , and 18 ( HPV-6/11/16/18 ) for the prevention of high- grade cervical lesions associated with HPV-16 and HPV-18 . METHODS In this r and omized , double-blind trial , we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo , administered at day 1 , month 2 , and month 6 . The primary analysis was performed for a per- protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose ( month 7 ) . The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3 , adenocarcinoma in situ , or cervical cancer related to HPV-16 or HPV-18 . RESULTS Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo .  Vaccine efficacy for the prevention of the primary composite end point was 98 % ( 95.89 % confidence interval [ CI ] , 86 to 100 ) in the per- protocol susceptible population and 44 % ( 95 % CI , 26 to 58 ) in an intention-to-treat population of all women who had undergone r and omization ( those with or without previous infection ) . The estimated vaccine efficacy against all high- grade cervical lesions , regardless of causal HPV type , in this intention-to-treat population was 17 % ( 95 % CI , 1 to 31 ) . CONCLUSIONS In young women who had not been previously infected with HPV-16 or HPV-18 , those in the vaccine group had a significantly lower occurrence of high- grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group . ( Clinical Trials.gov number , NCT00092534 [ Clinical Trials.gov ] . ) BACKGROUND The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions . Some vaccines induce long-term immunity , while others require booster doses . Vaccines that induce long-term protection are usually characterized by the generation of immune memory . Recent trials of a quadrivalent ( types 6 , 11 , 16 , 18 ) human papillomavirus ( HPV ) vaccine have demonstrated high efficacy through 5 years of follow-up . We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory . METHODS A total of 552 , 16 - 23-year-old women were enrolled in a double-blind , placebo-controlled study . At enrollment , subjects were r and omized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years ' follow-up . A subset of 241 subjects ( n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group ) underwent 2 further years of follow-up . All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series . RESULTS Serum anti-HPV levels declined post-vaccination , but reached a plateau at month 24 that remained stable through month 60 . Administration of a challenge dose of vaccine induced a classic anamnestic response , with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series . At 1 month post-challenge , anti-HPV responses were higher than those observed 1-month post-dose 3 . DISCUSSION A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years . Vaccination also induces robust immune memory . These findings suggest that the efficacy of this vaccine will be long lasting BACKGROUND We evaluated the impact of a quadrivalent human papillomavirus ( HPV ) vaccine on infection and cervical disease related to 10 nonvaccine HPV types ( 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , and 59 ) associated with > 20 % of cervical cancers . The population evaluated included HPV-naive women and women with preexisting HPV infection and /or HPV-related disease at enrollment . METHODS Phase 3 efficacy studies enrolled 17,622 women aged 16 - 26 years . Subjects underwent cervicovaginal sampling and Pap testing on day 1 and then at 6 - 12-month intervals for up to 4 years . HPV typing was performed on sample s from enrollment and follow-up visits , including sample s obtained for diagnosis or treatment of HPV-related disease . All subjects who received 1 dose and returned for follow-up were included . RESULTS Vaccination reduced the rate of HPV-31/33/45/52/58 infection by 17.7 % ( 95 % confidence interval [ CI ] , 5.1 % to 28.7 % ) and of cervical intraepithelial neoplasia ( CIN ) 1 - 3 or adenocarcinoma in situ ( AIS ) by 18.8 % ( 95 % CI , 7.4 % to 28.9 % ) . Vaccination also reduced the rate of HPV-31/58/59-related CIN1 - 3/AIS by 26.0 % ( 95 % CI , 6.7 % to 41.4 % ) , 28.1 % ( 95 % CI , 5.3 % to 45.6 % ) , and 37.6 % ( 95 % CI , 6.0 % to 59.1 % ) , respectively . Although a modest reduction in HPV-31/33/45/52/58-related CIN2 or worse was observed , the estimated reduction was not statistically significant . CONCLUSIONS These cross-protection results complement the vaccine 's prophylactic efficacy against disease associated with HPV-6 , -11 , -16 , and -18 . Long-term monitoring of vaccinated population s are needed to fully ascertain the population -based impact and public health significance of these findings . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00092521 , NCT00092534 , and NCT00092482 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 This observer-blind study compared the prophylactic human papillomavirus ( HPV ) vaccines , Cervarix ™ ( GlaxoSmithKline ) and Gardasil ® ( Merck ) , by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course . Women ( n=1106 ) were stratified by age ( 18–26 , 27–35 , 36–45 years ) and r and omized ( 1:1 ) to receive Cervarix ™ ( Months 0 , 1 , 6 ) or Gardasil ® ( Months 0 , 2 , 6 ) . At Month 7 after first vaccination , all women in the according-to- protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies , as measured by pseudovirion-based neutralization assay ( PBNA ) , except for two women aged 27–35 years in the Gardasil ® group who did not seroconvert for HPV-18 ( 98 % ) . Geometric mean titers of serum neutralizing antibodies ranged from 2.3–4.8-fold higher for HPV-16 and 6.8–9.1-fold higher for HPV-18 after vaccination with Cervarix ™ compared with Gardasil ® , across all age strata . In the total vaccinated cohort ( all women who received at least one vaccine dose , regardless of their serological and DNA status prior to vaccination ) , Cervarix ™ induced significantly higher serum neutralizing antibody titers in all age strata ( 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 c and i date vaccine against infection with human papillomavirus ( HPV ) types 16 and 18 in young women . METHODS 18,644 women aged 15 - 25 years were r and omly 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 clinical ly 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 BACKGROUND Cervical cancer and its obligate precursors , cervical intraepithelial neoplasia grade s 2 and 3 ( CIN2/3 ) , and adenocarcinona in situ ( AIS ) , are caused by oncogenic human papillomavirus ( HPV ) . In this combined analysis of four clinical trials we assessed the effect of prophylactic HPV vaccination on these diseases . METHODS 20,583 women aged 16 - 26 years were r and omised to receive quadrivalent HPV6/11/16/18 vaccine ( n=9087 ) , its HPV16 vaccine component ( n=1204 ) , or placebo ( n=10 292 ) . They underwent periodic Papanicolaou testing , with colposcopy or biopsy for detected abnormalities . The primary composite endpoint was the combined incidence of HPV16/18-related CIN2/3 , AIS , or cervical cancer . These trials are registered at Clinical Trials.gov , numbers NCT00365378 , NCT00365716 , NCT00092521 , and NCT00092534 . FINDINGS Mean follow-up was 3.0 years ( SD 0.66 ) after first dose . In women negative for HPV16 or HPV18 infection during the vaccination regimen ( n=17 129 , per protocol ) , vaccine efficacy was 99 % for the primary endpoint ( 95 % CI 93 - 100 ) , meeting the statistical criterion for success . In an intention-to-treat analysis of all r and omised women ( including those who were HPV16/18 naive or HPV16/18-infected at day 1 ) , efficacy was 44 % ( 95 % CI 31 - 55 ) ; all but one case in vaccine recipients occurred in women infected with HPV16 or HPV18 before vaccination . In a second intention-to-treat analysis we noted an 18 % reduction ( 95 % CI 7 - 29 ) in the overall rate of CIN2/3 or AIS due to any HPV type . INTERPRETATION Administration of HPV vaccine to HPV-naive women , and women who are already sexually active , could substantially reduce the incidence of HPV16/18-related cervical precancers and cervical cancer 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 r and omly assigned ( 1:1 ) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central r and omisation 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 population s 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 population s 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 Clinical Trials.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 Objective In the quadrivalent ( types 6/11/16/18 ) HPV vaccine ( GARDASIL ® /SILGARD ® ) clinical program , 73 % of women aged 16 - 26 were naïve to all vaccine HPV types . In these women , prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease . Of the remaining women , 15 % of had evidence of past infection with one or more vaccine HPV types ( seropositive and DNA negative ) at the time of enrollment . Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared . Vaccine tolerability in this previously infected population was also assessed . Methods 18,174 women were enrolled into 3 clinical studies . The data presented comprise a subset of these subjects ( n = 2,617 ) who were HPV seropositive and DNA negative at enrollment ( for ≥1 vaccine type ) . In each study , subjects were r and omized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1 , month 2 and month 6 ( without knowledge of baseline HPV status ) . Procedures performed for efficacy data evaluation included detailed genital examination , Pap testing , and collection of cervicovaginal and external genital specimens . Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment . Results Subjects were followed for an average of 40 months . Seven subjects in the placebo group developed cervical disease , and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered . No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment . Conclusions These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time , however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types . Vaccine-related adverse experiences were higher among subjects receiving vaccine , mostly due to increased injection site adverse experiences BACKGROUND A r and omised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus ( HPV ) types associated with 70 % of cervical cancers ( types 16 and 18 ) and with 90 % of genital warts ( types 6 and 11 ) . METHODS 277 young women ( mean age 20.2 years [ SD 1.7 ] ) were r and omly assigned to quadrivalent HPV ( 20 microg type 6 , 40 microg type 11 , 40 microg type 16 , and 20 microg type 18 ) L1 virus-like-particle ( VLP ) vaccine and 275 ( mean age 20.0 years [ 1.7 ] ) to one of two placebo preparations at day 1 , month 2 , and month 6 . For 36 months , participants underwent regular gynaecological examinations , cervicovaginal sampling for HPV DNA , testing for serum antibodies to HPV , and Pap testing . The primary endpoint was the combined incidence of infection with HPV 6 , 11 , 16 , or 18 , or cervical or external genital disease ( ie , persistent HPV infection , HPV detection at the last recorded visit , cervical intraepithelial neoplasia , cervical cancer , or external genital lesions caused by the HPV types in the vaccine ) . Main analyses were done per protocol . FINDINGS Combined incidence of persistent infection or disease with HPV 6 , 11 , 16 , or 18 fell by 90 % ( 95 % CI 71 - 97 , p<0.0001 ) in those assigned vaccine compared with those assigned placebo . INTERPRETATION A vaccine targeting HPV types 6 , 11 , 16 , 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types BACKGROUND Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus ( HPV ) . These cancers are preceded by high- grade vulval intraepithelial neoplasia ( VIN2 - 3 ) and vaginal intraepithelial neoplasia ( VaIN2 - 3 ) . Our aim was to do a combined analysis of three r and omised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases . METHODS 18 174 women ( 16 - 26 years ) were enrolled and r and omised to receive either quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine or placebo at day 1 , and months 2 and 6 . Individuals underwent detailed anogenital examination at day 1 , 1 month after dose three , and at 6 - 12-month intervals for up to 48 months . Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done . The primary endpoint was the combined incidence of VIN2 - 3 or VaIN2 - 3 associated with HPV16 or HPV18 . Primary efficacy analyses were done in a per- protocol population . FINDINGS The mean follow-up time was 3 years . Among women naive to HPV16 or HPV18 through 1 month after dose three ( per- protocol population ; vaccine n=7811 ; placebo n=7785 ) , the vaccine was 100 % effective ( 95 % CI 72 - 100 ) against VIN2 - 3 or VaIN2 - 3 associated with HPV16 or HPV18 . In the intention-to-treat population ( which included 18 174 women who , at day 1 , could have been infected with HPV16 or HPV18 ) , vaccine efficacy against VIN2 - 3 or VaIN2 - 3 associated with HPV16 or HPV18 was 71 % ( 37 - 88 ) . The vaccine was 49 % ( 18 - 69 ) effective against all VIN2 - 3 or VaIN2 - 3 , irrespective of whether or not HPV DNA was detected in the lesion . The most common treatment-related adverse event was injection-site pain . INTERPRETATION Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high- grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination . With time , such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers
BACKGROUND It is unclear whether L1-VLP-based human papillomavirus ( HPV ) vaccines are efficacious in reducing the likelihood of anogenital pre-cancer in women with evidence of prior vaccine-type HPV exposure .
This study aims to determine whether the combined results of the vaccine trials published to date provide evidence of efficacy compared with control ( hepatitis A vaccine/placebo ) .