Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. Direct Comparison of HPV16 Serological Assays Used to Define HPV-Naïve Women in HPV Vaccine Trials A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like-particle vaccine in Latin American women. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. Sustained efficacy up to 4·5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial Enrolment of 22,000 adolescent women to cancer registry follow-up for long-term human papillomavirus vaccine efficacy: guarding against guessing The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24. Comparison of the immunogenicity and safety of Cervarix™ and Gardasil® human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45 years Genital warts and chlamydia in Australian women: comparison of national population-based surveys in 2001 and 2011 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 Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. 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 Clinical trial experience with prophylactic HPV 6/11/16/18 VLP vaccine in young women from the Asia-Pacific region. 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. 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 bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine
CONTEXT Low- grade squamous intraepithelial lesions ( LSILs ) have been described as a benign cytological consequence of active human papillomavirus ( HPV ) replication . Several studies have reported that certain behavioral and biological risks exist for LSIL , suggesting that HPV alone is not sufficient for the development of LSIL . However , because most of these studies have been cross-sectional , it is not known whether behavioral and biological risks are simply risks for HPV infection itself . OBJECTIVE To prospect ively examine risks of incident HPV infection in HPV-negative females and of incident LSIL development in females with HPV infection . DESIGN Prospect i ve cohort study conducted between 1990 - 2000 , with a median follow-up of 50 months . SETTING AND PARTICIPANTS Females aged 13 to 21 years who attended 2 family planning clinics in the San Francisco bay area ; 496 had prevalent HPV infection and 105 were HPV-negative . MAIN OUTCOME MEASURE Incident development of HPV infection and LSIL , analyzed by various demographic , behavioral , and clinical risk factors . RESULTS Fifty-four incident HPV infections occurred in the 105 females who were HPV-negative at study entry ( median duration of follow-up for those who remained HPV-negative was 26 months ) . Multivariable analysis showed that risks of HPV included sexual behavior ( relative hazard [ RH ] , 10.10 ; 95 % confidence interval [ CI ] , 3.24 - 31.50 per new partner per month ) , history of herpes simplex virus ( RH , 3.54 ; 95 % CI , 1.37 - 9.10 ) , and history of vulvar warts ( RH , 2.73 ; 95 % CI , 1.27 - 5.87 ) . Current use of oral contraceptives had a significantly protective effect ( RH , 0.49 ; 95 % CI , 0.28 - 0.86 ) . Among the 496 individuals who were HPV-positive at baseline or in follow-up , there were 109 incident cases of LSIL during the follow-up interval , with a median follow-up time of 60 months for those who never developed LSIL . Human papillomavirus infection was the most significant risk factor for development of LSIL . The multivariable model showed the following risks for LSIL : HPV infection for less than 1 year ( RH , 7.40 ; 95 % CI , 4.74 - 11.57 ) ; HPV infection for 1 to 2 years ( RH , 10.27 ; 95 % CI , 5.64 - 18.69 ) ; HPV infection for 2 to 3 years ( RH , 6.11 ; 95 % CI , 1.86 - 20.06 ) ; and daily cigarette smoking ( RH , 1.67 ; 95 % CI , 1.12 - 2.48 ) . CONCLUSION Our results indicate distinct risks for HPV and LSIL . In addition , most women with HPV infection in our study did not develop LSIL within a median follow-up period of 60 months . These findings underscore the hypothesis that certain biological risks thought to be associated with LSIL are , in fact , risks for acquisition of HPV . Cigarette smoking was a risk specific to LSIL , supporting the role of tobacco in neoplastic development Background : Two HPV serological assays , the competitive Luminex immunoassay ( cLIA ) , and an enzyme-linked immunoassay ( ELISA ) against HPV16 have been used to define HPV-naïve subcohorts within large HPV vaccination trials . Some of the variation in estimated vaccine efficacies may be due to the differences in these assays used to define the HPV-naïve subgroups . To guide the interpretation of published results , we compared these assays . Methods : Replicate enrollment sera from a stratified sample of 388 unvaccinated women from the control arm of the Costa Rica HPV 16/18 Vaccine Trial were measured for antibodies against HPV16  using cLIA and ELISA . Agreement between the assays was estimated using st and ard and alternative assay cutoffs . Results : Using laboratory-determined seropositivity cutoffs , sampling-adjusted HPV16 seropositivity was 24.8 % by ELISA and 7.2 % by cLIA . Comparing cLIA and ELISA antibody levels based on the st and ard cutoffs , overall agreement was 53 % ( positive-agreement = 49 % ) . The poor agreement was mainly driven by the higher sensitivity of the ELISA than cLIA , result ing in 30 % of the ELISA-positive sample that were cLIA-negative ( none of the ELISA-negatives were cLIA-positive ) . Increasing ELISA cutoff to 54 ELISA units (EU)/mL ( the level which maximized agreement with cLIA ; ELISA st and ard cutoff is 8 EU/mL ) result ed in higher agreement ( overall agreement = 91 % ; positive agreement = 78 % ) . Conclusions : ELISA and cLIA are different from each other based on the laboratory-determined cutoff . Increasing ELISA cutoff increased agreement with cLIA , which could facilitate comparisons among studies that use different assays . Impact : Keeping cLIA at the laboratory-determined cutoff but altering ELISA cutoff for seropositivity might facilitate vaccine efficacy comparisons in the naïve cohorts defined by cLIA . Cancer Epidemiol Biomarkers Prev ; 21(9 ) ; 1547–54 . © 2012 AACR BACKGROUND The investigational 9-valent viruslike particle vaccine against human papillomavirus ( HPV ) includes the HPV types in the quadrivalent HPV ( qHPV ) vaccine ( 6 , 11 , 16 , and 18 ) and five additional oncogenic types ( 31 , 33 , 45 , 52 , and 58 ) . Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age . METHODS We performed a r and omized , international , double-blind , phase 2b-3 study of the 9vHPV vaccine  in 14,215 women . Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6 . Serum was collected for analysis of antibody responses . Swabs of labial , vulvar , perineal , perianal , endocervical , and ectocervical tissue were obtained and used for HPV DNA testing , and liquid-based cytologic testing ( Papanicolaou testing ) was performed regularly . Tissue obtained by means of biopsy or as part of definitive therapy ( including a loop electrosurgical excision procedure and conization ) was tested for HPV . RESULTS The rate of high- grade cervical , vulvar , or vaginal disease irrespective of HPV type ( i.e. , disease caused by HPV types included in the 9vHPV vaccine and those not included ) in the modified intention-to-treat population ( which included participants with and those without prevalent infection or disease ) was 14.0 per 1000 person-years in both vaccine groups . The rate of high- grade cervical , vulvar , or vaginal disease related to HPV-31 , 33 , 45 , 52 , and 58 in a prespecified per- protocol efficacy population ( susceptible population ) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group ( efficacy of the 9vHPV vaccine , 96.7 % ; 95 % confidence interval , 80.9 to 99.8 ) . Antibody responses to HPV-6 , 11 , 16 , and 18 were noninferior to those generated by the qHPV vaccine . Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group . CONCLUSIONS The 9vHPV vaccine prevented infection and disease related to HPV-31 , 33 , 45 , 52 , and 58 in a susceptible population and generated an antibody response to HPV-6 , 11 , 16 , and 18 that was noninferior to that generated by the qHPV vaccine . The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine . ( Funded by Merck ; Clinical Trials.gov number , NCT00543543 ) The prevalence of HPV infection in Latin America is among the highest in the world . A quadrivalent ( types 6/11/16/18 ) human papillomavirus L1 virus-like-particle vaccine has been shown to be 95 - 100 % effective in preventing HPV 6/11/16/18-related cervical and genital disease in women naive to vaccine HPV types . A total of 6,004 female subjects aged 9 - 24 were recruited from Brazil , Mexico , Colombia , Costa Rica , Guatemala and Peru . Subjects were r and omized to immunization with intramuscular ( deltoid ) injections of HPV vaccine or placebo at enrollment ( day 1 ) , month 2 and month 6 . Among vaccinated subjects in the per- protocol population from Latin America , quadrivalent HPV vaccine was 92.8 and 100 % effective in preventing cervical intraepithelial neoplasia and external genital lesions related to vaccine HPV types , respectively . These data support vaccination of adolescents and young adults in the region , which is expected to greatly reduce the burden of cervical and genital cancers , precancers and genital warts 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 ] . ) The efficacy of the quadrivalent Human Papillomavirus ( HPV ) vaccine is thought to be mediated by humoral immunity . We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy . 17,622 women were vaccinated at day 1 , and months 2 and 6 . At day 1 and at 6 - 12 months intervals for up to 48 months , subjects underwent Papanicolaou and genital HPV testing . No immune correlate of protection could be found due to low number of cases . Although 40 % of vaccine subjects were anti-HPV 18 seronegative at end-of- study , efficacy against HPV 18-related disease remained high ( 98.4 % ; 95 % CI : 90.5 - 100.0 ) despite high attack rates in the placebo group . These results suggest vaccine-induced protection via immune memory , or lower than detectable HPV 18 antibody titers Human papillomavirus ( HPV ) causes cervical , vulvar , and vaginal cancers , precancerous dysplasia , and genital warts . We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine . In total , 552 women ( 16–23 years ) were enrolled in a r and omised , placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0 , 2 , and 6 . At regular intervals through 3 years , subjects underwent gynaecologic examination , cervicovaginal sampling for HPV DNA , serum anti-HPV testing , and Pap testing , with follow-up biopsy as indicated . A subset of 241 subjects underwent two further years of follow-up . At 5 years post enrolment , the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96 % ( two cases vaccine versus 46 placebo ) . There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients , and six cases in placebo recipients ( efficacy=100 % ; 95 % CI:12–100 % ) . Through 5 years , vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection . In conclusion , a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18 . This duration supports vaccination of adolescents and young adults , which is expected to greatly reduce the burden of cervical and genital cancers , precancerous dysplasia , and genital warts BACKGROUND The impact of the prophylactic vaccine against human papillomavirus ( HPV ) types 6 , 11 , 16 , and 18 ( HPV6/11/16/18 ) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were " negative to 14 HPV types " and in a mixed population of HPV-exposed and -unexposed women ( intention-to-treat group ) . METHODS This analysis studied 17 622 women aged 15 - 26 years who were enrolled in one of two r and omized , placebo-controlled , efficacy trials for the HPV6/11/16/18 vaccine  ( first patient on December 28 , 2001 , and studies completed July 31 , 2007 ) . Vaccine or placebo was given at day 1 , month 2 , and month 6 . All women underwent cervicovaginal sampling and Papanicolaou ( Pap ) testing at day 1 and every 6 - 12 months thereafter . Outcomes were any cervical intraepithelial neoplasia ; any external anogenital and vaginal lesions ; Pap test abnormalities ; and procedures such as colposcopy and definitive therapy . Absolute rates are expressed as women with endpoint per 100 person-years at risk . RESULTS The average follow-up was 3.6 years ( maximum of 4.9 years ) . In the population that was negative to 14 HPV types , vaccination was up to 100 % effective in reducing the risk of HPV16/18-related high- grade cervical , vulvar , and vaginal lesions and of HPV6/11-related genital warts . In the intention-to-treat group , vaccination also statistically significantly reduced the risk of any high- grade cervical lesions ( 19.0 % reduction ; rate vaccine = 1.43 , rate placebo = 1.76 , difference = 0.33 , 95 % confidence interval [ CI ] = 0.13 to 0.54 ) , vulvar and vaginal lesions ( 50.7 % reduction ; rate vaccine = 0.10 , rate placebo = 0.20 , difference = 0.10 , 95 % CI = 0.04 to 0.16 ) , genital warts ( 62.0 % reduction ; rate vaccine = 0.44 , rate placebo = 1.17 , difference = 0.72 , 95 % CI = 0.58 to 0.87 ) , Pap abnormalities ( 11.3 % reduction ; rate vaccine = 10.36 , rate placebo = 11.68 , difference = 1.32 , 95 % CI = 0.74 to 1.90 ) , and cervical definitive therapy ( 23.0 % reduction ; rate vaccine = 1.97 , rate placebo = 2.56 , difference = 0.59 , 95 % CI = 0.35 to 0.83 ) , irrespective of causal HPV type . CONCLUSIONS High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts , cervical cytological abnormalities , and diagnostic and therapeutic procedures . In the longer term , substantial reductions in the rates of cervical , vulvar , and vaginal cancers may follow 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 Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions . Our aim was to assess the long-term efficacy , immunogenicity , and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes . METHODS We did a follow-up study of our multicentre , double-blind , r and omised , placebo-controlled trial reported in 2004 . We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine ( 0.5 mL ; n=393 ) or placebo ( n=383 ) . We assessed HPV DNA , using cervical sample s , and did yearly cervical cytology assessment s. We also studied the long-term immunogenicity and safety of the vaccine . FINDINGS More than 98 % seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase . We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints : incident infection , 96.9 % ( 95 % CI 81.3 - 99.9 ) ; persistent infection : 6 month definition , 94.3 ( 63.2 - 99.9 ) ; 12 month definition , 100 % ( 33.6 - 100 ) . In a combined analysis of the initial efficacy and extended follow-up studies , vaccine efficacy of 100 % ( 42.4 - 100 ) against cervical intraepithelial neoplasia ( CIN ) lesions associated with vaccine types . We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31 . The vaccine has a good long-term safety profile . INTERPRETATION Up to 4.5 years , the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe , and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions . There is also evidence of cross protection 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 can not 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 Finl and 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+ BACKGROUND Quadrivalent human papillomavirus ( HPV types 6/11/16/18 ) L1 VLP vaccine is highly effective in preventing HPV 6/11/16/18-related cervical and external genital disease . Herein , we evaluated the impact of the quadrivalent HPV 6/11/16/18 L1 VLP vaccine on prevention of HPV-associated cervico-genital lesions in a broad population of sexually active European women . METHODS Female subjects ( N = 9265 ) aged 16 - 24 with four or fewer lifetime sexual partners were enrolled and r and omized to quadrivalent HPV vaccine or placebo . Subjects underwent cervicovaginal sampling for HPV DNA detection . Papanicolaou testing and anti-HPV 6/11/16/18 serology testing was also performed . RESULTS Vaccine efficacy against lesions representing immediate cervical cancer precursors ( cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ ) related to HPV 6/11/16/18 in the per- protocol population was 100.0%[95 % confidence interval ( 95 % CI ) , 89.8 - 100.0 ] . Efficacy against external genital lesions ( vulvar or vaginal intraepithelial neoplasia , condyloma , vulvar or vaginal cancer ) related to vaccine HPV types in the per- protocol European population was 99.0 % ( 95 % CI , 94.4 - 100.0 ) . CONCLUSION These data demonstrate that quadrivalent HPV 6/11/16/18 vaccination programs in 16- to 24-year-old European women can be beneficial . NCT0009252 , NCT00092534 , NCT00092495 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 ( Objectives Australia introduced a nationwide human papillomavirus ( HPV ) vaccination programme for women aged 12–26 years in 2007 and has implemented various chlamydia control strategies over the last 10 years . We compared reported diagnoses of warts and chlamydia in two national population -based sample s surveyed 10 years apart . Methods An Australia-wide survey of women aged 18–39 years was conducted by r and om-digit dialling mobile phone numbers in 2011 . The proportion of women self-reporting genital warts and chlamydia was compared with that in equivalent-aged women interviewed in another national telephone survey conducted 10 years earlier using logistic regression adjusting for age , and other factors . Results 2394 women were included in the 2011 survey . 88 ( 3.7 % ) reported a genital warts diagnosis , and 127 ( 5.3 % ) had at least one chlamydia diagnosis . For women with warts and chlamydia , the majority were seen in general practice ( 63.3 % and 70.0 % , respectively ) . Comparing women surveyed in 2011 to 4874 women surveyed in 2001 , among women eligible for free HPV vaccine through the national programme ( women aged 18–30 years ) , there was a 41 % decrease in warts ( adjusted OR 0.59 , 95 % CI 0.39 to 0.89 ) but among ineligible women ( 31–39 years ) there was a 64 % increase ( aOR 1.64 , 95 % CI 1.05 to 2.54 ) . Over the same period chlamydia diagnoses increased by 97 % ( aOR 1.97 , 95 % CI 1.15 to 3.37 ) in women aged 18–24 years . Conclusions Our results add to evidence from clinic-based studies showing a significant reduction in genital warts among HPV vaccine-eligible women in the general community and increases in the proportion of Australian women diagnosed with chlamydia 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 Human papillomavirus ( HPV ) testing is known to be more sensitive , but less specific than cytology for detecting cervical intraepithelial neoplasia ( CIN ) . We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing . METHODS Between March , 2004 , and December , 2004 , in two separate recruitment phases , women aged 25 - 60 years were r and omly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology ( first phase ) or alone ( second phase ) . R and omisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres . During phase one , women who were HPV-positive and aged 35 - 60 years were referred to colposcopy , whereas women aged 25 - 34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive . During phase two , women in the HPV group were referred for colposcopy if the HPV test was positive . Two rounds of screening occurred in each phase , and all women had cytology testing only at the second round . The primary endpoint was the detection of grade 2 and 3 CIN , and of invasive cervical cancers during the first and second screening rounds . Analysis was done by intention to screen . This trial is registered , number IS RCT N81678807 . FINDINGS In total for both phases , 47,001 women were r and omly assigned to the cytology group and 47,369 to HPV testing . 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening . We also retrieved the histological diagnoses from screening done elsewhere . The detection of invasive cervical cancers was similar for the two groups in the first round of screening ( nine in the cytology group vs seven in the HPV group , p=0.62 ) ; no cases were detected in the HPV group during round two , compared with nine in the cytology group ( p=0.004 ) . Overall , in the two rounds of screening , 18 invasive cancers were detected in the cytology group versus seven in the HPV group ( p=0.028 ) . Among women aged 35 - 60 years , at round one the relative detection ( HPV vs cytology ) was 2.00 ( 95 % CI 1.44 - 2.77 ) for CIN2 , 2.08 ( 1.47 - 2.95 ) for CIN3 , and 2.03 ( 1.60 - 2.57 ) for CIN2 and 3 together . At round two the relative detection was 0.54 ( 0.23 - 1.28 ) for CIN2 , 0.48 ( 0.21 - 1.11 ) for CIN3 , and 0.51 ( 0.28 - 0.93 ) for CIN2 and 3 together . Among women aged 25 - 34 years , there was significant heterogeneity between phases in the relative detection of CIN3 . At round one the relative detection was 0.93 ( 0.52 - 1.64 ) in phase one and 3.91 ( 2.02 - 7.57 ) in phase two . At round two the relative detection was 1.34 ( 0.46 - 3.84 ) in phase one and 0.20 ( 0.04 - 0.93 ) in phase two . Pooling both phases , the detection ratio of CIN2 for women aged 25 - 34 years was 4.09 ( 2.24 - 7.48 ) at round one and 0.64 ( 0.23 - 1.27 ) at round two . INTERPRETATION HPV-based screening is more effective than cytology in preventing invasive cervical cancer , by detecting persistent high- grade lesions earlier and providing a longer low-risk period . However , in younger women , HPV screening leads to over-diagnosis of regressive CIN2 . FUNDING European Union , Italian Ministry of Health , Regional Health Administrations of Piemonte , Tuscany , Veneto and Emilia-Romagna , and Public Health Agency of Lazio BACKGROUND Prophylactic human papillomavirus ( HPV ) vaccines have to provide sustained protection . We assessed efficacy , immunogenicity , and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years . METHODS Women aged 15 - 25 years , with normal cervical cytology , who were HPV-16/18 seronegative and oncogenic HPV DNA-negative ( 14 types ) at screening participated in a double-blind , r and omised , placebo-controlled initial study ( n=1113 ; 560 vaccine group vs 553 placebo group ) and follow-up study ( n=776 ; 393 vs 383 ) . 27 sites in three countries participated in the follow-up study . Cervical sample s were tested every 6 months for HPV DNA . Management of abnormal cytologies was prespecified , and HPV-16/18 antibody titres were assessed . The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18 , or both . We report the analyses up to 6.4 years of this follow-up study and combined with the initial study . For the primary endpoint , the efficacy analysis was done in the according-to- protocol ( ATP ) cohort ; the analysis of cervical intraepithelial neoplasia grade 2 and above ( CIN2 + ) was done in the total vaccinated cohort ( TVC ) . The study is registered with Clinical Trials.gov , number NCT00120848 . FINDINGS For the combined analysis of the initial and follow-up studies , the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group ; the TVC included 560 women in the vaccine group and 553 in the placebo group . Vaccine efficacy against incident infection with HPV 16/18 was 95.3 % ( 95 % CI 87.4 - 98.7 ) and against 12-month persistent infection was 100 % ( 81.8 - 100 ) . Vaccine efficacy against CIN2 + was 100 % ( 51.3 - 100 ) for lesions associated with HPV-16/18 and 71.9 % ( 20.6 - 91.9 ) for lesions independent of HPV DNA . Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection ( both antigens ) . Safety outcomes were similar between groups : during the follow-up study , 30 ( 8 % ) participants reported a serious adverse event in the vaccine group versus 37 ( 10 % ) in the placebo group . None was judged related or possibly related to vaccination , and no deaths occurred . INTERPRETATION Our findings show excellent long-term efficacy , high and sustained immunogenicity , and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years . FUNDING GlaxoSmithKline Biologicals ( Belgium ) 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 OBJECTIVE To evaluate results of three phase 3 clinical trials of quadrivalent HPV 6/11/16/18 vaccination of young Asia-Pacific women . METHODS A total of 814 women from the Asia-Pacific region ( aged 16 to 26 years ) received vaccine or placebo in 1 of 3 protocol s. Descriptive analyses focused on the efficacy , safety , and immunogenicity of the vaccine and the natural history of HPV disease . RESULTS Vaccine efficacy against disease caused by HPV types 6 , 11 , 16 , or 18 was 100 % for cervical intraepithelial neoplasia ( 0 vs 12 cases ; 95 % confidence interval [ CI ] , 63.1%-100 % ) and 100 % for vulvar and vaginal intraepithelial neoplasia or condylomata accuminata ( 0 vs 5 cases ; 95 % CI , -11.8 % to 100 % ) . The vaccination was highly immunogenic . Vaccine recipients experienced a significantly higher injection site adverse event rate ( P=0.002 ) . Compared with other world regions , lower rates of smoking and baseline positivity to 14 HPV types ( including the vaccine types ) were observed among Asia-Pacific participants . CONCLUSION Prophylactic quadrivalent HPV 6/11/16/18 vaccination of young Asia-Pacific women demonstrated high efficacy , safety , and tolerability . Together with an observed low baseline HPV positivity rate , the Asia-pacific population is potentially an important cohort to benefit from vaccination 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 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 Vaccination against the most common oncogenic human papillomavirus ( HPV ) types , HPV-16 and HPV-18 , could prevent development of up to 70 % of cervical cancers worldwide . We did a r and omised , double-blind , controlled trial to assess the efficacy , safety , and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types , associated cervical cytological abnormalities , and precancerous lesions . METHODS We r and omised 1113 women between 15 - 25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo  on a 0 month , 1 month , and 6 month schedule in North America and Brazil . Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal sample s for up to 27 months , and for vaccine safety and immunogenicity . FINDINGS In the according-to- protocol analyses , vaccine efficacy was 91.6 % ( 95 % CI 64.5 - 98.0 ) against incident infection and 100 % against persistent infection ( 47.0 - 100 ) with HPV-16/18 . In the intention-to-treat analyses , vaccine efficacy was 95.1 % ( 63.5 - 99.3 ) against persistent cervical infection with HPV-16/18 and 92.9 % ( 70.0 - 98.3 ) against cytological abnormalities associated with HPV-16/18 infection . The vaccine was generally safe , well tolerated , and highly immunogenic . INTERPRETATION The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18 , and associated cytological abnormalities and lesions . Vaccination against such infections could substantially reduce incidence of cervical cancer In this observer-blind study ( NCT00423046 ) , women ( N=1,106 ) , stratified by age ( 18–26 , 27–35 , 36–45 years ) , were r and omized ( 1:1 ) to receive the HPV-16/18 vaccine ( Cervarix ® , GlaxoSmithKline Biologicals , Months 0,1,6 ) or the HPV-6/11/16/18 vaccine ( Gardasil ® Merck & Co. , Inc. , Months 0,2,6 ) . Month 7 results were previously reported ; we now report Month 24 results . In the according-to- protocol cohort for immunogenicity ( seronegative and DNA-negative at baseline for HPV type analyzed ) , seropositivity rates of neutralizing antibodies ( nAbs ) [ pseudovirion-based neutralization assay ] were , across all age strata , 100 % ( HPV-16/18 vaccine ) and 97.5–100 % ( HPV-6/11/16/18 vaccine ) for HPV-16 , and 99.0–100 % ( HPV-16/18 vaccine ) and 72.3–84.4 % ( HPV-6/11/16/18 vaccine ) for HPV-18 . Corresponding geometric mean titers ( GMTs ) were 2.4–5.8-fold higher for HPV-16 and 7.7–9.4-fold higher for HPV-18 with the HPV-16/18 vaccine versus the HPV-6/11/16/18 vaccine ; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine ( p<0.0001 ) in the total vaccinated cohort ( received ≥1 vaccine dose , irrespective of baseline sero/DNA-status ) . Similar results were obtained using enzyme-linked immunosorbent assay ( ELISA ) . Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions ( ELISA ) were not significantly different between vaccines . At Month 24 , CD4 + T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine ; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16 . Both vaccines were generally well tolerated . Although an immunological correlate of protection has not been defined , differences in the magnitude of immune response between vaccines may represent determinants of duration of protection
BACKGROUND When the bivalent and the quadrivalent HPV vaccines were marketed they were presented as having comparable efficacy against cervical cancer .
Differences between the vaccines are HPV types included and formulation of the adjuvant .