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 Safety and Immunogenicity of Human Papillomavirus-16/18 AS04-Adjuvanted Vaccine: A Randomized Trial in 10–25-Year-Old HIV-Seronegative African Girls and Young Women Occurrence of vaccine and non-vaccine human papillomavirus types in adolescent Finnish females 4 years post-vaccination. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Co-administration of human papillomavirus-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Efficacy of Human Papillomavirus 16 and 18 (HPV-16/18) AS04-Adjuvanted Vaccine against Cervical Infection and Precancer in Young Women: Final Event-Driven Analysis of the Randomized, Double-Blind PATRICIA Trial Multisite HPV16/18 Vaccine Efficacy Against Cervical, Anal, and Oral HPV Infection. Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub-Saharan Africa Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. 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 Vaccination with a Human Papillomavirus (HPV)-16/18 AS04-Adjuvanted Cervical Cancer Vaccine in Korean Girls Aged 10-14 Years Safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in adolescents aged 12–15 years: Interim analysis of a large community-randomized controlled trial Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18–25 years: Results from a randomized controlled trial 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 Prevention of persistent human papillomavirus infection by an HPV16/18 vaccine: a community-based randomized clinical trial in Guanacaste, Costa Rica. 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 A Randomized, Double-Blind, Phase III Study of the Immunogenicity and Safety of a 9-Valent Human Papillomavirus L1 Virus-Like Particle Vaccine (V503) Versus Gardasil® in 9–15-Year-Old Girls Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV-infected adults: a randomized, double-blind clinical trial. Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine: a randomized, controlled trial in adolescent girls. Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica Efficacy of Human Papillomavirus Type 16/18 AS04-Adjuvanted Vaccine in Japanese Women Aged 20 to 25 Years: Final Analysis of a Phase 2 Double-Blind, Randomized Controlled Trial Safety and immunogenicity of co-administered quadrivalent human papillomavirus (HPV)-6/11/16/18 L1 virus-like particle (VLP) and hepatitis B (HBV) vaccines. Safety and Persistent Immunogenicity of a Quadrivalent Human Papillomavirus Types 6, 11, 16, 18 L1 Virus-Like Particle Vaccine in Preadolescents and Adolescents: A Randomized Controlled Trial Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women 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. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo-controlled trial in 176 Korean subjects Impact of a quadrivalent HPV6/11/16/18 vaccine in Mexican women: public health implications for the region.
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 . Cervical cancer is a major public health problem for women in sub-Saharan Africa . Availability of a human papillomavirus ( HPV ) vaccine could have an important public health impact . Methods . In this phase IIIb , double-blind , r and omized , placebo-controlled , multicenter trial ( NCT00481767 ) , healthy African girls and young women seronegative for human immunodeficiency virus ( HIV ) were stratified by age ( 10–14 or 15–25 years ) and r and omized ( 2:1 ) to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 450 ) or placebo ( n = 226 ) at 0 , 1 , and 6 months . The primary objective was to evaluate HPV-16/18 antibody responses at month 7 . Seropositivity rates and corresponding geometric mean titers ( GMTs ) were measured by enzyme-linked immunosorbent assay . Results . In the according-to- protocol analysis at month 7 , 100 % of initially seronegative participants in the vaccine group were seropositive for both anti – HPV-16 and anti – HPV-18 antibodies ( n = 130 and n = 128 for 10–14-year-olds , respectively ; n = 190 and n = 212 for 15–25-year-olds ) . GMTs for HPV-16 and HPV-18 were higher in 10–14-year-olds ( 18 423 [ 95 % confidence interval , 16 185–20 970 ] and 6487 [ 5590–7529 ] enzyme-linked immunosorbent assay units (EU)/mL , respectively ) than in 15–25-year-olds ( 10 683 [ 9567–11 930 ] and 3743 [ 3400–4120 ] EU/mL , respectively ) . Seropositivity was maintained at month 12 . No participant withdrew owing to adverse events . No vaccine-related serious adverse events were reported . Conclusions . The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinical ly acceptable safety profile when administered to healthy HIV-seronegative African girls and young women Control of human papillomavirus (HPV)-related cancers by inclusion of HPV vaccination into national vaccination programmes is likely . One open question is replacement of the vaccine types with other high-risk ( hr ) HPV types in the vaccination era . We studied occurrence of HPV types in adolescent females participating in a population -based vaccination trial . A total of 4,808 16- to 17-year-old females from Finl and were enrolled in the 1:1 r and omized phase III ( PATRICIA ) trial of the efficacy of vaccination with the  AS04-adjuvanted HPV-16/18 virus-like particle vaccine as compared to hepatitis A virus ( HAV ) vaccine .  HPV infection was assessed from cervical sample s taken every 6 months for 4 years post-vaccination by polymerase chain reaction ( PCR ) for genital oncogenic HPV types 16 , 18 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 58 , 59 , 66 , 68 , and 73 as well as low-risk types HPV-6 and HPV-11 . The  HPV-16/18 vaccine coverage ranged between 1 and 22 % by age-cohort and study community . Odds ratios ( ORs ) for infections with different HPV types in baseline PCR negative HPV-16/18 vs. HAV vaccinated women , and Poisson regression derived HPV incidence rate ratios ( IRRs ) in baseline positive vs. negative women were calculated . The OR and IRR estimates for acquisition of any genital HPV types showed no excess risk neither in baseline HPV DNA-negative HPV-16/18-vaccinated women compared to baseline HPV DNA-negative HAV vaccinated women nor in HPV-16/18-vaccinated baseline HPV-16/18-positive women compared to baseline HPV-16/18-negative women . In the HAV-vaccinated , baseline HPV-18-positive women showed an increased risk of acquiring other clade A7 HPV types ( 39 , 45 , 59 , 68 ) ( IRR 1.8 , 95 % confidence interval = 1.01.-3.1 ) . We found no increased occurrence of non-vaccine HPV types suggestive of type-replacement 1 - 4 years post-vaccination among HPV-16/18-vaccinated Finnish adolescents Objective The study assessed the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Korean women aged 15 - 25 years . Methods Phase IIIB , double-blind , r and omised ( 2:1 ) , multi-centre trial was conducted in Korea from June 2007 to March 2008 . The study enrolled 225 women in the HPV ( N=149 ) and placebo ( N=76 ) groups who received three doses of HPV-16/18 AS04-adjuvanted vaccine or placebo ( aluminium hydroxide ) administered intramuscularly at 0 , 1 , and 6 months and were followed until one month post-dose 3 . Serum sample s were collected pre-vaccination and one month post-dose 3 . Safety and reactogenicity data were collected throughout . Results In this trial , 208 women completed the study ( 141 in HPV group ; 67 in placebo group ) . At month 7 , all initially seronegative women had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titres of 9,351.4 El . U/mL ( 95 % CI , 8,145.5 to 10,735.8 ) and 4204.1 El . U/mL ( 95 % CI , 3,626.5 to 4,873.6 ) , respectively . Initially seropositive women showed similar increase in geometric mean titre levels . Compliance to the three dose vaccination course was 95.3 % in HPV and 89.5 % in placebo group . Solicited local ( pain ) and general ( fatigue , myalgia or headache ) symptoms were commonly reported in both groups . Three serious adverse events were reported ( two in HPV group ; one in placebo group ) , all unrelated to vaccination by the investigator ; all recovered . Conclusion The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic with a clinical ly acceptable safety profile in Korean women . This study was in line with previous global studies in Europe , North America , and Brazil . ( Clinical Trials.gov number , NCT 00485732 . 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 ) Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND To evaluate co-administration of GlaxoSmithKline Biologicals ' human papillomavirus-16/18 AS04-adjuvanted vaccine ( HPV ) and hepatitis B vaccine ( HepB ) . METHODS This was a r and omized , controlled , open , multicenter study . Healthy girls , aged 9 - 15 years , were r and omized to receive HPV ( n=247 )  , HepB ( n=247 ) or HPV co-administered with HepB ( HPV+HepB ; n=247 ) at Months 0 , 1 and 6 . Antibodies against hepatitis B surface antigen ( HBs ) , HPV-16 and HPV-18 were measured , and reactogenicity and safety monitored . Co- primary objectives were to demonstrate non-inferiority of hepatitis B and HPV-16/18 immune responses at Month 7 for co-administered vaccines , compared with vaccines administered alone , in the according-to- protocol cohort . RESULTS The pre-defined criteria for non-inferiority were met for all co- primary immunogenicity endpoints at Month 7 . Anti-HBs seroprotection rates ≥10mIU/mL were achieved by 97.9 % and 100 % of girls , respectively , following co-administration or HepB alone . Anti-HBs geometric mean titers ( GMTs ) ( 95 % confidence interval ) were 1280.9 ( 973.3 - 1685.7 ) and 3107.7 ( 2473.1 - 3905.1 ) milli-international units/mL , respectively . Anti-HPV-16 and -18 seroconversion rates were achieved by ≥99 % of girls following co-administration or HPV alone . Anti-HPV-16 GMTs were 19819.8 ( 16856.9 - 23303.6 ) and 21712.6 ( 19460.2 - 24225.6 ) ELISA units (ELU)/mL , respectively . Anti-HPV-18 GMTs were 8835.1 ( 7636.3 - 10222.1 ) and 8838.6 ( 7948.5 - 9828.4 ) ELU/mL , respectively . Co-administration was generally well tolerated . CONCLUSIONS The study results support the co-administration of HPV-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine in adolescent girls aged 9 - 15 years . CLINICAL TRIALS REGISTRATION Clinical Trials.gov registration number NCT00652938 BACKGROUND Although the risk of human papillomavirus ( HPV ) infection is greatest in young women , women older than 25 years remain at risk . We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up . METHODS In this phase 3 , double-blind , r and omised controlled trial , healthy women older than 25 years were enrolled ( age stratified : 26 - 35 years , 36 - 45 years , and ≥46 years ) . Up to 15 % in each age stratum had a history of HPV infection or disease . Women were r and omly assigned ( 1:1 ) to receive HPV 16/18 vaccine or aluminium hydroxide control , with an internet-based system . The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater ( CIN1 + ) associated with HPV 16/18 . We did analyses in the according-to- protocol cohort for efficacy and total vaccinated cohort . Data for the combined primary endpoint in the according-to- protocol cohort for efficacy were considered significant when the lower limit of the 96·2 % CI around the point estimate was greater than 30 % . For all other endpoints and cohorts , data were considered significant when the lower limit of the 96·2 % CI was greater than 0 % . This study is registered with Clinical Trials.gov , number NCT00294047 . FINDINGS The first participant was enrolled on Feb 16 , 2006 , and the last study visit took place on Jan 29 , 2014 . 4407 women were in the according-to- protocol cohort for efficacy ( n=2209 vaccine , n=2198 control ) and 5747 women in the total vaccinated cohort ( n=2877 vaccine , n=2870 control ) . At month 84 , in women seronegative for the corresponding HPV type in the according-to- protocol cohort for efficacy , vaccine efficacy against 6-month persistent infection or CIN1 + associated with HPV 16/18 was significant in all age groups combined ( 90·5 % , 96·2 % CI 78·6 - 96·5 ) . Vaccine efficacy against HPV 16/18-related cytological abnormalities ( atypical squamous cells of undetermined significance and low- grade squamous intraepithelial lesion ) and CIN1 + was also significant . We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 ( 65·8 % , 96·2 % CI 24·9 - 85·8 ) and HPV 45 ( 70·7 % , 96·2 % CI 34·2 - 88·4 ) . In the total vaccinated cohort , vaccine efficacy against CIN1 + irrespective of HPV was significant ( 22·9 % , 96·2 % CI 4·8 - 37·7 ) . Serious adverse events related to vaccination occurred in five ( 0·2 % ) of 2877 women in the vaccine group and eight ( 0·3 % ) of 2870 women in the control group . INTERPRETATION In women older than 25 years , the HPV 16/18 vaccine continues to protect against infections , cytological abnormalities , and lesions associated with HPV 16/18 and CIN1 + irrespective of HPV type , and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up . FUNDING GlaxoSmithKline Biologicals SA ABSTRACT We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ( ( HPV-16/18 ) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . The total vaccinated cohort ( TVC ) included all r and omized participants who received at least one vaccine dose ( vaccine , n = 9,319 ; control , n = 9,325 ) at months 0 , 1 , and /or 6 . The TVC-naive ( vaccine , n = 5,822 ; control , n = 5,819 ) had no evidence of high-risk HPV infection at baseline , approximating adolescent girls targeted by most HPV vaccination programs . Mean follow-up was approximately 39 months after the first vaccine dose in each cohort . At baseline , 26 % of women in the TVC had evidence of past and /or current HPV-16/18 infection . HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds . In the TVC , vaccine efficacy ( VE ) against cervical intraepithelial neoplasia grade 1 or greater ( CIN1 + ) , CIN2 + , and CIN3 + associated with HPV-16/18 was 55.5 % ( 96.1 % confidence interval [ CI ] , 43.2 , 65.3 ) , 52.8 % ( 37.5 , 64.7 ) , and 33.6 % ( −1.1 , 56.9 ) . VE against CIN1 + , CIN2 + , and CIN3 + irrespective of HPV DNA was 21.7 % ( 10.7 , 31.4 ) , 30.4 % ( 16.4 , 42.1 ) , and 33.4 % ( 9.1 , 51.5 ) and was consistently significant only in 15- to 17-year-old women ( 27.4 % [ 10.8 , 40.9 ] , 41.8 % [ 22.3 , 56.7 ] , and 55.8 % [ 19.2 , 76.9 ] ) . In the TVC-naive , VE against CIN1 + , CIN2 + , and CIN3 + associated with HPV-16/18 was 96.5 % ( 89.0 , 99.4 ) , 98.4 % ( 90.4 , 100 ) , and 100 % ( 64.7 , 100 ) , and irrespective of HPV DNA it was 50.1 % ( 35.9 , 61.4 ) , 70.2 % ( 54.7 , 80.9 ) , and 87.0 % ( 54.9 , 97.7 ) . VE against 12-month persistent infection with HPV-16/18 was 89.9 % ( 84.0 , 94.0 ) , and that against HPV-31/33/45/51 was 49.0 % ( 34.7 , 60.3 ) . In conclusion , vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high- grade cervical abnormalities , and catch-up vaccination up to 18 years of age is most likely effective . ( This study has been registered at Clinical Trials.gov under registration no. NCT001226810 . BACKGROUND Previous Costa Rica Vaccine Trial ( CVT ) reports separately demonstrated vaccine efficacy against HPV16 and HPV18 ( HPV16/18 ) infections at the cervical , anal , and oral regions ; however , the combined overall multisite efficacy ( protection at all three sites ) and vaccine efficacy among women infected with HPV16 or HPV18 prior to vaccination are less known . METHODS Women age 18 to 25 years from the CVT were r and omly assigned to the HPV16/18 vaccine ( Cervarix ) or a hepatitis A vaccine . Cervical , oral , and anal specimens were collected at the four-year follow-up visit from 4186 women . Multisite and single-site vaccine efficacies ( VEs ) and 95 % confidence intervals ( CIs ) were computed for one-time detection of point prevalent HPV16/18 in the cervical , anal , and oral regions four years after vaccination . All statistical tests were two-sided . RESULTS The multisite woman-level vaccine efficacy was highest among " naïve " women ( HPV16/18 seronegative and cervical HPV high-risk DNA negative at vaccination ) ( vaccine efficacy = 83.5 % , 95 % CI = 72.1 % to 90.8 % ) . Multisite woman-level vaccine efficacy was also demonstrated among women with evidence of a pre-enrollment HPV16 or HPV18 infection ( seropositive for HPV16 and /or HPV18 but cervical HPV16/18 DNA negative at vaccination ) ( vaccine efficacy = 57.8 % , 95 % CI = 34.4 % to 73.4 % ) , but not in those with cervical HPV16 and /or HPV18 DNA at vaccination ( anal/oral HPV16/18 VE = 25.3 % , 95 % CI = -40.4 % to 61.1 % ) . Concordant HPV16/18 infections at two or three sites were also less common in HPV16/18-infected women in the HPV vaccine vs control arm ( 7.4 % vs 30.4 % , P < .001 ) . CONCLUSIONS This study found high multisite vaccine efficacy among " naïve " women and also suggests the vaccine may provide protection against HPV16/18 infections at one or more anatomic sites among some women infected with these types prior to HPV16/18 vaccination Due to sporadic and not easily accessible cervical cancer screening , human papillomavirus (HPV)-related cervical cancer is a leading cause of cancer death in Sub-Saharan African women . This study was design ed to assess the safety and immunogenicity of a quadrivalent human papillomavirus ( qHPV ) vaccine in sub-Saharan African women . This seven month , double-blind study enrolled 250 healthy , human immunodeficiency virus (HIV)-uninfected females ages 9–26 residing in Ghana , Kenya , and Senegal . Thirty females ages 13–15 and 120 females ages 16–26 received qHPV vaccine . In addition , 100 females ages 9–12 y were r and omized in a 4:1 ratio to receive either qHPV vaccine ( n = 80 ) or placebo ( n = 20 ) . The primary immunogenicity hypothesis was that an acceptable percentage of subjects who received the qHPV vaccine seroconvert to HPV6/11/16/18 at 4 weeks post-dose 3 , defined as the lower bound of the corresponding 95 % confidence interval ( CI ) exceeding 90 % . The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen . The pre-specified statistical criterion for the primary immunogenicity hypothesis was met : the lower bound of the 95 % exact binomial CI on the seroconversion rate was at least 98 % for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3 . Across vaccination groups , the most common adverse events ( AE ) were at the injection site , including pain , swelling , and erythema . No subject discontinued study medication due to an AE and no serious AEs were reported . There were no deaths . This study demonstrated that qHPV vaccination of sub-Saharan African women was highly immunogenic and generally well tolerated BACKGROUND A community-based r and omized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine ( NCT00128661 ) . The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease ( CIN2 + ) associated with incident HPV-16/18 cervical infections . Secondary objectives were to evaluate efficacy against CIN2 + associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18 . Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated . METHODS We r and omized ( 3727 HPV arm ; 3739 control arm ) , vaccinated ( HPV-16/18 or Hepatitis A ) and followed ( median 53.8 months ) 7466 healthy women aged 18 - 25 years . 5312 women ( 2635 HPV arm ; 2677 control arm ) were included in the according to protocol analysis for efficacy . The full cohort was evaluated for safety . Immunogenicity was considered on a subset of 354 ( HPV-16 ) and 379 ( HPV-18 ) women . HPV type was assessed by PCR on cervical specimens . Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays . Disease outcomes were histologically confirmed . Vaccine efficacy and 95 % confidence intervals ( 95%CI ) were computed . RESULTS Vaccine efficacy was 89.8 % ( 95 % CI : 39.5 - 99.5 ; N=11 events total ) against HPV-16/18 associated CIN2 + , 59.9 % ( 95 % CI : 20.7 - 80.8 ; N=39 events total ) against CIN2 + associated with non-HPV-16/18 oncogenic HPVs and 61.4 % ( 95 % CI : 29.5 - 79.8 ; N=51 events total ) against CIN2 + irrespective of HPV type . The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses . CONCLUSIONS Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types . These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial . TRIAL REGISTRATION Registered with clinical trials.gov : NCT00128661 BACKGROUND Infection with human papillomavirus ( HPV ) and diseases caused by HPV are common in boys and men . We report on the safety of a quadrivalent vaccine ( active against HPV types 6 , 11 , 16 , and 18 ) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men . METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age , from 18 countries in a r and omized , placebo-controlled , double-blind trial . The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6 , 11 , 16 , or 18 . Efficacy analyses were conducted in a per- protocol population , in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment , and in an intention-to-treat population , in which subjects received vaccine or placebo , regardless of baseline HPV status . RESULTS In the intention-to-treat population , 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group , for an observed efficacy of 60.2 % ( 95 % confidence interval [ CI ] , 40.8 to 73.8 ) ; the efficacy was 65.5 % ( 95 % CI , 45.8 to 78.6 ) for lesions related to HPV-6 , 11 , 16 , or 18 . In the per- protocol population , efficacy against lesions related to HPV-6 , 11 , 16 , or 18 was 90.4 % ( 95 % CI , 69.2 to 98.1 ) . Efficacy with respect to persistent infection with HPV-6 , 11 , 16 , or 18 and detection of related DNA at any time was 47.8 % ( 95 % CI , 36.0 to 57.6 ) and 27.1 % ( 95 % CI , 16.6 to 36.3 ) , respectively , in the intention-to-treat population and 85.6 % ( 97.5 % CI , 73.4 to 92.9 ) and 44.7 % ( 95 % CI , 31.5 to 55.6 ) in the per- protocol population . Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo ( 57 % vs. 51 % , P<0.001 ) . CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6 , 11 , 16 , and 18 and the development of related external genital  lesions in males 16 to 26 years of age . ( Funded by Merck and others ; Clinical Trials.gov number , NCT00090285 . ) 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 The human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine has been demonstrated to be highly efficacious and immunogenic with a favorable safety profile . This study assessed the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Korean girls aged 10 - 14 yr . This multi-center , observer-blind trial r and omly assigned 321 healthy girls to receive three doses ( 0 , 1 , 6-month schedule ) of HPV-16/18 AS04-adjuvanted vaccine or hepatitis A vaccine . Immunogenicity against vaccine antigens was assessed one month post-Dose 3 . Solicited and unsolicited adverse events ( AEs ) and serious AEs ( SAEs ) were recorded . In the according-to- protocol analysis , all initially seronegative subjects vaccinated with the HPV-16/18 AS04-adjuvanted vaccine had seroconverted at Month 7 , with a peak geometric mean titer ( GMT ) that was 600-fold higher than the natural infection titer of 29.8 EU/mL for HPV-16 and a peak GMT that was 400-fold higher than the natural infection titer of 22.6 EU/mL for HPV-18 . The vaccine was well tolerated with no increase in reactogenicity with subsequent doses and no reports of vaccine-related SAEs . In conclusion , the HPV-16/18 AS04-adjuvanted vaccine is shown to be highly immunogenic and generally well-tolerated in Korean girls aged 10 - 14 yr ABSTRACT This community-r and omized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus ( HPV ) immunization strategies in over 80,000 girls and boys aged 12–15 y in 33 communities in Finl and ( Clinical Trials.gov NCT00534638 ) . Overall , 14,838 adolescents received HPV-16/18 vaccine ( 2,440 boys and 12,398 girls ) and 17,338 received hepatitis-B virus ( HBV ) vaccine ( 9,221 boys and 8,117 girls ) . In an interim analysis , vaccine safety was assessed by active monitoring and surveillance via health registry linkage . Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys . In all study participants , the observed incidences ( per 100,000 person-years ) of serious adverse events ( SAEs ) possibly related to vaccination were 54.3 ( 95 % Confidence Interval [ CI ] : 34.0–82.1 ) in the HPV-16/18 group and 64.0 ( 95 % CI : 43.2–91.3 ) in the HBV group . During the follow-up period for this interim analysis , the most common new-onset autoimmune diseases ( NOADs ; with incidence rate ≥15 per 100,000 ) in any group based on hospital discharge registry ( HILMO ) download were ulcerative colitis , juvenile arthritis , celiac disease , insulin-dependent diabetes mellitus ( IDDM ) and Crohn 's disease . No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients . In both the SAE possibly related- and HILMO-analyses , a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees ( relative risks , 0.26 [ 95 % CI : 0.03–1.24 ] and 0.16 [ 95 % CI : 0.03–0.55 ] , respectively ) HPV-023 ( NCT00518336 ; Clinical Trial.gov ) is a long-term follow-up of an initial double-blind , r and omized ( 1:1 ) , placebo-controlled study ( HPV-001 , NCT00689741 ) evaluating the efficacy against  human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities  , persistence of immunogenicity , and safety of the HPV-16/18 AS04-adjuvanted vaccine . Among the women , aged 15–25 years , enrolled in HPV-001 and who participated in the follow-up study HPV-007 ( NCT00120848 ) , a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up ( HPV-023 ) for a total of 113 months ( 9.4 years ) . During HPV-023 , anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay ( ELISA ) and pseudovirion-based neutralisation assay ( PBNA ) . Cervical sample s were tested for HPV DNA every 6 months , and cyto-pathological examinations were performed annually . During HPV-023 , no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group . Vaccine efficacy ( VE ) against HPV-16/18 incident infection was 100 % ( 95%CI : 66.1 , 100 ) . Over the 113 months ( 9.4 years ) , VE was 95.6 % ( 86.2 , 99.1 ; 3/50 cases in vaccine and placebo groups , respectively ) against incident infection , 100 % ( 84·1 , 100 ; 0/21 ) against 6-month persistent infection ( PI ) ; 100 % ( 61·4 , 100 ; 0/10 ) against 12-month PI ; 97·1 % ( 82.5 , 99.9 ; 1/30 ) against ≥ ASC-US ; 95·0 % ( 68.0 , 99.9 ; 1/18 ) against ≥ LSIL ; 100 % ( 45.2 , 100 ; 0/8 ) against CIN1 + ; and 100 % ( –128.1 , 100 ; 0/3 ) against CIN2 + associated with HPV-16/18 . All vaccinees remained seropositive to HPV-16/18 , with antibody titers remaining several folds above natural infection levels , as measured by ELISA and PBNA . There were no safety concerns . To date , these data represent the longest follow-up reported for a licensed HPV vaccine 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 This phase II/III , double-blind , r and omized trial assessed the efficacy , immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women ( Clinical Trials.gov registration NCT00779766 ) . Women aged 18–25 years from Jiangsu province were r and omized ( 1:1 ) to receive  HPV vaccine ( n = 3,026 ) or Al(OH)3 control ( n = 3,025 ) at months 0 , 1 and 6 . The primary objective was vaccine efficacy ( VE ) against HPV-16/18 associated 6-month persistent infection ( PI ) and /or cervical intraepithelial neoplasia ( CIN ) 1 + . Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types , immunogenicity and safety . Mean follow-up for the according-to- protocol cohort for efficacy ( ATP-E ) was ∼15 months after the third dose . In the ATP-E ( vaccine = 2,889 ; control = 2,894 ) , for initially HPV DNA negative and seronegative subjects , HPV-16/18 related VE ( 95 % CI ) was 94.2 % ( 62.7 , 99.9 ) against 6-month PI and /or CIN1 + and 93.8 % ( 60.2 , 99.9 ) against cytological abnormalities . VE against HPV-16/18 associated CIN1 + and CIN2 + was 100 % ( −50.4 , 100 ) and 100 % ( −140.2 , 100 ) , respectively ( no cases in the vaccine group and 4 CIN1 + and 3 CIN2 + cases in the control group ) . At Month 7 , at least 99.7 % of initially seronegative vaccine recipients had seroconverted for HPV-16/18 ; geometric mean antibody titres ( 95 % CI ) were 6,996 ( 6,212 to 7,880 ) EU/mL for anti-HPV-16 and 3,309 ( 2,942 to 3,723 ) EU/mL for anti-HPV-18 . Safety outcomes between groups were generally similar . The HPV-16/18 AS04-adjuvanted vaccine is effective , immunogenic and has a clinical ly acceptable safety profile in young Chinese women . Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China . What 's New ? With an estimated 75,000 new cases and 34,000 women dying from the disease annually , cervical cancer is a major public-health concern in China . This is the first large scale r and omised clinical trial of a human papillomavirus ( HPV ) vaccine in China . The vaccine was found to be effective , immunogenic , and to have a clinical ly acceptable safety profile in young Chinese women .  Prophylactic HPV vaccination thus has the potential to substantially reduce the burden of cervical cancers and precancers in China 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 Target groups for human papillomavirus ( HPV ) vaccination are controversial . We evaluated vaccine efficacy ( VE ) against 1-year persistent infection , stratified by age and sexual behavior , among young women in Costa Rica . We r and omized 7,466 healthy women 18 to 25 years of age to HPV16/18 or hepatitis A vaccine ( follow-up , 50.4 months ) . According-to- protocol ( ATP ) cohorts included compliant HPV-negative women ; intention-to-treat ( ITT ) included all r and omized women .  ATP VE was 90.9 % ( 95 % CI , 82.0 - 95.9 ) against HPV16/18 infections , 44.5 % against HPV31/33/45 ( 95 % CI , 17.5 - 63.1 ) , and 12.4 % ( 95 % CI , -3.2 to 25.6 ) against any oncogenic infection . Overall ITT VE against HPV16/18 infections was 49.0 % , but ATP and ITT VE almost reached 100 % in year 4 of follow-up . ATP efficacy against HPV16/18 was similar by age , but ITT VE was greatest among youngest women ( 68.9 % among those 18 - 19 years of age ; 21.8 % among those 24 - 25 years of age ) and 79.8 % among virgins . Among previously unexposed women , vaccination is highly efficacious against HPV16/18 and partially against HPV31/33/45 . Vaccination is most effective in women and girls before they initiate sexual activity , with programmatic and individual decision implication 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 : A 9-valent human papillomavirus ( 9vHPV ) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 [ as per the licensed quadrivalent HPV ( qHPV ) vaccine ] , as well as 5 additional oncogenic HPV types ( HPV 31/33/45/52/58 ) . Compared with the qHPV vaccine , the 9vHPV vaccine potentially increases the coverage of protection from 70 % to 90 % of cervical cancers . We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 9–15-year-old girls . Methods : Participants ( n = 600 ) were r and omized to receive 9vHPV or qHPV vaccines on day 1 , month 2 and month 6 . Serology testing was performed on day 1 and month 7 . HPV type-specific antibody titers ( anti-HPV 6/11/16/18/31/33/45/52/58 ) were determined by competitive Luminex immunoassay and expressed as geometric mean titers and seroconversion rates . Vaccine safety was also assessed . Results : The HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine . All participants ( except 1 for HPV 45 ) receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58 . The 9vHPV and qHPV vaccines showed comparable safety profiles , although the incidence of injection-site swelling was higher in the 9vHPV vaccine group . Conclusions : In addition to immune responses to HPV 31/33/45/52/58 , a 3-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 9–15 years . The safety profile was also similar for the 2 vaccines BACKGROUND We compared the immunogenicity and reactogenicity of Cervarix or Gardasil human papillomavirus ( HPV ) vaccines in adults infected with the human immunodeficiency virus ( HIV ) . METHODS This was a double-blind , controlled trial r and omizing HIV-positive adults to receive 3 doses of Cervarix or Gardasil at 0 , 1.5 , and 6 months . Immunogenicity was evaluated for up to 12 months . Neutralizing anti-HPV-16/18 antibodies were measured by pseudovirion-based neutralization assay . Laboratory tests and diary cards were used for safety assessment . The HPV-DNA status of the participants was determined before and after immunization . RESULTS Ninety-two participants were included in the study .  Anti-HPV-18 antibody titers were higher in the Cervarix group compared with the Gardasil group at 7 and 12 months . No significant differences in anti-HPV-16 antibody titers were found among vaccine groups . Among Cervarix vaccinees , women had higher anti-HPV-16/18 antibody titers compared to men . No sex-specific differences in antibody titers were found in the Gardasil group . Mild injection site reactions were more common in the Cervarix group than in the Gardasil group ( 91.1 % vs 69.6 % ; P = .02 ) . No serious adverse events occurred . CONCLUSIONS Both vaccines were immunogenic and well tolerated . Compared with Gardasil , Cervarix induced superior vaccine responses among HIV-infected women , whereas in HIV-infected men the difference in immunogenicity was less pronounced Prophylactic vaccination with a quadrivalent HPV ( types 6 , 11 , 16 , 18 ) vaccine ( qHPV ) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently , in men . Here we report on the safety and reactogenicity of the qHPV vaccine in males . A total of 4,065 healthy males aged 16 - 26 years were enrolled into a r and omized , placebo-controlled , double-blind trial . Subjects were r and omized 1:1 to receive qHPV vaccine or placebo at day 1 , month 2 , and month 6 . Safety and tolerability were assessed via the collection of reported adverse experiences ( AEs ) . All serious AEs ( vaccine- or procedure-related or not ) and all deaths occurring during the study were recorded . Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo . The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group ( 60.1 % vs 53.7 % , respectively ) , however most of these AEs were mild/moderate in intensity . The incidence of at least one systemic AE was comparable between the vaccine and placebo groups ( 31.7 % vs 31.4 % , respectively ) . There were no vaccine-related serious AEs or deaths . The occurrence of AEs did not increase with each successive injection , and among trial participants who were seropositive for at least one vaccine HPV type at enrollment , the profile of adverse events was similar to that of the entire study cohort . The qHPV vaccine was generally well tolerated  in males aged 16 - 26 years and had a favorable safety profile PURPOSE Immunization of girls against oncogenic human papillomavirus ( HPV ) types before sexual debut is important for cervical cancer prevention . This phase III blinded , r and omized , controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine . METHODS Girls ( mean age 12 years ) in 12 countries received the  HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine ( N = 1,035 ) or hepatitis A virus vaccine as control ( N = 1,032 ) at 0 , 1 , and 6 months . The primary objective was to compare the occurrence of serious adverse events ( SAEs ) between groups . HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination . RESULTS Up to study month 7 , 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs . The difference in SAE incidence between groups was .20 % ( 95 % CI , -.78 , 1.20 ) . No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal . The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control . The incidence of unsolicited symptoms , new onset of chronic diseases , and medically significant conditions was similar between groups . All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine ; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies , respectively , in initially seronegative girls . CONCLUSIONS The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females , the primary target of organized vaccination programs Background Human papillomavirus ( HPV ) infection , particularly with type 16 , causes a growing fraction of oropharyngeal cancers , whose incidence is increasing , mainly in developed countries . In a double-blind controlled trial conducted to investigate vaccine efficacy ( VE ) of the bivalent HPV 16/18 vaccine against cervical infections and lesions , we estimated VE against prevalent oral HPV infections 4 years after vaccination . Methods and Findings A total of 7,466 women 18–25 years old were r and omized ( 1∶1 ) to receive the HPV16/18 vaccine or hepatitis A vaccine as control . At the final blinded 4-year study visit , 5,840 participants provided oral specimens ( 91·9 % of eligible women ) to evaluate VE against oral infections . Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results . Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison . Oral prevalence of identifiable mucosal HPV was relatively low ( 1·7 % ) . Approximately four years after vaccination , there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group , for an estimated VE of 93·3 % ( 95 % CI = 63 % to 100 % ) . Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0 % ( 95 % CI = 63 % to 79 % ) ( p versus oral VE = 0·04 ) . There was no statistically significant protection against other oral HPV infections , though power was limited for these analyses . Conclusions HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm , suggesting that the vaccine affords strong protection against oral HPV16/18 infection , with potentially important implication s for prevention of increasingly common HPV-associated oropharyngeal cancer . Clinical Trials.gov , Registry number Background : Human papillomavirus ( HPV ) type 16/18 AS04-adjuvanted vaccine was shown to be highly immunogenic and generally well tolerated in the interim analysis of a phase 2 double-blind , r and omized controlled multicenter study in Japanese healthy women aged 20 to 25 years .  Vaccine efficacy , immunogenicity , and safety are assessed in this study through 24 months after the first vaccination . Methods : Japanese women aged 20 to 25 years were r and omly assigned to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 519 ) or hepatitis A vaccine ( n = 521 ) at 0 , 1 , and 6 months . Women were assessed for virological , cytological , and histological end points associated with HPV-16/18 and 12 other oncogenic HPV types ( types 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 66 , and 68 ) in cervical specimens and for the vaccine safety and immunogenicity . Antibody concentrations were measured by an enzyme-linked immunosorbent assay . Primary efficacy analysis was performed in the according-to- protocol cohort for efficacy , primary immunogenicity analysis was performed in the according-to- protocol cohort for immunogenicity , and primary safety analysis was done in the total vaccinated cohort . Results : Vaccine efficacy against persistent infections ( 6 month definition ) associated with HPV-16/18 was 100 % ( 95.5 % confidence interval , 71.3 - 100 ; P < 0.0001 ) . Vaccine efficacy against cervical intraepithelial neoplasia 1 + associated with 14 oncogenic HPV types was 64.9 % ( 95.5 % confidence interval , 4.9 - 89.0 ; P = 0.02 ) . At 24 months after the first dose of the vaccine , geometric mean antibody titers against HPV-16 and HPV-18 were 1521.5 enzyme-linked immunosorbent assay U/mL and 627.4 enzyme-linked immunosorbent assay U/mL , respectively . The HPV-16/18 AS04-adjuvanted vaccine had a clinical ly acceptable safety profile . Conclusions : The HPV-16/18 AS04-adjuvanted vaccine showed excellent prophylactic efficacy against 6-month persistent infection with HPV-16/18 . The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic in the study population of healthy Japanese women aged 20 to 25 years Adolescents and young adults are at high risk for human papillomavirus ( HPV ) and hepatitis B virus ( HBV ) infections , which are preventable by currently available , safe and effective , prophylactic vaccines . However , development of a combined immunization strategy may lead to better compliance for these vaccines , thereby contributing to the overall goal of protection against these diseases . This study assessed the safety and immunogenicity of co-administered quadrivalent HPV-6/11/16/18 L1 VLP and HBV vaccines in women ( n=1877 ) aged 16 - 23 years . Co-administration of HPV and HBV vaccines induced robust anti-HPV-6 , HPV-11 , HPV-16 , HPV-18 geometric mean titers ( GMTs ) and > or = 99 % seroconversion rates ( Month 7 ) that were both non-inferior ( p<0.001 ) to those induced by HPV vaccine alone . High Month 7 anti-HBs GMTs were also observed following concomitant vaccination . These GMTs were lower compared to those induced by the HBV vaccine itself ; however , > 96 % of subjects achieved an anti-HBs seroprotection level of > or = 10 mIU/mL that was non-inferior ( p<0.001 ) to that of HBV vaccine alone . Overall , co-administered and individual vaccines were generally well-tolerated and did not interfere with the immune response of either vaccine ( Clinical Trials.gov number , NCT00092521 ) Objective : Administration of a quadrivalent HPV-6/11/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/11/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts . As the risk of acquiring HPV significantly rises after sexual debut , HPV vaccines should have the greatest benefit in sexually naive adolescents . We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment . Methods : In this r and omized , double-blind trial , 1781 sexually naive children were assigned ( 2:1 ) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6 . Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers ( GMTs ) and seroconversion rates . Primary analyses were done per- protocol ( subjects received 3 doses , had no major protocol violations and were HPV type-specific seronegative at day 1 ) . Adverse experiences were collected by diary card . Results : At month 7 , seroconversion rates were ≥99.5 % for the 4 vaccine-HPV-types . GMTs and seroconversion rates in boys were noninferior to those in girls ( P < 0.001 ) . At month 18 , ≥91.5 % of vaccine recipients were seropositive , regardless of gender . A higher proportion of vaccine recipients ( 75.3 % ) than placebo recipients ( 50.0 % ) reported one or more injection-site adverse experiences following any vaccination . Rates of fever were similar between vaccination groups . No serious vaccine-related adverse experiences were reported . Conclusions : In 9- to 15-year-old adolescents , the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen . The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease , particularly cervical cancer and precancers In this open , extended follow-up study ( NCT00929526 , Clinical trials.gov ) , we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy , immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20–25 years . In the initial r and omized , double-blind study ( NCT00316693 ) , 1040 women received the  study vaccine or hepatitis A control vaccine ;  752 women were included in the follow-up study . In women from the according-to- protocol efficacy cohort ( ATP-E ) , who were initially seronegative for the HPV type analyzed , no cervical intraepithelial neoplasia ( CIN ) grade 1 or greater ( CIN1 + ) cases associated with HPV-16/18 were reported in the HPV group , while in the control group , 5 cases were identified in extended follow-up analyses ( vaccine efficacy [ VE ] 100 % [ 95 % CI : −3.7–100 ] ) and 8 cases in combined initial and follow-up studies analyses ( VE 100 % [ 42.2–100 ] ) . In the ATP-E , VE against CIN1 + and CIN2 + associated with high-risk HPV types reached 66.4 % ( 21.6–87.1 ) and 83.0 % ( 22.1–98.2 ) in extended follow-up analyses , and 63.4 % ( 28.8–82.3 ) and 77.3 % ( 30.4–94.4 ) in analyses of combined studies , respectively . During the 4-year period , protection against CIN1 + and CIN2 + , irrespective of the HPV type , was 56.7 % ( 32.8–72.6 ) and 54.9 % ( 20.5–75.3 ) in women receiving ≥1 vaccine dose , regardless of baseline serostatus ( total vaccinated cohort [ TVC ] ) and 61.0 % ( 11.8–84.2 ) and 73.9 % ( 1.1–95.3 ) in women naïve to HPV infection at baseline ( TVC-naïve ) , respectively . The high VE observed in Japanese women , accompanied by a sustained immune response and a clinical ly acceptable safety profile , support findings of large , international trials 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 Human papillomavirus ( HPV ) is a major causative agent of anogenital warts and a necessary cause of cervical cancer . This report will serve to assess the safety and immunogenicity of quadrivalent ( types 6 , 11 , 16 , and 18 ) HPV L1 virus-like particle ( VLP ) vaccine in the Korean population . We performed a r and omized , double-blind , placebo-controlled study in 176 volunteers aged 9–23 years . Using a 2:1 ratio for r and omization , 117 women were assigned to quadrivalent HPV ( 20 μg type 6 , 40 μg type 11 , 40 μg type 16 , and 20 μg type 18 ) vaccine and 59 women  to placebo . Individuals received vaccine at day 1 , month 2 , and month 6 and provided blood sample s for analysis at enrollment at month 7 . Analyses were done as specified in the study protocol . Quadrivalent HPV vaccine was generally well tolerated , with no vaccine-related serious adverse experiences . Quadrivalent HPV vaccine induced seroconversion for each vaccine-related HPV type . At month 7 , vaccine-induced type-specific antibody titer was high . In conclusion , administration of quadrivalent HPV VLP vaccine to Korean women aged 9–23 years was generally well tolerated and highly BACKGROUND AND AIMS Recognition of human papillomavirus ( HPV ) as a necessary cause of cervical cancer ( CC ) led to new perspectives for its control and the demonstration of an effective primary prevention strategy through vaccination . We undertook this study to evaluate the safety , efficacy and immunogenicity of a quadrivalent HPV6/11/16/18 vaccine in Mexican women . METHODS A total of 679 Mexican women between 18 and 23 years old participated in two Phase III double-blind , r and omized , placebo-controlled clinical trials of a quadrivalent HPV 6/11/16/18 vaccine .  Women were enrolled who tested negative for pregnancy and reported having four or less sexual partners during their lifetime .  Vaccine or placebo was administered at day 1 , month 2 and month 6 . RESULTS Among Mexican women who were naïve to the respective vaccine type at enrollment , the quadrivalent vaccine was highly efficacious , preventing 100 % of HPV6/11/16/18-related cervical intraepithelial neoplasia grade 2/3 , adenocarcinoma in situ , condyloma and vaginal intraepithelial neoplasia . Statistical significance was not reached for every endpoint due to the limited sample size . Vaccination was generally well tolerated and immunogenic . DISCUSSION To widely administer the vaccine , collaborative efforts should be coordinated among public , private and local community sectors . In light of the scarce knowledge of many health professionals with respect to the primary prevention of CC , it will be necessary to educate health providers on the advantages and specific recommendations of HPV vaccines and secondary prevention . Decision making should be based on scientific evidence , allowing health professionals to provide an organized social response that supports the universal right to health
Our purpose was to determine the effectiveness and harms of vaccination in patients with any sexual history to prevent the prevalence of papillomavirus infection .