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 Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. 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 The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18–45 years Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine
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 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 ] . ) 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 BACKGROUND We evaluated the impact of a quadrivalent human papillomavirus ( HPV ) vaccine on infection and cervical disease related to 10 nonvaccine HPV types ( 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , and 59 ) associated with > 20 % of cervical cancers . The population evaluated included HPV-naive women and women with preexisting HPV infection and /or HPV-related disease at enrollment . METHODS Phase 3 efficacy studies enrolled 17,622 women aged 16 - 26 years . Subjects underwent cervicovaginal sampling and Pap testing on day 1 and then at 6 - 12-month intervals for up to 4 years . HPV typing was performed on sample s from enrollment and follow-up visits , including sample s obtained for diagnosis or treatment of HPV-related disease . All subjects who received 1 dose and returned for follow-up were included . RESULTS Vaccination reduced the rate of HPV-31/33/45/52/58 infection by 17.7 % ( 95 % confidence interval [ CI ] , 5.1 % to 28.7 % ) and of cervical intraepithelial neoplasia ( CIN ) 1 - 3 or adenocarcinoma in situ ( AIS ) by 18.8 % ( 95 % CI , 7.4 % to 28.9 % ) . Vaccination also reduced the rate of HPV-31/58/59-related CIN1 - 3/AIS by 26.0 % ( 95 % CI , 6.7 % to 41.4 % ) , 28.1 % ( 95 % CI , 5.3 % to 45.6 % ) , and 37.6 % ( 95 % CI , 6.0 % to 59.1 % ) , respectively . Although a modest reduction in HPV-31/33/45/52/58-related CIN2 or worse was observed , the estimated reduction was not statistically significant . CONCLUSIONS These cross-protection results complement the vaccine 's prophylactic efficacy against disease associated with HPV-6 , -11 , -16 , and -18 . Long-term monitoring of vaccinated population s are needed to fully ascertain the population -based impact and public health significance of these findings . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00092521 , NCT00092534 , and NCT00092482 Protection against oncogenic non-vaccine types ( cross-protection ) offered by human papillomavirus ( HPV ) vaccines may provide a significant medical benefit . Available clinical efficacy data suggest the two licensed vaccines ( HPV-16/18 vaccine , GlaxoSmithKline Biologicals [ GSK ] , and HPV-6/11/16/18 vaccine , Merck & Co. , Inc. ) differ in terms of protection against oncogenic non-vaccine HPV types -31/45 . The immune responses induced by the two vaccines against these two non-vaccine HPV types ( cross-reactivity ) was compared in an observer-blind study up to Month 24 ( 18 months post-vaccination ) , in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed ( HPV-010 [ NCT00423046 ] ) . Geometric mean antibody titers ( GMTs ) measured by pseudovirion-based neutralization assay ( PBNA ) and enzyme-linked immunosorbent assay ( ELISA ) were similar between vaccines for HPV-31/45 . Seropositivity rates for HPV-31 were also similar between vaccines ; however , there was a trend for higher seropositivity with the HPV-16/18 vaccine ( 13.0–16.7 % ) versus the HPV-6/11/16/18 vaccine ( 0.0–5.0 % ) for HPV-45 with PBNA , but not ELISA . HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines . Circulating antigen-specific CD4 + T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine ( HPV-31 [ geometric mean ratio [ GMR ] = 2.0 ; p=0.0002 ] and HPV-45 [ GMR=2.6 ; p=0.0092 ] ) , as were the proportion of T-cell responders ( HPV-31 , p=0.0009 ; HPV-45 , p=0.0793 ) . In conclusion , immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine . Considering the differences in cross-protective efficacy between the two vaccines , the results might provide insights into the underlying mechanism(s ) of protection BACKGROUND We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of- study analysis after 4 years of follow-up in PATRICIA ( PApilloma TRIal against Cancer In young Adults ) . METHODS Healthy women aged 15 - 25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status , HPV-16 or HPV-18 serostatus , or cytology . Women were r and omly assigned ( 1:1 ) to HPV-16/18 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 study was double-blind . The primary endpoint of PATRICIA has been reported previously ; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of- study analysis . Analyses were done for three cohorts : the according-to- protocol cohort for efficacy ( ATP-E ; vaccine n=8067 , control n=8047 ) , total vaccinated HPV-naive cohort ( TVC-naive ; no evidence of infection with 14 oncogenic HPV types at baseline , approximating young adolescents before sexual debut ; vaccine n=5824 , control n=5820 ) , and the total vaccinated cohort ( TVC ; all women who received at least one vaccine dose , approximating catch-up population s that include sexually active women ; vaccine n=9319 , control=9325 ) . Vaccine efficacy was evaluated against 6-month persistent infection , cervical intraepithelial neoplasia grade 2 or greater ( CIN2 + ) associated with 12 non-vaccine HPV types ( individually or as composite endpoints ) , and CIN3 + associated with the composite of 12 non-vaccine HPV types . This study is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Consistent vaccine efficacy against persistent infection and CIN2 + ( with or without HPV-16/18 co-infection ) was seen across cohorts for HPV-33 , HPV-31 , HPV-45 , and HPV-51 . In the most conservative analysis of vaccine efficacy against CIN2 + , where all cases co-infected with HPV-16/18 were removed , vaccine efficacy was noted for HPV-33 in all cohorts , and for HPV-31 in the ATP-E and TVC-naive . Vaccine efficacy against CIN2 + associated with the composite of 12 non-vaccine HPV types ( 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 66 , and 68 ) , with or without HPV-16/18 co-infection , was 46·8 % ( 95 % CI 30·7 - 59·4 ) in the ATP-E , 56·2 % ( 37·2 - 69·9 ) in the TVC-naive , and 34·2 % ( 20·4 - 45·8 ) in the TVC . Corresponding values for CIN3 + were 73·8 % ( 48·3 - 87·9 ) , 91·4 % ( 65·0 - 99·0 ) , and 47·5 % ( 22·8 - 64·8 ) . INTERPRETATION Data from the end-of- study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine  against four oncogenic non-vaccine HPV types-HPV-33 , HPV-31 , HPV-45 , and HPV-51-in different trial cohorts representing diverse groups of women . FUNDING GlaxoSmithKline Biologicals BACKGROUND Human papillomavirus (HPV)-6/11/16/18 vaccine reduces the risk of HPV-6/11/16/18-related cervical intraepithelial neoplasia ( CIN ) 1 - 3 or adenocarcinoma in situ ( AIS ) . Here , its impact on CIN1 - 3/AIS associated with nonvaccine oncogenic HPV types was evaluated . METHODS We enrolled 17,622 women aged 16 - 26 years . All underwent cervicovaginal sampling and Pap testing at regular intervals for up to 4 years .  HPV genotyping was performed for biopsy sample s , and histological diagnoses were determined by a pathology panel . Analyses were conducted among subjects who were negative for 14 HPV types on day 1 . Prespecified analyses included infection of 6 months ' duration and CIN1 - 3/AIS due to the 2 and 5 most common HPV types in cervical cancer after HPV types 16 and 18 , as well as all tested nonvaccine types . RESULTS Vaccination reduced the incidence of HPV-31/45 infection by 40.3 % ( 95 % confidence interval [ CI ] , 13.9 % to 59.0 % ) and of CIN1 - 3/AIS by 43.6 % ( 95 % CI , 12.9 % to 64.1 % ) , respectively . The reduction in HPV-31/33/45/52/58 infection and CIN1 - 3/AIS was 25.0 % ( 95 % CI , 5.0 % to 40.9 % ) and 29.2 % ( 95 % CI , 8.3 % to 45.5 % ) , respectively . Efficacy for CIN2 - 3/AIS associated with the 10 nonvaccine HPV types was 32.5 % ( 95 % CI , 6.0 % to 51.9 % ) . Reductions were most notable for HPV-31 . CONCLUSIONS HPV-6/11/16/18 vaccine reduced the risk of CIN2 - 3/AIS associated with nonvaccine types responsible for approximately 20 % of cervical cancers . The clinical benefit of cross-protection is not expected to be fully additive to the efficacy already observed against HPV-6/11/16/18-related disease , because women may have > 1 CIN lesion , each associated with a different HPV type . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00092521 , NCT00092534 , and NCT00092482 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 The extent of cross-protection is a key element in the choice of human papillomavirus ( HPV ) vaccine to use in vaccination programmes .
We compared the cross-protective efficacy of the bivalent vaccine ( HPV 16 and 18 ; Cervarix , GlaxoSmithKline Biologicals , Rixensart , Belgium ) and quadrivalent vaccine ( HPV 6 , 11 , 16 , and 18 ; Gardasil , Merck , Whitehouse Station , NJ , USA ) against non-vaccine type HPVs .