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 Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. 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 Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. Sustained efficacy up to 4·5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. A controlled trial of a human papillomavirus type 16 vaccine. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years.
BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic , generally well tolerated , and effective against HPV-16 or HPV-18 infections , and associated precancerous lesions in an event-triggered interim analysis of the phase III 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 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 ] . ) CONTEXT Viruslike particle human papillomavirus ( HPV ) vaccines were design ed to prevent HPV infection and development of cervical precancers and cancer . Women with oncogenic HPV infections might consider vaccination as therapy . OBJECTIVE To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV . DESIGN AND SETTING Phase 3 , masked , community-based r and omized trial conducted in 2 provinces of Costa Rica . PARTICIPANTS A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005 . Participants were positive for HPV DNA at enrollment , had at least 6 months of follow-up , and had follow-up HPV DNA results . INTERVENTION Participants were r and omly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 c and i date vaccine ( n = 1088 ) or a control hepatitis A vaccine ( n = 1101 ) over 6 months . MAIN OUTCOME MEASURES Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination . We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit ( after 2 doses ) and 12-month visit ( after 3 doses ) in the 2 study groups . RESULTS There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group . Clearance rates for HPV-16/18 infections at 6 months were 33.4 % ( 82/248 ) in the HPV vaccine group and 31.6 % ( 95/298 ) in the control group ( vaccine efficacy for viral clearance , 2.5 % ; 95 % confidence interval , -9.8 % to 13.5 % ) . Human papillomavirus 16/18 clearance rates at 12 months were 48.8 % ( 86/177 ) in the HPV vaccine group and 49.8 % ( 110/220 ) in the control group ( vaccine efficacy for viral clearance , -2.0 % ; 95 % confidence interval , -24.3 % to 16.3 % ) . There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories , among women receiving all vaccine doses , among women with single infections , or among women stratified by the following entry variables : HPV-16/18 serology , cytologic results , HPV DNA viral load , time since sexual debut , Chlamydia trachomatis or Neisseria gonorrhoeae infection , hormonal contraceptive use , or smoking . CONCLUSION In women positive for HPV DNA , HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00128661 Human papillomavirus ( HPV ) causes cervical , vulvar , and vaginal cancers , precancerous dysplasia , and genital warts . We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine . In total , 552 women ( 16–23 years ) were enrolled in a r and omised , placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0 , 2 , and 6 . At regular intervals through 3 years , subjects underwent gynaecologic examination , cervicovaginal sampling for HPV DNA , serum anti-HPV testing , and Pap testing , with follow-up biopsy as indicated . A subset of 241 subjects underwent two further years of follow-up . At 5 years post enrolment , the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96 % ( two cases vaccine versus 46 placebo ) . There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients , and six cases in placebo recipients ( efficacy=100 % ; 95 % CI:12–100 % ) . Through 5 years , vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection . In conclusion , a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18 . This duration supports vaccination of adolescents and young adults , which is expected to greatly reduce the burden of cervical and genital cancers , precancerous dysplasia , and genital warts BACKGROUND Human papillomavirus types 16 ( HPV-16 ) and 18 ( HPV-18 ) cause approximately 70 % of cervical cancers worldwide . A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6 , 11 , 16 , and 18 ( HPV-6/11/16/18 ) for the prevention of high- grade cervical lesions associated with HPV-16 and HPV-18 . METHODS In this r and omized , double-blind trial , we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo , administered at day 1 , month 2 , and month 6 . The primary analysis was performed for a per- protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose ( month 7 ) . The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3 , adenocarcinoma in situ , or cervical cancer related to HPV-16 or HPV-18 . RESULTS Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo .  Vaccine efficacy for the prevention of the primary composite end point was 98 % ( 95.89 % confidence interval [ CI ] , 86 to 100 ) in the per- protocol susceptible population and 44 % ( 95 % CI , 26 to 58 ) in an intention-to-treat population of all women who had undergone r and omization ( those with or without previous infection ) . The estimated vaccine efficacy against all high- grade cervical lesions , regardless of causal HPV type , in this intention-to-treat population was 17 % ( 95 % CI , 1 to 31 ) . CONCLUSIONS In young women who had not been previously infected with HPV-16 or HPV-18 , those in the vaccine group had a significantly lower occurrence of high- grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group . ( Clinical Trials.gov number , NCT00092534 [ Clinical Trials.gov ] . ) BACKGROUND Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions . Our aim was to assess the long-term efficacy , immunogenicity , and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes . METHODS We did a follow-up study of our multicentre , double-blind , r and omised , placebo-controlled trial reported in 2004 . We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine ( 0.5 mL ; n=393 ) or placebo ( n=383 ) . We assessed HPV DNA , using cervical sample s , and did yearly cervical cytology assessment s. We also studied the long-term immunogenicity and safety of the vaccine . FINDINGS More than 98 % seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase . We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints : incident infection , 96.9 % ( 95 % CI 81.3 - 99.9 ) ; persistent infection : 6 month definition , 94.3 ( 63.2 - 99.9 ) ; 12 month definition , 100 % ( 33.6 - 100 ) . In a combined analysis of the initial efficacy and extended follow-up studies , vaccine efficacy of 100 % ( 42.4 - 100 ) against cervical intraepithelial neoplasia ( CIN ) lesions associated with vaccine types . We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31 . The vaccine has a good long-term safety profile . INTERPRETATION Up to 4.5 years , the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe , and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions . There is also evidence of cross protection 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 BACKGROUND The aim of this interim analysis of a large , international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic c and i date vaccine against infection with human papillomavirus ( HPV ) types 16 and 18 in young women . METHODS 18,644 women aged 15 - 25 years were r and omly assigned to receive either HPV16/18 vaccine ( n=9319 ) or hepatitis A vaccine ( n=9325 ) at 0 , 1 , and 6 months . Of these women , 88 were excluded because of high- grade cytology and 31 for missing cytology results . Thus , 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy , which included women who had prevalent oncogenic HPV infections , often with several HPV types , as well as low- grade cytological abnormalities at study entry and who received at least one vaccine dose . We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR . The primary endpoint -- vaccine efficacy against cervical intraepithelial neoplasia ( CIN ) 2 + associated with HPV16 or HPV18 - -was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline ( month 0 ) and allowed inclusion of lesions with several oncogenic HPV types . This interim event-defined analysis was triggered when at least 23 cases of CIN2 + with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy . Analyses were done on a modified intention-to-treat basis . This trial is registered with the US National Institutes of Health clinical trial registry , number NCT00122681 . FINDINGS Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14.8 ( SD 4.9 ) months . Two cases of CIN2 + associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group ; 21 were recorded in the control group . Of the 23 cases , 14 ( two in the HPV16/18 vaccine group , 12 in the control group ) contained several oncogenic HPV types . Vaccine efficacy against CIN2 + containing HPV16/18 DNA was 90.4 % ( 97.9 % CI 53.4 - 99.3 ; p<0.0001 ) . No clinical ly meaningful differences were noted in safety outcomes between the study groups . INTERPRETATION The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2 + associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention Objective In the quadrivalent ( types 6/11/16/18 ) HPV vaccine ( GARDASIL ® /SILGARD ® ) clinical program , 73 % of women aged 16 - 26 were naïve to all vaccine HPV types . In these women , prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease . Of the remaining women , 15 % of had evidence of past infection with one or more vaccine HPV types ( seropositive and DNA negative ) at the time of enrollment . Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared . Vaccine tolerability in this previously infected population was also assessed . Methods 18,174 women were enrolled into 3 clinical studies . The data presented comprise a subset of these subjects ( n = 2,617 ) who were HPV seropositive and DNA negative at enrollment ( for ≥1 vaccine type ) . In each study , subjects were r and omized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1 , month 2 and month 6 ( without knowledge of baseline HPV status ) . Procedures performed for efficacy data evaluation included detailed genital examination , Pap testing , and collection of cervicovaginal and external genital specimens . Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment . Results Subjects were followed for an average of 40 months . Seven subjects in the placebo group developed cervical disease , and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered . No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment . Conclusions These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time , however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types . Vaccine-related adverse experiences were higher among subjects receiving vaccine , mostly due to increased injection site adverse experiences BACKGROUND A r and omised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus ( HPV ) types associated with 70 % of cervical cancers ( types 16 and 18 ) and with 90 % of genital warts ( types 6 and 11 ) . METHODS 277 young women ( mean age 20.2 years [ SD 1.7 ] ) were r and omly assigned to quadrivalent HPV ( 20 microg type 6 , 40 microg type 11 , 40 microg type 16 , and 20 microg type 18 ) L1 virus-like-particle ( VLP ) vaccine and 275 ( mean age 20.0 years [ 1.7 ] ) to one of two placebo preparations at day 1 , month 2 , and month 6 . For 36 months , participants underwent regular gynaecological examinations , cervicovaginal sampling for HPV DNA , testing for serum antibodies to HPV , and Pap testing . The primary endpoint was the combined incidence of infection with HPV 6 , 11 , 16 , or 18 , or cervical or external genital disease ( ie , persistent HPV infection , HPV detection at the last recorded visit , cervical intraepithelial neoplasia , cervical cancer , or external genital lesions caused by the HPV types in the vaccine ) . Main analyses were done per protocol . FINDINGS Combined incidence of persistent infection or disease with HPV 6 , 11 , 16 , or 18 fell by 90 % ( 95 % CI 71 - 97 , p<0.0001 ) in those assigned vaccine compared with those assigned placebo . INTERPRETATION A vaccine targeting HPV types 6 , 11 , 16 , 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types BACKGROUND Approximately 20 percent of adults become infected with human papillomavirus type 16 ( HPV-16 ) . Although most infections are benign , some progress to anogenital cancer . A vaccine that reduces the incidence of HPV-16 infection may provide important public health benefits . METHODS In this double-blind study , we r and omly assigned 2392 young women ( defined as females 16 to 23 years of age ) to receive three doses of placebo or HPV-16 virus-like-particle vaccine ( 40 microg per dose ) , given at day 0 , month 2 , and month 6 . Genital sample s to test for HPV-16 DNA were obtained at enrollment , one month after the third vaccination , and every six months thereafter . Women were referred for colposcopy according to a protocol . Biopsy tissue was evaluated for cervical intraepithelial neoplasia and analyzed for HPV-16 DNA with use of the polymerase chain reaction . The primary end point was persistent HPV-16 infection , defined as the detection of HPV-16 DNA in sample s obtained at two or more visits . The primary analysis was limited to women who were negative for HPV-16 DNA and HPV-16 antibodies at enrollment and HPV-16 DNA at month 7 . RESULTS The women were followed for a median of 17.4 months after completing the vaccination regimen . The incidence of persistent HPV-16 infection was 3.8 per 100 woman-years at risk in the placebo group and 0 per 100 woman-years at risk in the vaccine group ( 100 percent efficacy ; 95 percent confidence interval , 90 to 100 ; P<0.001 ) . All nine cases of HPV-16-related cervical intraepithelial neoplasia occurred among the placebo recipients . CONCLUSIONS Administration of this HPV-16 vaccine reduced the incidence of both HPV-16 infection and HPV-16-related cervical intraepithelial neoplasia . Immunizing HPV-16-negative women may eventually reduce the incidence of cervical cancer BACKGROUND Vaccination against the most common oncogenic human papillomavirus ( HPV ) types , HPV-16 and HPV-18 , could prevent development of up to 70 % of cervical cancers worldwide . We did a r and omised , double-blind , controlled trial to assess the efficacy , safety , and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types , associated cervical cytological abnormalities , and precancerous lesions . METHODS We r and omised 1113 women between 15 - 25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo  on a 0 month , 1 month , and 6 month schedule in North America and Brazil . Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal sample s for up to 27 months , and for vaccine safety and immunogenicity . FINDINGS In the according-to- protocol analyses , vaccine efficacy was 91.6 % ( 95 % CI 64.5 - 98.0 ) against incident infection and 100 % against persistent infection ( 47.0 - 100 ) with HPV-16/18 . In the intention-to-treat analyses , vaccine efficacy was 95.1 % ( 63.5 - 99.3 ) against persistent cervical infection with HPV-16/18 and 92.9 % ( 70.0 - 98.3 ) against cytological abnormalities associated with HPV-16/18 infection . The vaccine was generally safe , well tolerated , and highly immunogenic . INTERPRETATION The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18 , and associated cytological abnormalities and lesions . Vaccination against such infections could substantially reduce incidence of cervical cancer We conducted an extended follow-up study ( March 2006-May 2008 ) to assess the longer term efficacy of a prophylactic monovalent human papillomavirus ( HPV ) type 16 L1 virus-like particle vaccine in women ( n=290 ) who had enrolled in a r and omized controlled trial of this vaccine ( October 1998-November 1999 ) in Seattle and remained HPV-16 DNA negative during the course of that trial . During the extended follow-up period , in the per- protocol susceptible population , none of the vaccine recipients was found to be infected with HPV-16 or developed HPV-16-related cervical lesions ; among placebo recipients , 6 women were found to be infected with HPV-16 ( vaccine efficacy [VE]=100 % ; 95 % confidence interval [ CI ] : 29 - 100 % ) and 3 women developed HPV-16-related cervical lesions ( VE=100 % ; 95 % CI : < 0 - 100 % ) . Approximately 86 % of vaccine recipients remained HPV-16 competitive Luminex immunoassay seropositive at an average of 8.5 years of follow-up . During the combined original trial and extended follow-up period , in the intention-to-treat population , 20 and 22 women developed any cervical lesion regardless of HPV type among the vaccine and placebo recipients , respectively ( VE=15 % ; 95 % CI : < 0 - 56 % ) . The results suggest that this monovalent HPV-16 vaccine remains efficacious through 8.5 years after its administration 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
Background We conducted a systematic review and meta- analysis to assess efficacy and safety of prophylactic HPV vaccines against cervical cancer precursor events in women .