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 Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women. Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. Impact of vaccination with Cervarix (trade mark) on subsequent HPV-16/18 infection and cervical disease in women 15-25 years of age. Safety and Immunogenicity Profile of Human Papillomavirus-16/18 AS04 Adjuvant Cervical Cancer Vaccine: A Randomized Controlled Trial in Healthy Adolescent Girls of Bangladesh Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. Vaccination with a Human Papillomavirus (HPV)-16/18 AS04-Adjuvanted Cervical Cancer Vaccine in Korean Girls Aged 10-14 Years Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. 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. 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 Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine: a randomized, controlled trial in adolescent girls. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials 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 Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo-controlled trial in 176 Korean subjects 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 Impact of a quadrivalent HPV6/11/16/18 vaccine in Mexican women: public health implications for the region. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials
BACKGROUND 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 ) AIM India has the highest number of annual incident cases and mortality rates for cervical cancer worldwide . This study was conducted to assess the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women aged 18 - 35 years old . METHODS This double-blind , r and omized ( 1:1 ) , controlled and multicenter trial with two parallel groups , the Vaccine and  Placebo groups , included 354 subjects in four centers across India . Subjects were given GlaxoSmithKline 's HPV-16/18 AS04-adjuvanted cervical cancer vaccine or aluminum hydroxide placebo according to a 0 , 1 and 6 month schedule and followed up until month 7 . Serum sample s were drawn at pre-vaccination and at month 7 . Safety data were collected throughout the study . RESULTS A total of 330 subjects completed the study . One month post-Dose 3 , all initially seronegative subjects in the Vaccine group had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titer levels of 10226.5 EL.U/ml ( 95 % confidence interval : 8847.1 - 11821.0 ) and 3953.0 EL.U/ml ( 95 % confidence interval : 3421.8 - 4566.8 ) , respectively . Initially seropositive subjects also showed an increase to similar geometric mean titer levels . Six serious adverse events ( two in the Vaccine group and four in the Placebo group ) , all unrelated to vaccination , were reported . Commonly reported solicited local ( injection-site pain ) and general ( fatigue , headache and fever ) symptoms were similar in both groups . Compliance to the three-dose vaccination course was > 97 % . CONCLUSIONS The AS04-adjuvanted HPV-16/18 cervical cancer vaccine was highly immunogenic and generally well-tolerated making it a potential tool for prevention and control of cervical cancer in India OBJECTIVE To assess the immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in Chinese women aged 18 to 35 years enrolled from Hong Kong . DESIGN Double-blind , r and omised controlled trial with vaccine and placebo groups . SETTING Single-centre study in Hong Kong . PARTICIPANTS Three hundred women enrolled ( 150 per group ) between March 2006 and June 2007 . INTERVENTIONS Subjects received three doses of human papillomavirus-16/18 vaccine or placebo ( aluminium hydroxide ) , administered intramuscularly at 0 , 1 , and 6 months . MAIN OUTCOME MEASURES Human papillomavirus-16/18 seroconversion rates and geometric mean titres at month 7 ( in human papillomavirus-16/18 recipients ) ; reactogenicity and safety ( in all subjects ) . RESULTS A total of 294 women completed the study ( 148 in the vaccine group , 146 in placebo group ) . All initially seronegative subjects in the vaccine group had seroconverted for human papillomavirus-16/18 antibodies by month 7 . Anti-human papillomavirus-16 and anti-human papillomavirus-18 antibody geometric mean titres were 10 422 ( 95 % confidence interval , 8730 - 12 442 ) EL.U/mL and 4649 ( 3975 - 5437 ) EL.U/mL , respectively . High compliance ( 99 % in both groups ) was observed for the three-vaccination course . The frequencies of local injection site reactions were higher in the vaccine than placebo group ; pain being the most common symptom in both groups . Regarding solicited symptoms , fatigue and myalgia were the most frequent in both groups . Five serious adverse events ( four in vaccine group , one in placebo group ) were reported , but all were considered unrelated to the vaccinations . CONCLUSION The human papillomavirus-16/18 AS04-adjuvanted vaccine was highly immunogenic , safe , and generally well tolerated in Chinese women from Hong Kong 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 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 ] . ) Cervical cancer of both squamous and adenocarcinoma types is considered virtually 100 % attributable to human papillomavirus ( HPV ) infection . HPV-16 and -18 are the predominant types worldwide accounting for over 70 % of all cervical cancer . Persistent oncogenic HPV infection has been confirmed as one key determinant in the development of cervical precancer ( cervical intraepithelial neoplasia [ CIN ] 2 + ) and cervical cancer . The impact of prophylactic HPV vaccination on the reduction of virological and cytohistological outcomes related to HPV-16 and -18 has been evaluated in clinical trials with the HPV-16/18 AS04-adjuvanted cervical cancer vaccine ( Cervarixtrade mark ) through a Phase IIb study with a long-term follow-up of efficacy up to 5.5 years , and a large Phase III trial in women 15 - 25 years of age . These individual studies include population s with different underlying risk factors , each of which shows high efficacy against both HPV-16/18 persistent infections and CIN2 + . When the two studies are combined and the respective population s are evaluated , vaccine efficacy against HPV-16 and -18-related CIN2 + remains at 100 % . As this vaccine is used over time in universal prophylactic HPV-16/18 vaccination of girls and women , reductions in cervical cancers at both the individual and public health levels will be appreciated Aim Bangladesh has the highest level of incidence and mortality rates due to cervical cancer among women . The prevalence of cervical cancer in Bangladeshi women is 25–30/100 000 . Human papillomavirus is an important cause of cervical cancer . The study was conducted to assess the immunogenicity and safety profile of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccines in healthy Bangladeshi girls aged 9–13 years . Procedure This was a r and omized ( 3:1 ) controlled trial with two parallel groups , the vaccine and control groups , that included 67 participants in Bangladesh . Subjects were given GlaxoSmithKline human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine ( and controls no vaccine ) at the first day of vaccination ( Day 0 ) , at 1- and 6-month schedule and followed up until 7 months . Blood sample s were taken for human papillomavirus antibody at enrollment and 1 month post-schedule at Month 7 from both subjects and controls . Safety data were gathered throughout the study period . Results Fifty subjects received vaccine at Day 0 , 1 month and 6 months . All subjects were initially sero-negative in the vaccine group , and developed sero-conversion for human papillomavirus-16 and -18 antibodies except for one at Month 7 . Seventeen controls did not receive vaccine . Clients were followed up for serious medically important events and blood sample s were taken for human papillomavirus antibody detection at Day 0 and Month 7 . Sero-conversion was found in 97.5 % of subjects and no sero-conversion was found in the controls . Bivalent human papillomavirus vaccine was generally well tolerated , with no vaccine-related serious adverse experiences . Conclusions The human papillomavirus-16/18 AS04-adjuvanted vaccine was generally well tolerated and highly immunogenic when administered to young adolescent females and could be a promising tool for the prevention and control of cervical cancer in Bangladesh BACKGROUND The impact of the prophylactic vaccine against human papillomavirus ( HPV ) types 6 , 11 , 16 , and 18 ( HPV6/11/16/18 ) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were " negative to 14 HPV types " and in a mixed population of HPV-exposed and -unexposed women ( intention-to-treat group ) . METHODS This analysis studied 17 622 women aged 15 - 26 years who were enrolled in one of two r and omized , placebo-controlled , efficacy trials for the HPV6/11/16/18 vaccine  ( first patient on December 28 , 2001 , and studies completed July 31 , 2007 ) . Vaccine or placebo was given at day 1 , month 2 , and month 6 . All women underwent cervicovaginal sampling and Papanicolaou ( Pap ) testing at day 1 and every 6 - 12 months thereafter . Outcomes were any cervical intraepithelial neoplasia ; any external anogenital and vaginal lesions ; Pap test abnormalities ; and procedures such as colposcopy and definitive therapy . Absolute rates are expressed as women with endpoint per 100 person-years at risk . RESULTS The average follow-up was 3.6 years ( maximum of 4.9 years ) . In the population that was negative to 14 HPV types , vaccination was up to 100 % effective in reducing the risk of HPV16/18-related high- grade cervical , vulvar , and vaginal lesions and of HPV6/11-related genital warts . In the intention-to-treat group , vaccination also statistically significantly reduced the risk of any high- grade cervical lesions ( 19.0 % reduction ; rate vaccine = 1.43 , rate placebo = 1.76 , difference = 0.33 , 95 % confidence interval [ CI ] = 0.13 to 0.54 ) , vulvar and vaginal lesions ( 50.7 % reduction ; rate vaccine = 0.10 , rate placebo = 0.20 , difference = 0.10 , 95 % CI = 0.04 to 0.16 ) , genital warts ( 62.0 % reduction ; rate vaccine = 0.44 , rate placebo = 1.17 , difference = 0.72 , 95 % CI = 0.58 to 0.87 ) , Pap abnormalities ( 11.3 % reduction ; rate vaccine = 10.36 , rate placebo = 11.68 , difference = 1.32 , 95 % CI = 0.74 to 1.90 ) , and cervical definitive therapy ( 23.0 % reduction ; rate vaccine = 1.97 , rate placebo = 2.56 , difference = 0.59 , 95 % CI = 0.35 to 0.83 ) , irrespective of causal HPV type . CONCLUSIONS High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts , cervical cytological abnormalities , and diagnostic and therapeutic procedures . In the longer term , substantial reductions in the rates of cervical , vulvar , and vaginal cancers may follow 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 Objective To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus ( qHPV ) vaccine .  Design Register based cohort study . Setting Denmark and Sweden , October 2006 to December 2010 . Participants 997 585 girls aged 10 - 17 , among whom 296 826 received a total of 696 420 qHPV vaccine doses . Main outcome measures Incident hospital diagnosed autoimmune , neurological , and venous thromboembolic events ( 53 different outcomes ) up to 180 days after each qHPV vaccine dose . Only events with at least five vaccine exposed cases were considered for further assessment . Rate ratios adjusted for age , country , calendar year , and parental country of birth , education , and socioeconomic status were estimated , comparing vaccinated and unvaccinated person time . For outcomes where the rate ratio was significantly increased , we regarded three criteria as signal strengthening : analysis based on 20 or more vaccine exposed cases ( reliability ) , rate ratio 3.0 or more ( strength ) , and significantly increased rate ratio in country specific analyses ( consistency ) . We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181 . Results Among the 53 outcomes , at least five vaccine exposed cases occurred in 29 and these were analysed further . Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased , exposure to qHPV vaccine was significantly associated with Behcet ’s syndrome , Raynaud ’s disease , and type 1 diabetes . Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria . Furthermore , the pattern of distribution in time after vaccination was r and om for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period . The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy ( rate ratio 0.66 , 95 % confidence interval 0.54 to 0.80 ) and paralysis ( 0.56 , 0.35 to 0.90 ) . There was no association between exposure to qHPV vaccine and venous thromboembolism ( 0.86 , 0.55 to 1.36 ) . Conclusions This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune , neurological , and venous thromboembolic adverse events . Although associations for three autoimmune events were initially observed , on further assessment these were weak and not temporally related to vaccine exposure . Furthermore , the findings need to be interpreted considering the multiple outcomes assessed 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 ] . ) 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 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 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 Cervical cancer and its obligate precursors , cervical intraepithelial neoplasia grade s 2 and 3 ( CIN2/3 ) , and adenocarcinona in situ ( AIS ) , are caused by oncogenic human papillomavirus ( HPV ) . In this combined analysis of four clinical trials we assessed the effect of prophylactic HPV vaccination on these diseases . METHODS 20,583 women aged 16 - 26 years were r and omised to receive quadrivalent HPV6/11/16/18 vaccine ( n=9087 ) , its HPV16 vaccine component ( n=1204 ) , or placebo ( n=10 292 ) . They underwent periodic Papanicolaou testing , with colposcopy or biopsy for detected abnormalities . The primary composite endpoint was the combined incidence of HPV16/18-related CIN2/3 , AIS , or cervical cancer . These trials are registered at Clinical Trials.gov , numbers NCT00365378 , NCT00365716 , NCT00092521 , and NCT00092534 . FINDINGS Mean follow-up was 3.0 years ( SD 0.66 ) after first dose . In women negative for HPV16 or HPV18 infection during the vaccination regimen ( n=17 129 , per protocol ) , vaccine efficacy was 99 % for the primary endpoint ( 95 % CI 93 - 100 ) , meeting the statistical criterion for success . In an intention-to-treat analysis of all r and omised women ( including those who were HPV16/18 naive or HPV16/18-infected at day 1 ) , efficacy was 44 % ( 95 % CI 31 - 55 ) ; all but one case in vaccine recipients occurred in women infected with HPV16 or HPV18 before vaccination . In a second intention-to-treat analysis we noted an 18 % reduction ( 95 % CI 7 - 29 ) in the overall rate of CIN2/3 or AIS due to any HPV type . INTERPRETATION Administration of HPV vaccine to HPV-naive women , and women who are already sexually active , could substantially reduce the incidence of HPV16/18-related cervical precancers and cervical cancer Objective : 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 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 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 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 BACKGROUND Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus ( HPV ) . These cancers are preceded by high- grade vulval intraepithelial neoplasia ( VIN2 - 3 ) and vaginal intraepithelial neoplasia ( VaIN2 - 3 ) . Our aim was to do a combined analysis of three r and omised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases . METHODS 18 174 women ( 16 - 26 years ) were enrolled and r and omised to receive either quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine or placebo at day 1 , and months 2 and 6 . Individuals underwent detailed anogenital examination at day 1 , 1 month after dose three , and at 6 - 12-month intervals for up to 48 months . Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done . The primary endpoint was the combined incidence of VIN2 - 3 or VaIN2 - 3 associated with HPV16 or HPV18 . Primary efficacy analyses were done in a per- protocol population . FINDINGS The mean follow-up time was 3 years . Among women naive to HPV16 or HPV18 through 1 month after dose three ( per- protocol population ; vaccine n=7811 ; placebo n=7785 ) , the vaccine was 100 % effective ( 95 % CI 72 - 100 ) against VIN2 - 3 or VaIN2 - 3 associated with HPV16 or HPV18 . In the intention-to-treat population ( which included 18 174 women who , at day 1 , could have been infected with HPV16 or HPV18 ) , vaccine efficacy against VIN2 - 3 or VaIN2 - 3 associated with HPV16 or HPV18 was 71 % ( 37 - 88 ) . The vaccine was 49 % ( 18 - 69 ) effective against all VIN2 - 3 or VaIN2 - 3 , irrespective of whether or not HPV DNA was detected in the lesion . The most common treatment-related adverse event was injection-site pain . INTERPRETATION Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high- grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination . With time , such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers
Recently , many studies have evaluated HPV vaccine safety and adverse effects .
Two vaccines have been recently evaluated in r and omized controlled trials : the bivalent vaccine for HPV 16 and 18 ( Cervarix , GlaxoSmithKline Biologicals , Rixensart , Belgium ) and the quadrivalent vaccine for HPV 6 , 11 , 16 , and 18 ( Gardasil , Merck and Co. , Inc. , Whitehouse Station , NJ ) .