Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10-18 years. Safety and Immunogenicity of Human Papillomavirus-16/18 AS04-Adjuvanted Vaccine: A Randomized Trial in 10–25-Year-Old HIV-Seronegative African Girls and Young Women Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, double-blind, placebo-controlled trial in Chinese males and females. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. Vaccination with a Human Papillomavirus (HPV)-16/18 AS04-Adjuvanted Cervical Cancer Vaccine in Korean Girls Aged 10-14 Years 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. Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults Immunogenicity and Safety of Human Papillomavirus-16/18 AS04-Adjuvanted Vaccine Administered According to an Alternative Dosing Schedule Compared With the Standard Dosing Schedule in Healthy Women Aged 15 to 25 Years: Results From a Randomized Study Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine: a randomized, controlled trial in adolescent girls. 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 Human Papillomavirus Types 16 and 18 Vaccine (Recombinant, AS04 Adjuvanted Adsorbed) [Cervarix™] Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo-controlled trial in 176 Korean subjects
PURPOSE The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine ( Cervarix ) has been shown to be well-tolerated and immunogenic in females aged 10 to 55 years , and up to 100 % effective for the prevention of HPV-16/18 infection and associated precancerous cervical lesions in females aged 15 to 25 years . This study is the first to evaluate the immunogenicity and safety of the vaccine in males . METHODS Healthy males aged 10 to 18 years were r and omized ( 2:1 ratio ) to receive  HPV-16/18 AS04-adjuvanted vaccine ( n = 181 ) or hepatitis B virus ( HBV ) control vaccine ( n = 89 ) at 0 , 1 , and 6 months , and were followed for 7 months . RESULTS All initially seronegative subjects in the HPV-16/18 group seroconverted for HPV-16 and 18 ( ELISA ) at month 2 . At month 7 , all subjects were seropositive , and the HPV-16 and -18 antibody levels were , respectively , four- and twofold higher than at month 2 . The anti-HPV-16 and -18 antibody responses for males aged 10 to 18 years and 10 to 14 years , respectively , were higher than those reported for females aged 15 to 25 years and 10 to 14 years , respectively , in a previous study . The reactogenicity profiles of the HPV-16/18 AS04 and HBV vaccines were similar , except that pain and swelling at the injection site were more common in the HPV-16/18 group . However , vaccine-related symptoms did not affect compliance with the three-dose course , which was equally high ( 97 % ) in both groups . CONCLUSIONS The HPV-16/18 AS04-adjuvanted vaccine is immunogenic and well tolerated in boys aged 10 to 18 years . However , further data on the potential public health benefits of vaccination of boys are required before any recommendations can be made Background . Cervical cancer is a major public health problem for women in sub-Saharan Africa . Availability of a human papillomavirus ( HPV ) vaccine could have an important public health impact . Methods . In this phase IIIb , double-blind , r and omized , placebo-controlled , multicenter trial ( NCT00481767 ) , healthy African girls and young women seronegative for human immunodeficiency virus ( HIV ) were stratified by age ( 10–14 or 15–25 years ) and r and omized ( 2:1 ) to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 450 ) or placebo ( n = 226 ) at 0 , 1 , and 6 months . The primary objective was to evaluate HPV-16/18 antibody responses at month 7 . Seropositivity rates and corresponding geometric mean titers ( GMTs ) were measured by enzyme-linked immunosorbent assay . Results . In the according-to- protocol analysis at month 7 , 100 % of initially seronegative participants in the vaccine group were seropositive for both anti – HPV-16 and anti – HPV-18 antibodies ( n = 130 and n = 128 for 10–14-year-olds , respectively ; n = 190 and n = 212 for 15–25-year-olds ) . GMTs for HPV-16 and HPV-18 were higher in 10–14-year-olds ( 18 423 [ 95 % confidence interval , 16 185–20 970 ] and 6487 [ 5590–7529 ] enzyme-linked immunosorbent assay units (EU)/mL , respectively ) than in 15–25-year-olds ( 10 683 [ 9567–11 930 ] and 3743 [ 3400–4120 ] EU/mL , respectively ) . Seropositivity was maintained at month 12 . No participant withdrew owing to adverse events . No vaccine-related serious adverse events were reported . Conclusions . The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinical ly acceptable safety profile when administered to healthy HIV-seronegative African girls and young women In this r and omized , double-blind , placebo-controlled trial , 9 - 15 year old Chinese males ( n=100 ) and 9 - 45 year old Chinese females ( n=500 ) from Wuzhou , Guangxi , China were r and omized ( 1:1 ) to receive either quadrivalent HPV vaccine or adjuvant-containing placebo .  Blood sample s were obtained at day 1 and one month post-dose 3 to determine the level of vaccine-induced antibodies . Among vaccine recipients , high antibody levels were observed for each of the four HPV types and seroconversion was > 96 % . The vaccine was generally well tolerated , with no vaccine-related serious adverse events . This study demonstrated that the quadrivalent HPV vaccine is highly immunogenic and generally well tolerated among Chinese males and females BACKGROUND A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus ( HPV ) types 6 , 11 , 16 , and 18 . METHODS In this r and omized , placebo-controlled , double-blind trial involving 5455 women between the ages of 16 and 24 years , we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1 , month 2 , and month 6 . The co primary composite end points were the incidence of genital warts , vulvar or vaginal intraepithelial neoplasia , or cancer and the incidence of cervical intraepithelial neoplasia , adenocarcinoma in situ , or cancer associated with HPV type 6 , 11 , 16 , or 18 . Data for the primary analysis were collected for a per- protocol susceptible population of women who had no virologic evidence of HPV type 6 , 11 , 16 , or 18 through 1 month after administration of the third dose . RESULTS The women were followed for an average of 3 years after administration of the first dose . In the per- protocol population , those followed for vulvar , vaginal , or perianal disease included 2261 women ( 83 % ) in the vaccine group and 2279 ( 83 % ) in the placebo group . Those followed for cervical disease included 2241 women ( 82 % ) in the vaccine group and 2258 ( 83 % ) in the placebo group . Vaccine efficacy was 100 % for each of the co primary end points . In an intention-to-treat analysis , including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV , vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34 % ( 95 % confidence interval [ CI ] , 15 to 49 ) , and the rate of cervical lesions regardless of the causal HPV type by 20 % ( 95 % CI , 8 to 31 ) . CONCLUSIONS The quadrivalent vaccine significantly reduced the incidence of  HPV-associated anogenital diseases in young women . ( Clinical Trials.gov number , NCT00092521 [ Clinical Trials.gov ] . ) The 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 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 Prophylactic vaccination with a quadrivalent HPV ( types 6 , 11 , 16 , 18 ) vaccine ( qHPV ) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently , in men . Here we report on the safety and reactogenicity of the qHPV vaccine in males . A total of 4,065 healthy males aged 16 - 26 years were enrolled into a r and omized , placebo-controlled , double-blind trial . Subjects were r and omized 1:1 to receive qHPV vaccine or placebo at day 1 , month 2 , and month 6 . Safety and tolerability were assessed via the collection of reported adverse experiences ( AEs ) . All serious AEs ( vaccine- or procedure-related or not ) and all deaths occurring during the study were recorded . Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo . The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group ( 60.1 % vs 53.7 % , respectively ) , however most of these AEs were mild/moderate in intensity . The incidence of at least one systemic AE was comparable between the vaccine and placebo groups ( 31.7 % vs 31.4 % , respectively ) . There were no vaccine-related serious AEs or deaths . The occurrence of AEs did not increase with each successive injection , and among trial participants who were seropositive for at least one vaccine HPV type at enrollment , the profile of adverse events was similar to that of the entire study cohort . The qHPV vaccine was generally well tolerated  in males aged 16 - 26 years and had a favorable safety profile Background : The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine is immunogenic , has a clinical ly acceptable safety profile , and prevents incident and persistent HPV-16/18 infection and cervical precancerous lesions . This study ( NCT00552279 ) evaluated the vaccine when administered according to an alternative dosing schedule ( 0–1–12 months ) compared with the st and ard dosing schedule ( 0–1–6 months ) . Methods : The study was of r and omized open design and was conducted at multiple centers in Europe . Healthy women aged 15 to 25 years were r and omized ( 1:1 ) to receive HPV-16/18 vaccine according to the st and ard schedule at months 0 , 1 , and 6 ( n = 401 ) or an alternative schedule at months 0 , 1 , and 12 ( n = 403 ) . HPV-16 and -18 antibodies were measured by enzyme-linked immunosorbent assay at months 0 , 2 , and 7 or 13 ( depending on group ) ; noninferiority evaluation was performed sequentially for seroconversion rates and geometric mean antibody titers . Primary analysis of immunogenicity was based on the according-to- protocol cohort . Vaccine safety and reactogenicity were assessed on the total vaccinated cohort . Results : Predefined noninferiority criteria were met 1 month after the third vaccine dose when the HPV-16/18 vaccine was administered according to the 0–1–12 month schedule compared with the 0–1–6 month schedule in terms of seroconversion rates for HPV-16 ( 100 % and 100 % ) and HPV-18 ( 99.7 % and 100 % ) and geometric mean antibody titers for HPV-16 ( 11884.7 and 10311.9 ELISA units/mL ) and HPV-18 ( 4501.3 and 3963.6 ELISA units/mL ) , respectively . The HPV-16/18 vaccine had a clinical ly acceptable safety profile when administered according to either schedule . Conclusions : The third dose of the HPV-16/18 vaccine can be administered any time between 6 and 12 months after the first dose , with adequate immunogenicity and a clinical ly acceptable safety profile PURPOSE Immunization of girls against oncogenic human papillomavirus ( HPV ) types before sexual debut is important for cervical cancer prevention . This phase III blinded , r and omized , controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine . METHODS Girls ( mean age 12 years ) in 12 countries received the  HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine ( N = 1,035 ) or hepatitis A virus vaccine as control ( N = 1,032 ) at 0 , 1 , and 6 months . The primary objective was to compare the occurrence of serious adverse events ( SAEs ) between groups . HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination . RESULTS Up to study month 7 , 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs . The difference in SAE incidence between groups was .20 % ( 95 % CI , -.78 , 1.20 ) . No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal . The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control . The incidence of unsolicited symptoms , new onset of chronic diseases , and medically significant conditions was similar between groups . All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine ; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies , respectively , in initially seronegative girls . CONCLUSIONS The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females , the primary target of organized vaccination programs 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 Abstract ▴ Cervarix ™ is a prophylactic vaccine comprised of a mixture of virus-like particles derived from the L1 capsid proteins of human papillomavirus ( HPV ) types 16 and 18 formulated with the AS04 adjuvant system . It is administered by intramuscular injection as a three-dose vaccine regimen at 0 , 1 and 6 months . The vaccine is indicated for the prevention of high- grade cervical intraepithelial neoplasia ( CIN 2 and CIN 3 ) and cervical cancer causally related to HPV types 16 and 18 . ▴ In r and omized , double-blind , phase II or III trials in > 19 000 women aged 15–25 years , the HPV 16/18 vaccine showed high efficacy in preventing CIN 2 + associated with HPV 16/18 . Cross-protection against new incident or 6-month persistent HPV 45 or HPV 31 infection was also evident . Phase II follow-up was for at least 5.5 years , and the phase III interim analysis was at ≈15 months after the first vaccine dose . ▴ In a bridging study , in adolescent girls aged 10–14 years , the HPV 16/18 vaccine induced twice the already high antibody titres as it did in young women ( aged 15–25 years ) . The immune response in older women ( aged 26–55 years ) at 24 months in another study was ≥8-fold higher than antibody levels reported in younger age groups . Anti-HPV 16/18 antibody responses were greater with an AS04-adjuvanted HPV 16/18 vaccine than with an aluminium salt-adjuvanted formulation . ▴ The HPV 16/18 vaccine was generally well tolerated and injection-site reactions were the most common vaccine-related adverse events reported 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
OBJECTIVE To identify and quantify the adverse effects associated with the  recombinant human papillomavirus ( types 6 , 11 , 16 and 18 ) vaccine in adolescents .