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 A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. Comparison of long-term immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: End-of-study analysis of a Phase III randomized trial Durable Antibody Responses Following One Dose of the Bivalent Human Papillomavirus L1 Virus-Like Particle Vaccine in the Costa Rica Vaccine Trial Health and Economic Impact of Switching from a 4-Valent to a 9-Valent HPV Vaccination Program in the United States. Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18–45 years Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV-infected adults: a randomized, double-blind clinical trial. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials. Comparison of adaptive and innate immune responses induced by licensed vaccines for human papillomavirus Comparison of the immunogenicity of Cervarix® and Gardasil® human papillomavirus vaccines for oncogenic non-vaccine serotypes HPV-31, HPV-33, and HPV-45 in HIV-infected adults Cross-protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses Potential cost-effectiveness of the nonavalent human papillomavirus (HPV) vaccine. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared to the licensed 3-dose schedule
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 BACKGROUND The investigational 9-valent viruslike particle vaccine against human papillomavirus ( HPV ) includes the HPV types in the quadrivalent HPV ( qHPV ) vaccine ( 6 , 11 , 16 , and 18 ) and five additional oncogenic types ( 31 , 33 , 45 , 52 , and 58 ) . Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age . METHODS We performed a r and omized , international , double-blind , phase 2b-3 study of the 9vHPV vaccine  in 14,215 women . Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6 . Serum was collected for analysis of antibody responses . Swabs of labial , vulvar , perineal , perianal , endocervical , and ectocervical tissue were obtained and used for HPV DNA testing , and liquid-based cytologic testing ( Papanicolaou testing ) was performed regularly . Tissue obtained by means of biopsy or as part of definitive therapy ( including a loop electrosurgical excision procedure and conization ) was tested for HPV . RESULTS The rate of high- grade cervical , vulvar , or vaginal disease irrespective of HPV type ( i.e. , disease caused by HPV types included in the 9vHPV vaccine and those not included ) in the modified intention-to-treat population ( which included participants with and those without prevalent infection or disease ) was 14.0 per 1000 person-years in both vaccine groups . The rate of high- grade cervical , vulvar , or vaginal disease related to HPV-31 , 33 , 45 , 52 , and 58 in a prespecified per- protocol efficacy population ( susceptible population ) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group ( efficacy of the 9vHPV vaccine , 96.7 % ; 95 % confidence interval , 80.9 to 99.8 ) . Antibody responses to HPV-6 , 11 , 16 , and 18 were noninferior to those generated by the qHPV vaccine . Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group . CONCLUSIONS The 9vHPV vaccine prevented infection and disease related to HPV-31 , 33 , 45 , 52 , and 58 in a susceptible population and generated an antibody response to HPV-6 , 11 , 16 , and 18 that was noninferior to that generated by the qHPV vaccine . The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine . ( Funded by Merck ; Clinical Trials.gov number , NCT00543543 ) IMPORTANCE Global use of human papillomavirus ( HPV ) vaccines to prevent cervical cancer is impeded by cost . A 2-dose schedule for girls may be possible . OBJECTIVE To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses . DESIGN , SETTING , AND PATIENTS R and omized , phase 3 , postlicensure , multicenter , age-stratified , noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011 . Follow-up blood sample s were provided by 675 participants ( 81 % ) . INTERVENTION Girls ( 9 - 13 years ) were r and omized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0 , 2 , and 6 months ( n = 261 ) or 2 doses at 0 and 6 months ( n = 259 ) . Young women ( 16 - 26 years ) received 3 doses at 0 , 2 , and 6 months ( n = 310 ) . Antibody levels were measured at 0 , 7 , 18 , 24 , and 36 months . MAIN OUTCOMES AND MEASURES Primary outcome was noninferiority ( 95 % CI , lower bound > 0.5 ) of geometric mean titer ( GMT ) ratios for HPV-16 and HPV-18 for girls ( 2 doses ) compared with young women ( 3 doses ) 1 month after last dose . Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine ; and durability of noninferiority to 36 months . RESULTS The GMT ratios were noninferior for girls ( 2 doses ) to women ( 3 doses ) : 2.07 ( 95 % CI , 1.62 - 2.65 ) for HPV-16 and 1.76 ( 95 % CI , 1.41 - 2.19 ) for HPV-18 . Girls ( 3 doses ) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL ( mMU/mL ) ( 95 % CI , 6651 - 8999 ) and HPV-18 of 1730 mMU/mL ( 95 % CI , 1512 - 1980 ) . The GMT ratios were noninferior for girls ( 2 doses ) to girls ( 3 doses ) : 0.95 ( 95 % CI , 0.73 - 1.23 ) for HPV-16 and 0.68 ( 95 % CI , 0.54 - 0.85 ) for HPV-18 . The GMT ratios for girls ( 2 doses ) to women ( 3 doses ) remained noninferior for all genotypes to 36 months . Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7 , but not for HPV-18 by month 24 or HPV-6 by month 36 . CONCLUSIONS AND RELEVANCE Among girls who received 2 doses of HPV vaccine 6 months apart , responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months . Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses , more data on the duration of protection are needed before reduced-dose schedules can be recommended . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00501137 The observer-blind , r and omized , age-stratified , head-to-head study ( NCT00423046 ) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18 - 45 y was completed . Five y after vaccination , in subjects from the Month 60 according-to- protocol cohort ( seronegative and DNA negative for HPV type analyzed at baseline ) , serum neutralizing antibody ( nAb ) responses induced by HPV-16/18 vaccine remained 7.8-fold ( 18 - 26-y stratum ) , 5.6-fold ( 27 - 35-y stratum ) and 2.3-fold ( 36 - 45-y stratum ) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16 . For HPV-18 , the fold differences were 12.1 , 13.0 and 7.8 , respectively . At Month 60 , all ( 100 % ) subjects in HPV-16/18 vaccine group and the majority ( 95.7%-97.5 % ) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16 . For HPV-18 , the majority ( 98.1%-100 % ) of subjects in HPV-16/18 vaccine group were seropositive ; however , seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably ( 61.1%-76.9 % ) across the 3 age strata . In the total vaccinated cohort ( received ≥ 1 dose regardless of baseline HPV serostatus and DNA status ) , geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group . Based on the 5-y data , piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine . Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses , comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection The Costa Rica HPV16/18 Vaccine Trial ( CVT ) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one , two , or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle ( VLP ) vaccine . Live-attenuated viral vaccines , but not simple-subunit vaccines , usually induce durable lifelong antibody responses after a single dose . It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard . To explore the likelihood that efficacy will persist longer term , we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment , vaccination , and annual visits through four years in four vaccinated groups ; one-dose ( n = 78 ) , two-doses separated by one month ( n = 140 ) ,  two doses separated by six months ( n = 52 ) , and three scheduled doses ( n = 120 , r and omly selected ) . We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination , presumably from natural infection . At four years , 100 % of women in all groups remained HPV16/18 seropositive ; both HPV16/18 geometric mean titers ( GMT ) among the extended two-dose group were non-inferior to the three-dose group , and ELISA titers were highly correlated with neutralization titers in all groups . Compared with the natural infection group , HPV16/18 GMTs were , respectively , at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees . Antibody levels following one-dose remained stable from month 6 through month 48 . Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection . Cancer Prev Res ; 6(11 ) ; 1242–50 . © 2013 AACR BACKGROUND R and omized clinical trials have shown the 9-valent human papillomavirus ( HPV ) vaccine to be highly effective against types 31/33/45/52/58 compared with the 4-valent . Evidence on the added health and economic benefit of the 9-valent is required for policy decisions . We compare population -level effectiveness and cost-effectiveness of 9- and 4-valent HPV vaccination in the United States . METHODS We used a multitype individual-based transmission-dynamic model of HPV infection and disease ( anogenital warts and cervical , anogenital , and oropharyngeal cancers ) , 3 % discount rate , and societal perspective . The model was calibrated to sexual behavior and epidemiologic data from the United States . In our base-case , we assumed 95 % vaccine-type efficacy , lifelong protection , and a cost/dose of $ 145 and $ 158 for the 4- and 9-valent vaccine , respectively . Predictions are presented using the mean ( 80 % uncertainty interval [ UI ] = 10(th)-90(th ) percentiles ) of simulations . RESULTS Under base-case assumptions , the 4-valent gender-neutral vaccination program is estimated to cost $ 5500 ( 80 % UI = 2400 - 9400 ) and $ 7300 ( 80 % UI = 4300 - 11 000)/ quality -adjusted life-year ( QALY ) gained with and without cross-protection , respectively . Switching to a 9-valent gender-neutral program is estimated to be cost-saving irrespective of cross-protection assumptions . Finally , the incremental cost/QALY gained of switching to a 9-valent gender-neutral program ( vs 9-valent girls/4-valent boys ) is estimated to be $ 140 200 ( 80 % UI = 4200->1 million ) and $ 31 100 ( 80 % UI = 2100->1 million ) with and without cross-protection , respectively . Results are robust to assumptions about HPV natural history , screening methods , duration of protection , and healthcare costs . CONCLUSIONS Switching to a 9-valent gender-neutral HPV vaccination program is likely to be cost-saving if the additional cost/dose of the 9-valent is less than $ 13 . Giving females the 9-valent vaccine provides the majority of benefits of a gender-neutral strategy Protection against oncogenic non-vaccine types ( cross-protection ) offered by human papillomavirus ( HPV ) vaccines may provide a significant medical benefit . Available clinical efficacy data suggest the two licensed vaccines ( HPV-16/18 vaccine , GlaxoSmithKline Biologicals [ GSK ] , and HPV-6/11/16/18 vaccine , Merck & Co. , Inc. ) differ in terms of protection against oncogenic non-vaccine HPV types -31/45 . The immune responses induced by the two vaccines against these two non-vaccine HPV types ( cross-reactivity ) was compared in an observer-blind study up to Month 24 ( 18 months post-vaccination ) , in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed ( HPV-010 [ NCT00423046 ] ) . Geometric mean antibody titers ( GMTs ) measured by pseudovirion-based neutralization assay ( PBNA ) and enzyme-linked immunosorbent assay ( ELISA ) were similar between vaccines for HPV-31/45 . Seropositivity rates for HPV-31 were also similar between vaccines ; however , there was a trend for higher seropositivity with the HPV-16/18 vaccine ( 13.0–16.7 % ) versus the HPV-6/11/16/18 vaccine ( 0.0–5.0 % ) for HPV-45 with PBNA , but not ELISA . HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines . Circulating antigen-specific CD4 + T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine ( HPV-31 [ geometric mean ratio [ GMR ] = 2.0 ; p=0.0002 ] and HPV-45 [ GMR=2.6 ; p=0.0092 ] ) , as were the proportion of T-cell responders ( HPV-31 , p=0.0009 ; HPV-45 , p=0.0793 ) . In conclusion , immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine . Considering the differences in cross-protective efficacy between the two vaccines , the results might provide insights into the underlying mechanism(s ) of protection BACKGROUND We compared the immunogenicity and reactogenicity of Cervarix or Gardasil human papillomavirus ( HPV ) vaccines in adults infected with the human immunodeficiency virus ( HIV ) . METHODS This was a double-blind , controlled trial r and omizing HIV-positive adults to receive 3 doses of Cervarix or Gardasil at 0 , 1.5 , and 6 months . Immunogenicity was evaluated for up to 12 months . Neutralizing anti-HPV-16/18 antibodies were measured by pseudovirion-based neutralization assay . Laboratory tests and diary cards were used for safety assessment . The HPV-DNA status of the participants was determined before and after immunization . RESULTS Ninety-two participants were included in the study .  Anti-HPV-18 antibody titers were higher in the Cervarix group compared with the Gardasil group at 7 and 12 months . No significant differences in anti-HPV-16 antibody titers were found among vaccine groups . Among Cervarix vaccinees , women had higher anti-HPV-16/18 antibody titers compared to men . No sex-specific differences in antibody titers were found in the Gardasil group . Mild injection site reactions were more common in the Cervarix group than in the Gardasil group ( 91.1 % vs 69.6 % ; P = .02 ) . No serious adverse events occurred . CONCLUSIONS Both vaccines were immunogenic and well tolerated . Compared with Gardasil , Cervarix induced superior vaccine responses among HIV-infected women , whereas in HIV-infected men the difference in immunogenicity was less pronounced BACKGROUND There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen . The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types , by number of doses received . METHODS Summary data from the Costa Rica Vaccine Trial ( CVT ; NCT00128661 ) and ~the PATRICIA trial ( NCT001226810 ) , two phase 3 , double-blind , r and omised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women , were combined in a post-hoc analysis ( GlaxoSmithKline [ GSK ] e-track number 202142 ) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up . Women were r and omly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine ; yet , some received fewer doses . After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment ( for the HPV-16/18 endpoint ) , we calculated vaccine efficacy against one-time detection of incident HPV infections after three , two , and one dose(s ) . The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase . FINDINGS We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort ( 22 327 received three doses , 1185 two doses , 543 one dose ) . Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0 % ( 95 % CI 74·7 - 79·1 ) , two doses was 76·0 % ( 62·0 - 85·3 ) , and one dose was 85·7 % ( 70·7 - 93·7 ) . Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7 % ( 56·0 - 63·0 ) , two doses was 37·7 % ( 12·4 - 55·9 ) , and one dose was 36·6 % ( -5·4 to 62·2 ) . Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3 % ( 54·2 - 87·5 ) and 82·6 % ( 42·3 - 96·1 ) for those who received the second dose at 6 months ( CVT data only ) . Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months ( 68·1 % , 27·0 - 87·0 ; CVT data only ) , but not those receiving it at one month ( 10·1 % , -42·0 to 43·3 ) , was similar to the three-dose group . INTERPRETATION 4 years after vaccination of women aged 15 - 25 years , one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections , similar to the protection provided by the three-dose schedule . Two doses separated by 6 months additionally provided some cross-protection . These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine . FUNDING US National Cancer Institute , National Institutes of Health Office of Research on Women 's Health , and Ministry of Health of Costa Rica ( CVT ) ; GlaxoSmithKline Biologicals SA ( PATRICIA ) Two HPV virus-like particle ( VLP ) vaccines , HPV-16/18 ( GlaxoSmithKline , Cervarix ® ) and HPV-6/11/16/18 ( Merck , Gardasil ® ) , are currently licensed in the United States . Given the similar antigenic content but different adjuvant formulations in the 2 vaccines , they provide an efficient method for evaluating adjuvants and comparing the kinetics of the innate and adaptive immune responses . We r and omized women to receive either Cervarix ® or Gardasil ® , followed 6 month vaccination delivery schedules per manufacturer 's recommendations , and analyzed the humoral immune response , T cell response , and circulating plasma cytokine levels in response to vaccination . Cervarix ® recipients had higher anti-HPV-16 antibody and neutralization titers at month 7 , and elevated anti-HPV-18 antibody and neutralization titers at months 7 and 12 . Antibody avidity was similar for the 2 vaccines . HPV-31 was the only phylogenetically related non-vaccine HPV type , for which there is evidence of cross-protection , to be cross-neutralized and only in response to Cervarix ® . Comparing CD4 + T cell cytokine responses at month 12 , there was a trend of increased levels of IL-2 and TNF-α in the Cervarix ® groups versus the Gardasil ® groups that was consistent across all 4 tested HPV types ( 16/18/33/45 ) . Elevated levels of circulating plasma cytokine/chemokines were observed post first vaccination in Gardasil ® recipients and proinflammatory cytokines were elevated following 1st and 3rd Cervarix ® vaccinations . Cervarix ® and Gardasil ® are both highly immunogenic vaccines . Higher antibody levels and CD4 T cell responses were achieved with Cervarix ® after 3 doses , although similar affinity maturation was measured for the 2 vaccines . The clinical implication s of the differences in immune responses are unknown Individuals infected with human immunodeficiency virus ( HIV ) have excess risk of developing human papillomavirus (HPV)-related disease . A substantial fraction of HPV-associated cancers is caused by HPV serotypes not included in the currently available vaccines . Among healthy women , both Cervarix ® ( HPV-16/18 , GlaxoSmithKline Biologicals , GSK ) and Gardasil ® ( HPV-6/11/16/18 , Merck ) have demonstrated partial cross-protection against certain oncogenic non-vaccine HPV-types . Currently , there are no available data on vaccine-induced cross-protection in men and little is known about cross-reactive immunity after HPV-vaccination of HIV-infected individuals . In an investigator-initiated trial , we r and omized 91 HIV-positive men and women to receive vaccination  with Cervarix ® or Gardasil ® . The HPV-DNA status of the participants was determined with pcr before and after immunization . Cross-reactive antibody responses against HPV-31 , HPV-33 , and HPV-45 were evaluated for up to 12 months using a pseudovirion-based neutralization assay ( PBNA ) . Geometric mean antibody titers ( GMTs ) were compared among vaccine groups and genders at 7 and 12 months . Both vaccines induced anti-HPV-31 , -33 , and -45 neutralizing antibodies in participants who were seronegative and HPV-DNA negative for those types at study entry . Geometric mean antibody titers were comparable between vaccine groups . Interestingly , anti-HPV-31 and -33 antibody titers were higher among women compared with men at 7 and 12 months . In conclusion , both licensed HPV-vaccines induced cross-neutralizing antibodies against frequent oncogenic non-vaccine serotypes HPV-31 , HPV-33 , and HPV-45 in HIV-infected adults , and women had greater serological responses against HPV-31 and -33 compared with men Background : We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies ( VE ) observed from r and omized clinical trials of the HPV16/18 bivalent vaccine . Results : HPV31 cases had lower HPV16 antibody levels than controls ( OR4th quartile compared with 1st quartile = 0.63 ; 95%CI : 0.36–1.08 ; p-trend = 0.03 ) . HPV31 cases were also less likely to have detectable HPV31 neutralization , and HPV16 avidity than controls . No statistically significant differences by HPV18 antibody or HPV45 neutralization were observed among HPV45 cases and controls . Protection against HPV58 was not associated with any of the markers , confirming the specificity of our findings . Methods : Sample s are from three-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial . Women with a new HPV31 , HPV45 , or HPV58 infections over four years of follow-up were compared with r and omly selected control women — with no new infection with HPV31/45/58—with respect to HPV16 and HPV18 antibody , HPV31 , HPV45 , and HPV58 neutralization , and HPV16 avidity . Conclusions : High HPV16 levels and avidity , and the ability to neutralize HPV31 were associated with protection against newly detected HPV31 infections , suggesting that the partial VE demonstrated for HPV31 is likely to be mediated at least in part through antibodies induced by HPV16/18 vaccination R and omized clinical trials are currently examining the efficacy of a nonavalent human papillomavirus ( HPV ) vaccine , including HPV-types 6/11/16/18/31/33/45/52/58 . Evidence on the cost-effectiveness of the nonavalent is required for timely policy-decisions . We compared the potential cost-effectiveness of the nonavalent and quadrivalent HPV vaccines . We used a multi-type individual-based transmission-dynamic model of HPV infection and diseases , 70-year time-horizon , 3 % discount rate and healthcare payer perspective . We calibrated the model to Canadian sexual behavior and epidemiologic data , and estimated Quality -Adjusted Life-Years ( QALYs ) lost and costs ( $ CAN 2010 ) from the literature . Under base-case assumptions ( vaccinating 10-year-old girls , 80 % coverage , 95$/dose , vaccine-type efficacy = 95 % , cross-protection for the quadrivalent vaccine , duration of vaccine-type protection ( cross-protection ) = 20 ( 10 ) years ) , using the quadrivalent and nonavalent vaccines is estimated to cost $ 15,528 [ 12,056 ; 19,140 ] and $ 12,203 [ 9,331 ; 17,292 ] per QALY-gained , respectively . At equal price , the nonavalent vaccine is more cost-effective than the quadrivalent vaccine , even when assuming both shorter duration of protection ( nonavalent = 20 years vs. quadrivalent = lifelong ) and lower vaccine-type efficacy ( nonavalent = 85 % vs. quadrivalent = 95 % ) . However , the additional cost per dose of the nonavalent vaccine should not exceed $ 11 to remain more cost-effective than the quadrivalent vaccine , and $ 24 to represent a cost-effective alternative to the quadrivalent vaccine ( using a $ 40,000/QALY-gained threshold ) . The nonavalent vaccine can be a cost-effective alternative to the quadrivalent vaccine , even in scenarios where nonavalent vaccine efficacy is 85 % . However , because most cervical cancers are caused by HPV-16/18 , it is unlikely that the nonavalent would be used if its efficacy against these types is lower than current HPV vaccines BACKGROUND We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of- study analysis after 4 years of follow-up in PATRICIA ( PApilloma TRIal against Cancer In young Adults ) . METHODS Healthy women aged 15 - 25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status , HPV-16 or HPV-18 serostatus , or cytology . Women were r and omly assigned ( 1:1 ) to HPV-16/18 vaccine or a control hepatitis A vaccine , via an internet-based central r and omisation system using a minimisation algorithm to account for age ranges and study sites . The study was double-blind . The primary endpoint of PATRICIA has been reported previously ; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of- study analysis . Analyses were done for three cohorts : the according-to- protocol cohort for efficacy ( ATP-E ; vaccine n=8067 , control n=8047 ) , total vaccinated HPV-naive cohort ( TVC-naive ; no evidence of infection with 14 oncogenic HPV types at baseline , approximating young adolescents before sexual debut ; vaccine n=5824 , control n=5820 ) , and the total vaccinated cohort ( TVC ; all women who received at least one vaccine dose , approximating catch-up population s that include sexually active women ; vaccine n=9319 , control=9325 ) . Vaccine efficacy was evaluated against 6-month persistent infection , cervical intraepithelial neoplasia grade 2 or greater ( CIN2 + ) associated with 12 non-vaccine HPV types ( individually or as composite endpoints ) , and CIN3 + associated with the composite of 12 non-vaccine HPV types . This study is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Consistent vaccine efficacy against persistent infection and CIN2 + ( with or without HPV-16/18 co-infection ) was seen across cohorts for HPV-33 , HPV-31 , HPV-45 , and HPV-51 . In the most conservative analysis of vaccine efficacy against CIN2 + , where all cases co-infected with HPV-16/18 were removed , vaccine efficacy was noted for HPV-33 in all cohorts , and for HPV-31 in the ATP-E and TVC-naive . Vaccine efficacy against CIN2 + associated with the composite of 12 non-vaccine HPV types ( 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 66 , and 68 ) , with or without HPV-16/18 co-infection , was 46·8 % ( 95 % CI 30·7 - 59·4 ) in the ATP-E , 56·2 % ( 37·2 - 69·9 ) in the TVC-naive , and 34·2 % ( 20·4 - 45·8 ) in the TVC . Corresponding values for CIN3 + were 73·8 % ( 48·3 - 87·9 ) , 91·4 % ( 65·0 - 99·0 ) , and 47·5 % ( 22·8 - 64·8 ) . INTERPRETATION Data from the end-of- study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine  against four oncogenic non-vaccine HPV types-HPV-33 , HPV-31 , HPV-45 , and HPV-51-in different trial cohorts representing diverse groups of women . FUNDING GlaxoSmithKline Biologicals BACKGROUND Human papillomavirus (HPV)-6/11/16/18 vaccine reduces the risk of HPV-6/11/16/18-related cervical intraepithelial neoplasia ( CIN ) 1 - 3 or adenocarcinoma in situ ( AIS ) . Here , its impact on CIN1 - 3/AIS associated with nonvaccine oncogenic HPV types was evaluated . METHODS We enrolled 17,622 women aged 16 - 26 years . All underwent cervicovaginal sampling and Pap testing at regular intervals for up to 4 years .  HPV genotyping was performed for biopsy sample s , and histological diagnoses were determined by a pathology panel . Analyses were conducted among subjects who were negative for 14 HPV types on day 1 . Prespecified analyses included infection of 6 months ' duration and CIN1 - 3/AIS due to the 2 and 5 most common HPV types in cervical cancer after HPV types 16 and 18 , as well as all tested nonvaccine types . RESULTS Vaccination reduced the incidence of HPV-31/45 infection by 40.3 % ( 95 % confidence interval [ CI ] , 13.9 % to 59.0 % ) and of CIN1 - 3/AIS by 43.6 % ( 95 % CI , 12.9 % to 64.1 % ) , respectively . The reduction in HPV-31/33/45/52/58 infection and CIN1 - 3/AIS was 25.0 % ( 95 % CI , 5.0 % to 40.9 % ) and 29.2 % ( 95 % CI , 8.3 % to 45.5 % ) , respectively . Efficacy for CIN2 - 3/AIS associated with the 10 nonvaccine HPV types was 32.5 % ( 95 % CI , 6.0 % to 51.9 % ) . Reductions were most notable for HPV-31 . CONCLUSIONS HPV-6/11/16/18 vaccine reduced the risk of CIN2 - 3/AIS associated with nonvaccine types responsible for approximately 20 % of cervical cancers . The clinical benefit of cross-protection is not expected to be fully additive to the efficacy already observed against HPV-6/11/16/18-related disease , because women may have > 1 CIN lesion , each associated with a different HPV type . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00092521 , NCT00092534 , and NCT00092482 In this observer-blind study ( NCT00423046 ) , women ( N=1,106 ) , stratified by age ( 18–26 , 27–35 , 36–45 years ) , were r and omized ( 1:1 ) to receive the HPV-16/18 vaccine ( Cervarix ® , GlaxoSmithKline Biologicals , Months 0,1,6 ) or the HPV-6/11/16/18 vaccine ( Gardasil ® Merck & Co. , Inc. , Months 0,2,6 ) . Month 7 results were previously reported ; we now report Month 24 results . In the according-to- protocol cohort for immunogenicity ( seronegative and DNA-negative at baseline for HPV type analyzed ) , seropositivity rates of neutralizing antibodies ( nAbs ) [ pseudovirion-based neutralization assay ] were , across all age strata , 100 % ( HPV-16/18 vaccine ) and 97.5–100 % ( HPV-6/11/16/18 vaccine ) for HPV-16 , and 99.0–100 % ( HPV-16/18 vaccine ) and 72.3–84.4 % ( HPV-6/11/16/18 vaccine ) for HPV-18 . Corresponding geometric mean titers ( GMTs ) were 2.4–5.8-fold higher for HPV-16 and 7.7–9.4-fold higher for HPV-18 with the HPV-16/18 vaccine versus the HPV-6/11/16/18 vaccine ; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine ( p<0.0001 ) in the total vaccinated cohort ( received ≥1 vaccine dose , irrespective of baseline sero/DNA-status ) . Similar results were obtained using enzyme-linked immunosorbent assay ( ELISA ) . Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions ( ELISA ) were not significantly different between vaccines . At Month 24 , CD4 + T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine ; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16 . Both vaccines were generally well tolerated . Although an immunological correlate of protection has not been defined , differences in the magnitude of immune response between vaccines may represent determinants of duration of protection The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine ( Cervarix ® , GlaxoSmithKline Biologicals ) administered according to its licensed vaccination schedule ( 3-dose , 3D ) and formulation ( 20 μg of each HPV antigen ; 20/20F ) has previously been demonstrated . This partially-blind , controlled , r and omized trial ( NCT00541970 ) evaluated 2-dose ( 2D ) schedules using the licensed 20/20F or an alternative formulation containing 40 μg of each antigen ( 40/40F ) , compared with the licensed 3D schedule . Healthy females stratified by age ( 9 - 14 , 15 - 19 , 20 - 25 years ) were r and omized to receive 2 doses of 20/20F at Months ( M ) 0,6 ( n=240 ) , 40/40F at M0,6 ( n=241 ) or 40/40F at M0,2 ( n=240 ) , or 3 doses of 20/20F at M0,1,6 ( licensed schedule/formulation , n=239 ) . One month after the last dose , the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 ( lower limit of 95 % CI geometric mean antibody titer ( GMT ) ratio [ 2D/3D ] < 0.5 ) . For both HPV-16 and HPV-18 , the 2D schedules in girls 9 - 14 years were immunologically non-inferior to the 3D schedule in women 15 - 25 years ( the age group in which efficacy has been demonstrated ) ( upper limit of 95 % CI for GMT ratio [ 3D/2D ] < 2 ) one month after the last dose . At Month 24 , non-inferiority was maintained for the 2D M0,6 schedules in girls 9 - 14 years versus the 3D schedule in women 15 - 25 years . All formulations had acceptable reactogenicity and safety profiles . These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9 - 14 years and that the 2D schedule is likely adequate for younger females
BACKGROUND Human papillomavirus vaccines have demonstrated remarkable efficacy against persistent infection and disease associated with vaccine-incorporated genotypes and a degree of efficacy against some genetically related , non-vaccine-incorporated genotypes .
The vaccines differ in the extent of cross-protection against these non-vaccine genotypes .
Data supporting the role for neutralizing antibodies as a correlate or surrogate of cross-protection are lacking , as is a robust assessment of the seroconversion rates against these non-vaccine genotypes .