human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic , generally well tolerated , and effective against HPV-16 or HPV-18 infections , and associated precancerous lesions in an event-triggered interim analysis of the phase III r and omised , double-blind , controlled PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . We now assess the vaccine efficacy in the final event-driven analysis . METHODS Women ( 15 - 25 years ) were vaccinated at months 0 , 1 , and 6 . Analyses were done in the according-to- protocol cohort for efficacy ( ATP-E ; vaccine , n=8093 ; control , n=8069 ) , total vaccinated cohort ( TVC , included all women receiving at least one vaccine dose , regardless of their baseline HPV status ; represents the general population , including those who are sexually active ; vaccine , n=9319 ; control , n=9325 ) , and TVC-naive ( no evidence of oncogenic HPV infection at baseline ; represents women before sexual debut ; vaccine , n=5822 ; control , n=5819 ) . The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2 + ( CIN2 + ) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline , and DNA negative at baseline and month 6 for the corresponding type ( ATP-E ) . This trial is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Mean follow-up was 34.9 months ( SD 6.4 ) after the third dose . Vaccine efficacy against CIN2 + associated with HPV-16/18 was 92.9 % ( 96.1 % CI 79.9 - 98.3 ) in the primary analysis and 98.1 % ( 88.4 - 100 ) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types ( ATP-E cohort ) . Vaccine efficacy against CIN2 + irrespective of HPV DNA in lesions was 30.4 % ( 16.4 - 42.1 ) in the TVC and 70.2 % ( 54.7 - 80.9 ) in the TVC-naive . Corresponding values against CIN3 + were 33.4 % ( 9.1 - 51.5 ) in the TVC and 87.0 % ( 54.9 - 97.7 ) in the TVC-naive . Vaccine efficacy against CIN2 + associated with 12 non-vaccine oncogenic types was 54.0 % ( 34.0 - 68.4 ; ATP-E ) . Individual cross-protection against CIN2 + associated with HPV-31 , HPV-33 , and HPV-45 was seen in the TVC . INTERPRETATION The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2 + associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes . FUNDING GlaxoSmithKline Biologicals Cervical cancer is a leading cause of cancer mortality in women worldwide . Human papillomavirus ( HPV ) types 16 and 18 cause about 70 % of all cervical cancers . Clinical trials have demonstrated that three doses of either commercially available HPV vaccine , Cervarix ® or Gardasil ® , prevent most new HPV 16/18 infections and associated precancerous lesions . Based on evidence of immunological non-inferiority , 2-dose regimens have been licensed for adolescents in the United States , European Union , and elsewhere . However , if a single dose were effective , vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified , enabling vaccination programs in developing countries . The National Cancer Institute ( NCI ) and the Agencia Costarricense de Investigaciones Biomédicas ( ACIB ) are conducting , with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer ( IARC ) , a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen . The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines . The second component is an observational study that estimates the vaccine efficacy ( VE ) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls . In this paper , we describe the design and statistical analysis for this study . We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and , given this definition , suggest an approach to account for missing clinic visits . We then describe the problem of estimating VE in the absence of a r and omized placebo arm and offer our solution Background The duration of antibody response following reduced human papillomavirus ( HPV ) vaccine doses has not been determined . We compared the antibody responses in girls previously vaccinated with zero , 1 , 2 , or 3 doses of quadrivalent HPV vaccine ( 4vHPV ; Gardasil , Merck )  6 years previously . Methods A prospect i ve cohort study was undertaken in 200 Fijian girls 15 - 19 years of age . Approximately equal numbers of girls from 2 main ethnic groups ( Fijians of Indian descent [ FID ] and Indigenous Fijians [ iTaukei ] ) in Fiji were recruited for each dosage groups . Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine ( 2vHPV ; Cervarix , GlaxoSmithKline ) . We measured neutralizing antibodies ( NAb ) against HPV-6 , -11 , -16 , and -18 using the pseudovirion-based neutralization assay . Results After 6 years ( before a dose of 2vHPV was given ) , the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose ( 2D ) and 3-dose ( 3D ) recipients : HPV-6 ( 3D : 2216 [ 95 % confidence interval {CI},1695 - 2896 ] ; 2D : 1476 [ 95 % CI , 1019 - 2137 ] ; P = .07 ) , HPV-11 ( 3D : 4431 [ 95 % CI , 3396 - 5783 ] ; 2D : 2951 [ 95 % CI , 1984 - 4390 ] ; P = .09 ) , HPV-16 ( 3D : 3373 [ 95 % CI , 2511 - 4530 ] ; 2D : 3275 [ 95 % CI , 2452 - 4373 ] ; P = .89 ) ; HPV-18 ( 3D : 628 [ 95 % CI : 445 - 888 ] ; 2D : 606 [ 95 % CI , 462 - 862 ] ; P = .89 ) , and were higher in FID than iTaukei girls . Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients , their NAb titers were 5- to 30-fold higher than unvaccinated girls . Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1 , 2 , or 3 doses of 4vHPV previously . Conclusions Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years , although the clinical significance is unknown . A single dose of 4vHPV elicits antibodies that persisted for at least 6 years , and induced immune memory , suggesting possible protection against HPV vaccine types after a single dose of 4vHPV Background Previously , we demonstrated similar human papillomavirus (HPV)16/18 vaccine efficacy estimates and stable HPV16/18 antibody levels four years postvaccination in a nonr and omized analysis of women who received a varying number of doses of the bivalent HPV16/18 vaccine .  Here we extend data to seven years following initial vaccination . Methods We evaluated  HPV16/18-vaccinated women who received one ( n = 134 ) , two ( n 0/1 = 193 , n 0/6 = 79 ) , or three doses ( n = 2043 ) to a median of 6.9 years postvaccination .  Cervical HPV DNA was measured with the SPF10- DEIA-LiPA PCR system ;  HPV16/18-specific antibody levels were measured using enzyme-linked immunosorbent assays ( n = 486 ) . Infection and immunological measures were compared across vaccine dose groups . Prevalent HPV infection at year 7 was also compared with an unvaccinated control group ( UCG ) . All statistical tests were two-sided . Results Among women in the three-dose , two-dose 0/6 , two-dose 0/1 , and one-dose groups , cumulative incident HPV16/18 infection rates ( No. of events/No . of individuals ) were 4.3 % ( 88/2036 , 95 % confidence interval [ CI ] = 3.5 % to 5.3 % ) , 3.8 % ( 3/78 , 95 % CI = 1.0 % to 10.1 % ) , 3.6 % ( 7/192 , 95 % CI = 1.6 % to 7.1 % ) , and 1.5 % ( 2/133 , 95 % CI = 0.3 % to 4.9 % ; P = 1.00 , .85 , .17 comparing the two-dose 0/6 , two-dose 0/1 , and one-dose groups to the three-dose group , respectively ) . The prevalence of other carcinogenic and noncarcinogenic HPV types , excluding HPV16/18/31/33/45 , were high and not statistically different among all dose groups , indicating that the low incidence of HPV16/18 in the one- and two-dose groups was not due to lack of exposure . At seven years , 100 % of participants in all dose groups remained HPV16 and HPV18 seropositive . A non-statistically significant decrease in the geometric mean of the HPV16 antibody levels between years 4 and 7 was observed among women in the three-dose group : -10.8 % ( 95 % CI = -25.3 % to 6.6 % ) ; two-dose ( 0/6 months ) group : -17.3 % ( 95 % CI = -39.3 % to 12.8 % ) , two-dose ( 0/1 month ) group : -6.9 % ( 95 % CI = -22.1 % to 11.2 % ) , and one-dose group : -5.5 % ( 95 % CI = -29.7 % to 27.0 % ) ; results were similar for HPV18 . Conclusions At an average of seven years of follow-up , we observed similar low rates of HPV16/18 infections and slight , if any , decreases in HPV16/18 antibody levels by dose group BACKGROUND Human papillomavirus ( HPV ) vaccination is a major strategy for preventing cervical and other ano-genital cancers . Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to ' no vaccination ' . METHODS In a multi-centre cluster r and omized trial of two vs three doses of quadrivalent HPV vaccination ( Gardasil ™ ) in India , suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10 - 18 year old girls leading to four study groups , two by design and two by default . They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres , neutralising antibody titres , and antibody avidity for the vaccine-targeted HPV types and HPV infections . Analysis was per actual number of vaccine doses received . This study is registered with IS RCT N , number IS RCT N98283094 ; and with Clinical Trials.gov , number NCT00923702 . FINDINGS Of the 17,729 vaccinated girls , 4348 ( 25 % ) received three doses on days 1 , 60 , 180 or later , 4979 ( 28 % ) received two doses on days 1 and 180 or later , 3452 ( 19 % ) received two doses on days 1 and 60 , and 4950 ( 28 % ) received one dose . One 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic , generally well tolerated , and effective against HPV-16 or HPV-18 infections , and associated precancerous lesions in an event-triggered interim analysis of the phase III r and omised , double-blind , controlled PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . We now assess the vaccine efficacy in the final event-driven analysis . METHODS Women ( 15 - 25 years ) were vaccinated at months 0 , 1 , and 6 . Analyses were done in the according-to- protocol cohort for efficacy ( ATP-E ; vaccine , n=8093 ; control , n=8069 ) , total vaccinated cohort ( TVC , included all women receiving at least one vaccine dose , regardless of their baseline HPV status ; represents the general population , including those who are sexually active ; vaccine , n=9319 ; control , n=9325 ) , and TVC-naive ( no evidence of oncogenic HPV infection at baseline ; represents women before sexual debut ; vaccine , n=5822 ; control , n=5819 ) . The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2 + ( CIN2 + ) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline , and DNA negative at baseline and month 6 for the corresponding type ( ATP-E ) . This trial is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Mean follow-up was 34.9 months ( SD 6.4 ) after the third dose . Vaccine efficacy against CIN2 + associated with HPV-16/18 was 92.9 % ( 96.1 % CI 79.9 - 98.3 ) in the primary analysis and 98.1 % ( 88.4 - 100 ) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types ( ATP-E cohort ) . Vaccine efficacy against CIN2 + irrespective of HPV DNA in lesions was 30.4 % ( 16.4 - 42.1 ) in the TVC and 70.2 % ( 54.7 - 80.9 ) in the TVC-naive . Corresponding values against CIN3 + were 33.4 % ( 9.1 - 51.5 ) in the TVC and 87.0 % ( 54.9 - 97.7 ) in the TVC-naive . Vaccine efficacy against CIN2 + associated with 12 non-vaccine oncogenic types was 54.0 % ( 34.0 - 68.4 ; ATP-E ) . Individual cross-protection against CIN2 + associated with HPV-31 , HPV-33 , and HPV-45 was seen in the TVC . INTERPRETATION The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2 + associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes . FUNDING GlaxoSmithKline Biologicals Cervical cancer is a leading cause of cancer mortality in women worldwide . Human papillomavirus ( HPV ) types 16 and 18 cause about 70 % of all cervical cancers . Clinical trials have demonstrated that three doses of either commercially available HPV vaccine , Cervarix ® or Gardasil ® , prevent most new HPV 16/18 infections and associated precancerous lesions . Based on evidence of immunological non-inferiority , 2-dose regimens have been licensed for adolescents in the United States , European Union , and elsewhere . However , if a single dose were effective , vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified , enabling vaccination programs in developing countries . The National Cancer Institute ( NCI ) and the Agencia Costarricense de Investigaciones Biomédicas ( ACIB ) are conducting , with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer ( IARC ) , a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen . The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines . The second component is an observational study that estimates the vaccine efficacy ( VE ) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls . In this paper , we describe the design and statistical analysis for this study . We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and , given this definition , suggest an approach to account for missing clinic visits . We then describe the problem of estimating VE in the absence of a r and omized placebo arm and offer our solution Background The duration of antibody response following reduced human papillomavirus ( HPV ) vaccine doses has not been determined . We compared the antibody responses in girls previously vaccinated with zero , 1 , 2 , or 3 doses of quadrivalent HPV vaccine ( 4vHPV ; Gardasil , Merck )  6 years previously . Methods A prospect i ve cohort study was undertaken in 200 Fijian girls 15 - 19 years of age . Approximately equal numbers of girls from 2 main ethnic groups ( Fijians of Indian descent [ FID ] and Indigenous Fijians [ iTaukei ] ) in Fiji were recruited for each dosage groups . Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine ( 2vHPV ; Cervarix , GlaxoSmithKline ) . We measured neutralizing antibodies ( NAb ) against HPV-6 , -11 , -16 , and -18 using the pseudovirion-based neutralization assay . Results After 6 years ( before a dose of 2vHPV was given ) , the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose ( 2D ) and 3-dose ( 3D ) recipients : HPV-6 ( 3D : 2216 [ 95 % confidence interval {CI},1695 - 2896 ] ; 2D : 1476 [ 95 % CI , 1019 - 2137 ] ; P = .07 ) , HPV-11 ( 3D : 4431 [ 95 % CI , 3396 - 5783 ] ; 2D : 2951 [ 95 % CI , 1984 - 4390 ] ; P = .09 ) , HPV-16 ( 3D : 3373 [ 95 % CI , 2511 - 4530 ] ; 2D : 3275 [ 95 % CI , 2452 - 4373 ] ; P = .89 ) ; HPV-18 ( 3D : 628 [ 95 % CI : 445 - 888 ] ; 2D : 606 [ 95 % CI , 462 - 862 ] ; P = .89 ) , and were higher in FID than iTaukei girls . Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients , their NAb titers were 5- to 30-fold higher than unvaccinated girls . Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1 , 2 , or 3 doses of 4vHPV previously . Conclusions Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years , although the clinical significance is unknown . A single dose of 4vHPV elicits antibodies that persisted for at least 6 years , and induced immune memory , suggesting possible protection against HPV vaccine types after a single dose of 4vHPV Background Previously , we demonstrated similar human papillomavirus (HPV)16/18 vaccine efficacy estimates and stable HPV16/18 antibody levels four years postvaccination in a nonr and omized analysis of women who received a varying number of doses of the bivalent HPV16/18 vaccine .  Here we extend data to seven years following initial vaccination . Methods We evaluated  HPV16/18-vaccinated women who received one ( n = 134 ) , two ( n 0/1 = 193 , n 0/6 = 79 ) , or three doses ( n = 2043 ) to a median of 6.9 years postvaccination .  Cervical HPV DNA was measured with the SPF10- DEIA-LiPA PCR system ;  HPV16/18-specific antibody levels were measured using enzyme-linked immunosorbent assays ( n = 486 ) . Infection and immunological measures were compared across vaccine dose groups . Prevalent HPV infection at year 7 was also compared with an unvaccinated control group ( UCG ) . All statistical tests were two-sided . Results Among women in the three-dose , two-dose 0/6 , two-dose 0/1 , and one-dose groups , cumulative incident HPV16/18 infection rates ( No. of events/No . of individuals ) were 4.3 % ( 88/2036 , 95 % confidence interval [ CI ] = 3.5 % to 5.3 % ) , 3.8 % ( 3/78 , 95 % CI = 1.0 % to 10.1 % ) , 3.6 % ( 7/192 , 95 % CI = 1.6 % to 7.1 % ) , and 1.5 % ( 2/133 , 95 % CI = 0.3 % to 4.9 % ; P = 1.00 , .85 , .17 comparing the two-dose 0/6 , two-dose 0/1 , and one-dose groups to the three-dose group , respectively ) . The prevalence of other carcinogenic and noncarcinogenic HPV types , excluding HPV16/18/31/33/45 , were high and not statistically different among all dose groups , indicating that the low incidence of HPV16/18 in the one- and two-dose groups was not due to lack of exposure . At seven years , 100 % of participants in all dose groups remained HPV16 and HPV18 seropositive . A non-statistically significant decrease in the geometric mean of the HPV16 antibody levels between years 4 and 7 was observed among women in the three-dose group : -10.8 % ( 95 % CI = -25.3 % to 6.6 % ) ; two-dose ( 0/6 months ) group : -17.3 % ( 95 % CI = -39.3 % to 12.8 % ) , two-dose ( 0/1 month ) group : -6.9 % ( 95 % CI = -22.1 % to 11.2 % ) , and one-dose group : -5.5 % ( 95 % CI = -29.7 % to 27.0 % ) ; results were similar for HPV18 . Conclusions At an average of seven years of follow-up , we observed similar low rates of HPV16/18 infections and slight , if any , decreases in HPV16/18 antibody levels by dose group BACKGROUND Human papillomavirus ( HPV ) vaccination is a major strategy for preventing cervical and other ano-genital cancers . Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to ' no vaccination ' . METHODS In a multi-centre cluster r and omized trial of two vs three doses of quadrivalent HPV vaccination ( Gardasil ™ ) in India , suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10 - 18 year old girls leading to four study groups , two by design and two by default . They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres , neutralising antibody titres , and antibody avidity for the vaccine-targeted HPV types and HPV infections . Analysis was per actual number of vaccine doses received . This study is registered with IS RCT N , number IS RCT N98283094 ; and with Clinical Trials.gov , number NCT00923702 . FINDINGS Of the 17,729 vaccinated girls , 4348 ( 25 % ) received three doses on days 1 , 60 , 180 or later , 4979 ( 28 % ) received two doses on days 1 and 180 or later , 3452 ( 19 % ) received two doses on days 1 and 60 , and 4950 ( 28 % ) received one dose . One 
    Output:
    