Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine. Sustained Antibody Responses 6 Years Following 1, 2, or 3 Doses of Quadrivalent Human Papillomavirus (HPV) Vaccine in Adolescent Fijian Girls, and Subsequent Responses to a Single Dose of Bivalent HPV Vaccine: A Prospective Cohort Study Durability of Protection Afforded by Fewer Doses of the HPV16/18 Vaccine: The CVT Trial Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. Durable Antibody Responses Following One Dose of the Bivalent Human Papillomavirus L1 Virus-Like Particle Vaccine in the Costa Rica Vaccine 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. Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study
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 dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18 , albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period . The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups ; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients . The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women . CONCLUSION Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules , although the study suffer from some limitations . Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented . Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current st and ard of care for cervical cancer prevention is ' no intervention ' 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 ) 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 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 ) Summary Background An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses . We originally aim ed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later , with three doses on days 1 , 60 , and 180 or later , in a cluster-r and omised trial . Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default . As a result , we re-analysed our data as an observational cohort study . Methods Our study was design ed to be done in nine locations ( 188 clusters ) in India . Participants were unmarried girls aged 10–18 years vaccinated in four cohorts : girls who received three doses of vaccine on days 1 , 60 , and 180 or later , two doses on days 1 and 180 or later , two doses on days 1 and 60 by default , and one dose by default . The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres , neutralising antibody titres , and antibody avidity after vaccination for the vaccine-targeted HPV types 16 , 18 , 6 , and 11 and incident and persistent infections with these HPVs . 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 Vaccination of eligible girls was initiated on Sept 1 , 2009 , and continued until April 8 , 2010 . Of 21 258 eligible girls identified at 188 clusters , 17 729 girls were recruited from 178 clusters before suspension . 4348 ( 25 % ) girls received three doses , 4979 ( 28 % ) received two doses on days 1 and 180 or later , 3452 ( 19 % ) received two doses at days 1 and 60 , and 4950 ( 28 % ) received one dose . Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group ( median fluorescence intensity ratio for HPV 16 1·12 [ 95 % CI 1·02–1·23 ] and for HPV 18 1·04 [ 0·92–1·19 ] ) at 7 months , but was inferior in the two-dose default ( 0·33 [ 0·29–0·38 ] for HPV 16 and 0·51 [ 0·43–0·59 ] for HPV 18 ) and one-dose default ( 0·09 [ 0·08–0·11 ] for HPV 16 and 0·12 [ 0·10–0·14 ] for HPV 18 ) groups at 18 months . The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine . Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types , but at much lower concentration after one dose . Cervical sample s from 2649 participants were tested and the frequency of incident HPV 16 , 18 , 6 , and 11 infections was similar irrespective of the number of vaccine doses received . The testing of at least two sample s from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years ( IQR 4·2–5·1 ) . Interpretation Despite the limitations imposed by the suspension of the HPV vaccination , our findings lend support to the WHO recommendation of two doses , at least 6 months apart , for routine vaccination of young girls . The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16 , 18 , 6 , and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment . Funding Bill & Melinda Gates Foundation
OBJECTIVES This study aim ed to systematic ally review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants .