Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point—registry-based follow-up of three cohorts from randomized trials

1 Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access Abs Ac Objec i e Due o long lag ime be ween in ec ion/ cance diagnoses human papilloma i us (HPV) accina ion p og ams will deli e accine e icacy (VE) es ima es agains cance end-poin s la e. Cance egis y ollow-up o popula ion-based, andomised ial coho s o accina ed and un accina ed women was unde aken o he es ima ion o VE agains ce ical in aepi helial neoplasia g ade h ee and in asi e cance (CIN3+). Me hods We epo in e im esul s wi h 98 561 pe son yea s o Finnish Cance Regis y -based ollow-up o indi idually and/o clus e andomised coho s o HPV- 16/18 accina ed and un accina ed adolescen women en olled in June 2003/2005, and be ween May 2004 and Ap il 2005, espec i ely. The coho s comp ised 15 627 18- o 19-yea -old un accina ed women (NCT01393470), and 2 401 and 64 16- o 17-yea -old HPV-16/18 accina ed women pa icipa ing he PATRICIA (NCT00122681) and HPV-012 (NCT00169494) ials, espec i ely. The age-aligned passi e ollow-up s a ed 6 mon hs a e he clinical ials’ end. esul s Du ing he ollow-up o 4.5 o 10 yea s pos en olmen we iden i ied 75 cases o ce ical in aepi helial neoplasia g ade 3 (CIN3) and 4 cases o in asi e ce ical cance (ICC) in he un accina ed coho , and 4 CIN3 cases in he HPV-16/18 accina ed women. Diagnos ic blocks we e a ailable o HPV yping om 87% o he cases. CIN3+ lesions we e de ec able in 54 cases. HPV16 was ound in 26 o 50 un accina ed CIN3+ cases, and in 3 CIN3+ cases in he HPV-16/18 accina ed women. The la e we e all baseline posi i e o ce ical HPV16 DNA. Baseline da a was no a ailable o he un accina ed women. In en ion- o- ea VE agains any CIN3+ was 66% (95% CI 8, 88). conclusions Ten yea s pos accina ion he AS04- adju an ed HPV-16/18 accine shows con inued e icacy agains CIN3+ i espec i ely o HPV ype. Vaccine e icacy was no obse ed in baseline HPV16 DNA posi i e subjec s. ial egis a ion numbe NCT01393470. In Oduc IOn High- isk (h ) human papilloma i uses (HPVs) cause up o 9% and 1% o cance s in emales and males.1 Bi alen , quad i- alen and nona alen accines agains HPV ypes 16/18, 6/11/16/18, and 6/11/16/18/31/33/45/52/58, espec- i ely, ha e an accep able sa e y p o ile and a e highly e icacious agains a numbe o in ec ions wi h h HPVs and associa ed p ecance s.2–6 P oo o accine e icacy (VE) agains HPV-associa ed cance s is, howe e , no easy o each due o he long lag ime be ween exposu e o he i us and diagnosis o he associa ed cance . This phenomenon is no uncommon, and has o ins ance hinde ed he de e mina ion o VE agains hepa i is B i us (HBV) associa ed hepa ocel- lula ca cinoma, since he ime lag be ween i us exposu e and diagnosis o ca cinoma is 15 o 25.7 8 P o ing he concep o accine induced p o ec ion agains (one o ) he majo Ten-yea ollow-up o human papilloma i us accine e icacy agains he mos s ingen ce ical neoplasia end-poin — egis y-based ollow-up o h ee coho s om andomized ials Ma i Leh inen,1,2 Camilla Lagheden,2 Tapio Luos a inen,2 Tiina E iksson,1 Dan Ap e ,3 Ka ja Ha jula,1 Ma jo Kuo i,1 Ka i Na unen,1 Johanna Palm o h,1 Tiina Pe äjä,1 Ee o Pukkala,4 Ma i Sii a i-Ma ila,1 F ank S uy ,5 Pekka Nieminen,6 Jo ma Paa onen,6 Ga y Dubin,7 Joakim Dillne 2 To ci e: Leh inenM, LaghedenC, Luos a inenT, e al. Ten-yea ollow-up o human papilloma i us accine e icacy agains he mos s ingen ce ical neoplasia end-poin — egis y-based ollow-up o h ee coho s om andomized ials. BMJ Open 2017;7:e015867. doi:10.1136/ bmjopen-2017-015867 ►P epublica ion his o y o his pape is a ailable online. To iew hese iles please isi he jou nal online (h p:// dx. doi. o g/ 10. 1136/ bmjopen- 2017015867) Recei ed 5 Janua y 2017 Re ised 24 Ap il 2017 Accep ed 25 Ap il 2017 1Uni e si y o Tampe e, Tampe e, Finland 2Depa men o Labo a o y Medicine, Ka olinska Ins i u e, S ockholm, Sweden 3VL-Medi, Helsinki, Finland 4Finnish Cance Regis y, Helsinki, Finland 5GSK Biologicals, Wa e, Belgium 6Uni e si y o Helsinki, Helsinki, Finland 7Takeda Pha maceu icals In e na ional, Zu ich, Swi ze land co espondence o D Ma i Leh inen; ma i. leh inen@ u a. i Resea ch s eng hs and limi a ions o his s udy ►Coun y-wide cance egis y ollow-up o sizeable andomised coho s o HPV accina ed and un accina ed women o 100.000 pe son yea s (up o10 yea s pos accina ion) p o ides mos eliable accine e icacy es ima es agains cance ous end- poin s. ►Re ie al o mos diagnos ic his opa hological blocks and s a e-o -science iden i ica ion o he causal HPV ype in he lesion enable iden i ica ion o HPV ype- speci ic accine e icacy es ima es. ►The pe p o ocol de ined in e im analysis has limi ed s a is ical powe . g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 2Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access HPV-associa ed cance s, i.e., in si u and in asi e ce ical ca cinoma is no only o concep ual bu also o p ac ical impo ance. I would gua an ee he impac o p ima y cance p e en ion ia p ophylac ic HPV accina ion, guide a ge ing his p ophylaxis, and p o ide he scien- i ic basis o unde s anding how and when such p oo will be a ailable o o he HPV-associa ed cance s such as non-ce ical anogeni al cance s, and head and neck cance s. Ou objec i e is o de e mine VE agains ce ical cance . To accomplish his we iden i y in asi e ce ical cance (ICC) and in aepi helial neoplasia g ade 3 (CIN3+) incidence in passi e, popula ion-based cance egis y ollow-up o a andomised clinical HPV accine ial coho (PATRICIA),4 and a clus e - andomised con ol coho en olled in 2003-2005.9–11 The ollow-up o o iginally adolescen emales has p e iously p o en o be easible.12 Wi h he obse ed CIN3+ incidence o 93.4/100 000 in he con ol coho ,12 which equals ha o he Finnish emale popula ion o simila age 99.5/100 000,12 i is well powe ed o e i y 65% VE agains CIN3+ and ICC, 10 and 15 yea s pos accina ion, espec i ely.9–12 We epo in e im esul s on he e icacy o he bi alen HPV16/18 accine agains o e all and HPV ype-speci ic CIN3+ end-poin s. Me hOds S udy design and E hics Ou clus e - andomised ollow-up s udy in ol es sepa a e bi h coho s o clinical ial pa icipan s4 12 13 aged 16–17 yea s and un accina ed non-pa icipan s9 10 aged 18–19 yea s assigned acco ding o he s a o PATRICIA14 ial in May 2004 by ML ( he p incipal in es iga o o phase III HPV accina ion ials in Finland). The o me we e also indi idually andomised.13 The ials, es ablishing he un accina ed con ol coho and hei Finnish Cance Regis y (FCR) –based ollow-up we e app o ed by he Finnish Na ional E hical Re iew Boa d (TUKIJA: 1174/2004 and 1153/2003), espec i ely The s udy in ol ed consecu i e ec ui men o adjacen , pa ially o e lapping bi h coho s subjec ed o i) HPV accina ion and 4 yea s o clinical ollow-up including ce ical cy ological sampling (bi h coho s Q2/1986 o Q1/1988), o ii) 4 yea s o clinical ollow-up including ce ical cy ological sampling (bi h coho s Q2/1986 o Q1/1988), and iii) un accina ed and no in e en ion (bi h coho s Q3/1984 o Q2/1985, and bi h coho s Q3/1985 o Q2/1987). The in e en ion measu ed was accina ion wi h he AS04-adju an ed HPV-16/18 accine agains no accina ion wi h he end-poin : ce ical in aepi helial neoplasia g ade h ee o in asi e ce ical cance (CIN3+). The end-poin s we e his opa holog- ically diagnosed 0–4 yea s pos accina ion (du ing he ac i e ollow-up), 4–4.5 yea s pos accina ion (du ing he in e mi en pe iod be ween he ac i e ollow-up and he passi e ollow-up), o 4.5–10 yea s pos accina ion (du ing he passi e ollow-up). Pa ien in ol emen Pa ien s (wi h ce ical neoplasia / condyloma) we e no in ol ed in he design o his s udy in 2000. A s udy on he easibili y o popula ion-based en olmen was done in 1998.14 En olmen S a ing in May 2004 o iginally all 24 046 (Q2/1986-Q1/1988 bo n) 16–17 yea old Finnish emales esiden in 17 ial communi ies we e sen in i- a ions o pa icipa e o he PATRICIA ial (HPV-008, NCT00122681) on he immunogenici y, sa e y and e i- cacy o he AS04-adju an ed HPV-16/18 accine agains HPV16/18 posi i e CIN2+ ( igu e 1). By June 2005 a o al o 4 808 women pa icipa ed. They we e andomly assigned o HPV-16/18 o hepa i is A- i us (HAV) accina- ion in 1:1 a io o ecei e h ee doses o he HPV-16/18 accine o he HAV accine a mon hs 0, 1 and 6, ollowed by se en ac i e ollow-up isi s wi h 6 mon h in e al up o 4 yea s.4 13 In addi ion, 64 16–17 yea olds ecei ed 3 doses o he HPV-16/18 accine by May 2005 in a concomi an HPV-012 ial which ended 4 yea s la e .15 Following he end o he ac i e ollow-up in May 2009, app oxima ely 50% o he HAV- accine ecipien s chose HPV-16/18 c oss- accina ion du ing 2009–2010. H HPV DNA posi i es a he las PATRICIA ial isi (215 om he HPV-16/18 coho and 318 om he HAV coho ) con inued ac i e clinical ollow-up (HPV-052 s udy p o ocol) o app oxima ely 1.9 yea s a e he end o he PATRICIA ial. They had annual HPV es ing cy ology un il HPV DNA nega i e o exi colposcopy a e 4 yea s. An un accina ed con ol coho om en i e adjacen bi h coho s o 18–19 yea olds was ec ui ed in i ing 30 947 and 58 996 in May/June 2003/5 by he Finnish Popu- la ion Regis e Cen e as desc ibed (NCT01393470).9–11 All PATRICIA4 13 and ea lie Fu u e12 ial pa icipan s we e excluded om he con ol coho . The e we e no heal hca e in e en ions a ge ed o he con ol coho . Follow-up Bo h he accina ed and un accina ed con ol coho s esponded a he age o 22–23 yea s o a ques ionnai e on li e habi s wi h special emphasis on sexual heal h, ha is, a he beginning o he passi e egis y-based ollow-up.16 17 Oppo unis ic accina ion by Ga dasil o Ce a ix accines a e hei licensu es in 2006 and 2007 was conside ed based on ques ionnai es in 2007 and 2009, and among he accina ed PATRICIA and HPV-012 ial coho s in 2010. In addi ion, i al s a us and emig a ion we e upda ed un il he end o 2014. In i a ions o ce ical sc eening we e sen o all s udy pa icipan s a he age o 25 yea s, also in communi ies which o ganise he sc eening om age 30 onwa ds. Wi h o e -lapping ime-windows o 5.5 yea s we age-aligned he passi e ollow-up o he di e en bi h coho s.12 The s udy ou comes we e CIN3+ lesions diagnosed du ing he passi e ollow-up. Acco ding o local s an- da d o ca e, women wi h cy ological abno mali ies we e e e ed o colposcopy biopsy o his opa hological diagnosis wi hin a 6 mon h pe iod ollowing cy ology.18 Thus, he passi e, Finnish Cance Regis y (FCR) -based ollow-up was s a ed 6 mon hs a e he end o ac i e clinical ollow-up o he PATRICIA (and 052) ial and g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 3 Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access Figu e 1 Conso diag am wi h ele an in i a ion, en olmen and exclusion c i e ia/s eps.*Due o mig a ion no eligible o Finnish Cance Regis y ollow-up. Table 1 Sample size and powe calcula ions o a egis y-based ollow-up s udy on he e icacy o human papilloma i us (HPV) ype 16/18 accine agains ce ical in aepi helial neoplasia g ade h ee and in asi e cance (CIN3+). (A)Requi ed sample sizes o he cance - egis y ollow-up phase III ial coho s assuming 90% accine e icacy agains CIN3+ (s a is ical powe : 1-β=80%, α=0.05) and 10 yea s o ollow-up.(B) S a is ical powe wi h ac ua ial*† sample sizes o he cance - egis y ollow-up o phase III ial coho s assuming 50%, 70% and 90% HPV accine e icacy (VE) agains CIN3+ Cumula i e incidence % Ca ego y Design 1:3 Design 1:4 0.2 HPV accina ed/un accina ed 3 990/11 970 3 880/15 520 0.4 HPV accina ed/un accina ed 1 773/5 319 1 685/6 740 0.6 HPV accina ed/un accina ed 936/2 808 889/3 556 0.8 HPV accina ed/un accina ed 795/2 385 755/3 220 1.2 HPV accina ed/un accina ed 495/1 485 470/1 880 Cumula i e incidence% Ca ego y VE 50% VE 70% VE90% 0.3 HPV accina ed*/un accina ed† 0.203 0.441 0.825 0.6 HPV accina ed*/un accina ed† 0.447 0.847 0.998 0.9 HPV accina ed*/un accina ed† 0.657 0.973 1.000 1.2 HPV accina ed*/un accina ed† 0.805 0.996 1.0000 *2465 HPV-16/18 accina ed and†15 627 un accina ed women ollowed up o up o 10 yea s pos accina ion by a popula ion-based cance egis y 012 ials. Fo he con ol coho he passi e ollow-up was age-aligned by a compa able ime-pe iod.12 Based on age-speci ic incidence o CIN3+ in he Finnish emale popula ion (www. cance . i) he en olled coho s o HPV-16/18 accina ed women and con ol women exceed he numbe s equi ed o a leas 80% powe o iden- i y s a is ically signi ican 65% accine e icacy agains CIN3+.9 10 An in e im analysis o CIN3+ was planned o ake place a e 5 yea s o passi e ollow-up, and he inal analysis o ICC a e 10 yea s o passi e ollow-up. The FCR is popula ion-based and ecei es cance no i i- ca ions om he en i e coun y wi h 100% co e age, and 80% co e age o CIN3 (www. cance . i). Indi idually, he passi e ollow-up o he di e en coho s ex ended un il 10 yea s pos accina ion o om he eceip o in o med consen (un accina ed women) up o he end o 2014. g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 4Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access Table 2 Demog aphic cha ac e is ics o he coho s subjec ed o Finnish Cance Regis y ollow-up. Ca ego y HPV-16/18 accina ed (n=2 472) HAV- accina ed (n=2 399) Un accina ed (n=15 627) Age a en olmen 16–17 yea s 16–17 yea s 18–19 yea s Age a passi e ollow-up 22–28 yea s 22–28 yea s 22–28 yea s Response a e* 1 107 (46.5%) 1 010 (42.1%) 7 118 (45.5%) Sexual debu (mean age) 15.8 yea s 16.0 yea s 16.4 yea s No. o li e- ime pa ne s 0 37 (3.3%) 32 (3.2%) 400 (5.6%) 1 143 (12.9%) 146 (14.5%) 1 335 (18.8%) 2 131 (11.8%) 114 (11.3%) 750 (10.5%) 3–9 511 (46.2%) 458 (45.3%) 3 023 (42.4%) 10 o mo e 284 (25.7%) 257 (25.4%) 1 588 (22.3%) No. o pa ne s in he pas 12 mon hs 0 531 (49.8%) 507 (50.2%) 3 848 (54.1%) 1 237 (21.4%) 230 (22.8%) 1 365 (19.2%) 2 111 (10.1%) 92 (9.1%) 580 (8.1%) h ee o mo e 170 (15.4%) 145 (14.4%) 914 (12.8%) Use o con acep ion BCP (e e ) 1 028 (92.9%) 920 (91.1%) 6 017 (84.5%) Condom† use 298 (26.9%) 261 (25.8%) 2 004 (28.2%) no use 787 (71.1%) 728 (72.1%) 4 977 (69.5%) No con acep ion 1 (0.1%) 5 (0.5%) 56 (0.8%) * e u ned ques ionnai es a he age o 22–23 yea s when he passi e ollow-up was s a ed †las yea Table 3 Incidence a e (/100 000 women yea s) o ce ical in aepi helial neoplasia g ade h ee and in asi e cance (CIN3+) in clus e - andomised coho s o 16- o 17-yea -old HPV-16/18 accine ecipien s, and un accina ed o iginally 18- o 19 yea old women. Passi e ollow- up was by he popula ion-based Finnish Cance Regis y up o 10 yea s pos accina ion. End poin o  he ollow-up Vaccine Con ol N Pe son y s n Ra e* N Pe son y s n Ra e* FCR egis e ed CIN3+ diagnoses Ac i e 2472   10199 – – 15 665  62628 – – In e mi en 2 466  1 232 1 81 15 634 7 815 – – Passi e 2465 12 561 4 32 15 627  85 328 79 93 KI e- e iewed CIN3+ diagnoses In e mi en 2 466  1 232 1 81 15 634  7 815 – – Passi e 2 465  12 561 3 24 15 627  85 328 50 59 Ac i e (0–4 yea s), In e mi en (4–4.5 yea s), Passi e (4.5–10 yea s) *incidence/100 000 women yea s Following Finnish na ional e hical commi ee clea - ances in 2003 and 2004, egis e s o HPV-16/18 accina ed and un accina ed coho s we e es ablished and ha e since been main ained a he Uni e si y o Tampe e.9 10 Pe mission o link hese egis e s wi h he FCR o he iden i ica ion new cance cases un il 2024 was ob ained om he Finnish Ins i u e o Heal h & Wel a e in 2004. Fo he in e im analysis he age-aligned HPV-16/18 accine (n=2 465) and he un accina ed con ol coho (n=15 627) we e linked using pe sonal iden i- ie s wi h he FCR o de e mine he incidence (pe 100 000 pe son yea s) o CIN3 and ICC (CIN3+) du ing he o e lapping 5.5 yea ollow-up pe iods o passi e ollow-up. g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 5 Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access Table 4 Cha ac e is ics o 5 CIN3 cases iden i ied among he 2 466 ecipien s o he HPV-16/18 accine in he Finnish Cance Regis y –based passi e long- e m ollow-up o he clinical ial pa icipan s be ween 4.5 and 10 yea s pos accina ion. Age a en olmen Baseline ce icalHPV DNA s a us Numbe o doses ecei ed in 2004-20 Da e o diagnosis d-poin (CIN3) HPV DNA s a us HPV-052 pa icipan 16 yea s HPV16 h ee doses Sep 2010 HPV16 no 17 yea s HPV16 h ee doses May 2012 HPV16 no 17 yea s HPV16 h ee doses Ma 2013 HPV16 no 16 yea s HPV31 h ee doses Ap 2013 n.a. yes* 17 yea s HPV16 h ee doses Ma 2012 HPV16 yes† *One HPV DNA es a e he end o he PATRICIA ial 3.5 yea s be o e he CIN3+ diagnosis †CIN3+ diagnosis made be o e s a o he passi e ollow-up His opa hological block e ie al and e-analysis Diag- nos ic, o malin- ixed his opa hological blocks we e iden i ied by he pe mission o Val i a, a depa men o he Finnish Minis y o Heal h and Social Wel a e. An expe ienced pa hologis con i med ha he e ie ed a chi al diagnos ic block con ained a CIN3+ lesion. All eligible blocks we e sec ioned acco ding o a PCR-p oo manne as desc ibed.19 Ex ac ion, ampli ica ion and yping o he lesional HPV DNA was pe o med as p e i- ously desc ibed.19 S a is ic analysis Vaccine e icacy (VE) was calcula ed as 1 - incidence a e in accina ed / incidence a e in un acc ina ed ollowing he in en ion- o- ea (ITT) p in- ciple including all indi iduals ega dless o baseline HPV s a us ecei ing a leas one HPV-16/18 accine dose in he a m o HPV accina ed using s a is ical so wa e SAS 9.4 so wa e (SAS Ins i u e, Ca y, NC, USA) acco ding o Ewell20 and Chan.21 The 95% con idence in e als we e based on exac binomial dis ibu ion o numbe o acci- na ed cases condi ional on o al numbe o cases.20 21 esul s Be ween May 2004 and June 2005 a o al o 4 808 16–17 yea -old Finnish women pa icipa ed he PATRICIA (HPV-008) ial ( igu e 1). Concomi an ly, 64 16–17 yea old Finnish emales ecei ed he AS04-adju an ed HPV-16/18 accine in an HPV-012 immunogenici y ial. In May o June 2003 and 2005 espec i ely 6 790 and 10 220 18–19 yea old non-HPV accina ed women esponded o a heal h ques ionnai e and consen ed o he passi e egis y-based ollow-up. Only he 15 627 women who we e willing o pa icipa e in an HPV accina- ion ial p o ided ha hey we e o app op ia e age, and e ained hei consen o 10 yea s we e eligible o he con ol coho o un accina ed women ( igu e 1). The ac ua ial numbe s o accina ed and un accina ed s udy pa icipan s ollowed up o 10 yea s yielded su icien s a is ical powe o he main s udy ou come: VE agains o e all CIN3+ ( able 1). The demog aphics o he HPV-16/18 accine and con ol coho s did no di e excep o he bi h coho ( able 2). The p opo ions o e e use s o o al con a- cep i es and he numbe o sexual pa ne s we e sligh ly highe , and he ime o sexual debu was sligh ly lowe in he accina ed women as compa ed wi h he un acci- na ed women. The sizeable coho s o un accina ed and HPV-16/18 accina ed women o ITT-analysis esul ed in 98 561 yea s o ollow-up. Mix u e o c oss- accina ion and con inua ion o ac i e ollow-up in he HAV accine a m p ecluded i om he passi e long- e m ollow-up. Re- e iew o all he 84 CIN3+ cases was pe o med in 87 pe cen o he cases. The p esence o CIN3+ was con i med in 74 pe cen o he diagnos ic blocks a ail- able ( able 3). Th ee o he 4 CIN3 cases iden i ied du ing he passi e ollow-up among he HPV-16/18 acci- na ed indi iduals could be con i med in he e- e iew. All we e baseline (p e- accina ion) posi i e o ce ical HPV16 DNA, and HPV16 DNA was iden i ied also in he diagnos ic blocks con aining he CIN3 lesion ( able 4). The ou h CIN3 case was baseline HPV31 DNA posi i e bu no diagnos ic block was a ailable. One CIN3 case was diagnosed du ing he p olonged ollow-up in he 052 s udy. All he CIN3+ cases we e ound in he FCR ollow-up be ween 4.5 o 10 yea s pos accina ion. Iden i ica- ion o 4 and 79 cases yielded o e all CIN3+ incidence a es o 32/100 000 and 93/100 000 women yea s in he HPV-16/18 accina ed coho and he un accina ed coho , espec i ely. This esul ed in 66% (95%CI 8, 88) o e all VE agains CIN3+, i espec i ely o HPV ype ( able 4). Fo he e- e iewed ma e ial he co e- sponding o e all VE agains CIN3+ was 59% (95%CI −26, 85). In he wo coho s, HPV16 was ound in all he h ee HPV-16/18 accina ed CIN3 cases and in 52% (26) o he un accina ed CIN3+ cases ha we e a ailable and eligible o HPV DNA yping ( able 5). VEs agains HPV16 o HPV16/18 associa ed CIN3+ we e low ( able 5). The VE es ima e agains o he han HPV16 clade A9 HPV ype, including 31/33/52/58, associa ed CIN3+ inc eased om 53% o 100% when CIN3+ lesions wi h HPV16 co-in ec- ion we e excluded om he analysis ( able 5). Numbe s o clade A7 o o he non clade A9 HPV ypes we e small. The e we e no heal hca e in e en ions a ge ed o he con ol coho , and he cance - egis y ollow-up was passi e. No ha m was caused in his s udy. g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 6Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access Table 5 Vaccine e icacy (VE, 95% CI) agains ce ical in aepi helial neoplasia g ade h ee and in asi e cance (CIN3+) associa ed wi h accine and/o non- accine HPV ypes in women accina ed in 2004/2005 wi h he HPV-16/18 accine be ween ages 16- o 17 yea s and in an age-aligned con ol coho o o iginally 18- o 19-yea -old women passi ely ollowed ia Finnish Cance Regis y o up o 10 yea s pos accina ion. End-poin (CIN3+) Vaccine Con ol N Pe son y s n Ra e# N Pe son y s n Ra e# VE (95% CI) HPV16 2 465  12 561 3 24 15 627  85 328 26 30 22 −160 o73 HPV18 2 465  12 561 – – 15 627  85 328 3 3.5 100 −1500 o100 HPV16/18 2 465  12 561 3 24 15 627  85 328 28 33 27 −140 o74 HPVA9 2 465 12 561 3 24 15 627 85 328 43 50 53 −48 o83 HPVA9* 2 465 12 561 – – 15 627 85 328 17 20 100 −65 o100 HPVA9/A7† 2 465 12 561 – – 15 627 85 328 18 21 100 −55 o100 HPV31/33/45 2 465 12 561 – – 15 627 85 328 13 15 100 −120 o100 All p o ec ed HPV ypes‡ 2 465 12 561 3 24 15 627 85 328 41 48 50 −60 o82 All p o ec ed HPV ypes§ 2 465 12 561 – – 15 627 85 328 13 15 100 −120 o100 All non-p o ec ed HPVs¶ 2 465 12 561 – – 15 627 85 328 6 7.0 100 -480 o100 All de ec ed HPV ypes 2 465 12 561 3 24 15 627 85 328 46 54 56 −38 o84 All de ec ed HPV ypes**† 2 465 12 561 – – 15 627 85 328 18 21 100 −55 o100 To al†† 2 465 12 561 3 24 15 627 85 328 50 56 59 −26 o85 To al all§§ 2 465 12 561 4 32 15 627 85 328 79 66 66 8.4 o88 A9=HPV16/31/33/35/52/58, A7=HPV18/39/45/59/68, All accine p o ec ed HPV ypes: 6/11/16/18/31/33/45/51/74, All non- accine p o ec ed HPV ypes: 34/35/39/40/42/43/44/52/53/54/56/58/59/66,/68/73 and 70 *(excluding co-in ec ions wi h 16) †(excluding co-in ec ions wi h 16/18) ‡HPV6/11/16/18/31/33/45/51/74 §HPV6/11/31/33/45/51/74 (excluding co-in ec ions wi h 16/18) ¶HPV34/35/39/40/42/43/44/52/53/54/56/58/59/66/68/70/73 (excluding co-in ec ions wi h 16/18), **HPV posi i e and HPV nega i e ††o iginal FCR egis e ed CIN3+ diagnoses §§incidence/100 000 women yea s g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 7 Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access dIscussIOn Ten yea s pos accina ion we ound s a is ically signi i- can VE o 66% o he HPV-16/18 accine agains any CIN3+ in passi e cance egis y -based ollow-up o ou popula ion-based coho s comp ising mo e han 18 000 o iginally 16- o 19 yea old women. Ou in e im ITT es ima es o VE agains any CIN3+ a e in line wi h wha we epo ed abou he 4 yea ollow-up o he o al accina ed coho (TVC) om he PATRICIA ial: VE was 45.3%.4 Wi h he close o 100.000 ollow-up yea s and FCR –based ollow-up, ou 80% powe , 0.6% cumula i e CIN3+ incidence and 70% VE assump ions9 10 we e conse a i e. Re ie al and e iew o he his o- pa hological blocks we e impo an quali y con ol s eps o he HPV yping which, e en i in o ma i e, was no always possible. I also di e si ied he end-poin s yielding e y wide con idence in e als. Howe e , e en wi h he educed numbe o HPV yped cases he o e all CIN3+ VE es ima e o 59% (CI included 0) was compa able wi h he abo e Finnish Cance Regis y in o ma ion-based es ima e. Un o una ely, he lack o baseline da a o he un accina ed coho p ecluded he TVC-nai e (ie, baseline HPV nega i e) ype o analyses which ea lie demons a ed a e y high (93.2%) VE agains any CIN3, i espec i ely o HPV ype in he PATRICIA ial 4 yea s pos accina ion.4 One limi a ion was ha some HPV-16/18 accina ed women (8.3%) also pa icipa ed in he HPV-052 s udy, he e ec s o which may ha e been con adic o y. In one o hese women annual HPV DNA sc eening may ha e led o an ea lie de ec ion o he CIN3 lesions, iden i- ied in he FCR ollow-up, due o he high sensi i i y o HPV DNA sc eening compa ed wi h con en ional oppo - unis ic cy ology.22 On he o he hand, emo al o an ea lie CIN lesion in an HPV-052 pa icipan could heo- e ically ha e led o excision o a lesion ha migh ha e su aced as CIN3+ in he FCR ollow-up. ITT analysis o he en i e coho s o HPV-16/18 accina ed and un acci- na ed women pa icipa ing in he passi e ollow-up does no allow dis inguishing be ween hese wo al e na i es bu is a conse a i e app oach. Mos impo an ly o he alidi y o he ongoing long- e m ollow-up, all ou accina ed and un accina ed s udy subjec s we e in i ed o o ganised cy ological sc eening isi s a he age o 25 yea s. Mo eo e , oppo unis ic HPV accina ion among he un accina ed con ols ollowing he licensu e o he quad i alen Ga dasil and bi alen Ce a ix HPV accines in 2006 and 2007, espec i ely has been negligible (da a no shown). We ound only a ela i ely low long- e m accine e i- cacy agains HPV-16/18 posi i e CIN3+. This was because se e al baseline, p e- accina ion HPV16 posi i e accine ecipien s, de eloped HPV16 posi i e CIN3 du ing he 10 yea s o pos accina ion ollow-up. The HPV-16/18 AS04-adju an ed accine,6 does no p o ec agains he HPV16 posi i e CIN3+ i i al in ec ion al eady exis s and pe sis en HPV16 in ec ion has been es ablished. The low e icacy obse ed in he PATRICIA ial among baseline posi i es al eady poin ed o his di ec ion.23 Vaccina ion o adul women24 o whom up o 30+% al eady ha e been exposed o h HPV in ec ion may no be he mos e ec i e HPV accina ion s a egy. In conclusion, en yea s pos accina ion he AS04-ad- ju an ed HPV-16/18 accine shows con inued e icacy agains CIN3+ i espec i ely o HPV ype. Ou esul s also sugges ha he wide c oss-p o ec i e e icacy o he HPV-16/18 accine epo ed in clinical ials agains HPV ypes 31/33/454 5 is ue o he associa ed CIN3+ end-poin in he long- e m con ex . I is wa an ed o con inue he long- e m ollow-up o he HPV accina- ion ial coho s o mo e accu a e HPV ype-speci ic CIN3+ end-poin s and all HPV-associa ed in asi e cance end-poin s. Acknowledgemen s The e ie al o his opa hological blocks om 21 Finnish pa hology labo a o ies is g a e ully acknowledged. con ibu o s Con ibu o s ML, GD, JPaa, EP and FS designed he s udy. ML and EP pa icipa ed in planning he s a is ical analysis. TL did he s a is ical analyses. DA, MK, JPa, TP and MS-M conduc ed he s udy as s udy doc o s, and TE and KN coo dina ed he s udy. KH, TE and EP we e esponsible o he egis y linkages. CL, PN, and JD we e esponsible o he lab analyses. ML and JPaa w o e he i s d a o he manusc ip , all he co-au ho s con ibu ed o he w i ing in impo an in ellec ual con en by e isions and commen s. Funding GlaxoSmi hKline Biologicals SA (Belgium), Academy o Finland, Finnish Cance O ganiza ions and he Swedish Cance Socie y compe ing in e es s DA, ML, JP and JD ha e ecei ed g an s om GSK g oup o companies and/o Me ck & Co. Inc. h ough hei employe s (DA, Family Fede a ion Finland; ML; Uni e si y o Tampe e; JP and PN Uni e si y o Helsinki; JD and ML, Ka olinska Ins i u e) o HPV accina ion s udies. GD was and FS is employee o GSK g oup o companies. FS has ecei ed sha es and s ock op ions om he GSK g oup o companies. e hics app o al TUKIJA: 1174/2004 and 1153/2003. P o enance and pee e iew No commissioned; ex e nally pee e iewed. da a sha ing s a emen Full da ase and s a is ical code a ailable om he lead au ho a llmale@ u a. i. Consen was no ob ained bu he p esen ed da a a e anonymised and isk o iden i ica ion is low. Open Access This is an Open Access a icle dis ibu ed in acco dance wi h he C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license, which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided he o iginal wo k is p ope ly ci ed and he use is non-comme cial. See: h p:// c ea i ecommons. o g/ licenses/ by- nc/ 4. 0/ © A icle au ho (s) (o hei employe (s) unless o he wise s a ed in he ex o he a icle) 2017. All igh s ese ed. No comme cial use is pe mi ed unless o he wise exp essly g an ed. eFe ences 1. Schi man M, Doo ba J, Wen zensen N, e al. Ca cinogenic human papilloma i us in ec ion. Na Re Dis P ime s 2016;2:16086. 2. zu Hausen H. HPV accines: wha emains o be done? Expe Re Vaccines 2011;10:1505–7. 3. Muñoz N, Kjae SK, Sigu dsson K, e al. Impac o human papilloma i us (HPV)-6/11/16/18 accine on all HPV- associa ed geni al diseases in young women. J Na l Cance Ins 2010;102:325–39. 4. Leh inen M, Paa onen J, Wheele C, e al. O e all e icacy o HPV-16/18 accine agains he mos s ingen ce ical p e-cance end-poin s: end-o s udy epo o a double blind, andomized ial. Lance Oncol 2012;13:89–99. 5. Leh inen M, Dillne J. Clinical HPV accine ials and beyond. Na u e Re Clin Oncol 2013;10:400–10. 6. Jou a EA, Giuliano AR, I e sen OE, e al. A 9- alen HPV accine agains in ec ion and in aepi helial neoplasia in women. N Engl J Med 2015;372:711–23. g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om 8Leh inenM, e al. BMJ Open 2017;7:e015867. doi:10.1136/bmjopen-2017-015867 Open Access 7. Chang M-H, Chen C-J, Lai M-S, e al. Uni e sal Hepa i is B accina ion in Taiwan and he incidence o hepa ocellula ca cinoma in Child en. N Engl J Med O e seas Ed 1997;336:1855–9. 8. McMahon BJ, Bulkow LR, Single on RJ, e al. Elimina ion o hepa ocellula ca cinoma and acu e hepa i is B in child en 25 yea s a e a hepa i is B newbo n and ca ch-up immuniza ion p og am. Hepa ology 2011;54:801–7. 9. Leh inen M, Idänpään-Heikkilä I, Lunnas T, e al. Popula ion-based en olmen o adolescen s in a long- e m ollow-up ial o human papilloma i us accine e icacy. In J STD AIDS 2006;17:237–46. 10. Leh inen M, Ap e D, Dubin G, e al. En olmen o 22,000 adolescen women o Cance egis y ollow-up o long- e m human papilloma i us accine e icacy: gua ding agains guessing. In J STD AIDS 2006;17:517–21. 11. Leh inen M, He e o R, Mayaud P, e al. Chap e 28: S udies o assess he long- e m e icacy and e ec i eness o HPV accina ion in de eloped and de eloping coun ies. Vaccine 2006;24 Suppl 3:S233–S241. 12. Rana M, Huh ala H, Ap e D, e al. Cance egis y based ollow- up in he unde s anding o long- e m p o ec ion o human papilloma i us accina ion agains ce ical ca cinoma. In J Cance 2013;132:2833–8. 13. Paa onen J, Jenkins D, Bosch FX, e al. E icacy o a p ophylac ic adju an ed bi alen L1 i us-like-pa icle accine agains in ec ion wi h human papilloma i us ypes 16 and 18 in young women: an in e im analysis o a phase III double-blind, andomised con olled ial. Lance 2007;369:2161–70. 14. Paa onen J, Hal unen M, Hansson B-G, e al. Feasibili y s udies on HPV accina ion. J Clin Vi ol 2000;19:25–30. 15. Pe äjä T, Pede sen C, Pode A, e al. Long- e m pe sis ence o sys emic and mucosal immune esponse o HPV-16/18 AS04- adju an ed accine in p e een/adolescen gi ls and young women. In J Cance 2011;129:2147–57. 16. Woodhall SC, E iksson T, Nykanen A-M, e al. Impac o HPV accina ion on quali y o li e. Eu J Con acep Rep oduc Heal h Ca e 2011;16:3–8. 17. E iksson T, To inen S, Woodhall SC, e al. Impac o HPV16/18 accina ion on quali y o li e: a pilo s udy. Eu J Con acep Rep od Heal h Ca e 2013;18:364–71. 18. Kohdunkaulan, Ulkosynny in en ja emä imen solumuu okse . Duodecim, 2010:1–32. www. kaypahoi o. i. 19. Lagheden C, Eklund C, Kleppe SN, e al. Valida ion o a s anda dized ex ac ion me hod o o malin- ixed pa a in-embedded issue samples. J Clin Vi ol 2016;80:36–9. 20. Ewell M. Compa ing me hods o calcula ing con idence in e als o accine e icacy. S a Med 1996;15:2379–92. 21. Chan IS. Exac es s o equi alence and e icacy wi h a non-ze o lowe bound o compa a i e s udies. S a Med 1998;17:1403–13. 22. Ronco G, Dillne J, El s öm KM, e al. E icacy o HPV-based sc eening o p e en ion o in asi e ce ical Cance : ollow-up o ou eu opean andomised con olled ials. Lance 2014;383:524–32. 23. Ap e D, Wheele CM, Paa onen J, e al. E icacy o human papilloma i us 16 and 18 (HPV-16/18) AS04-adju an ed accine agains ce ical in ec ion and p ecance in young women: inal e en - d i en analysis o he andomized, double-blind PATRICIA ial. Clin Vaccine Immunol 2015;22:361–73. 24. Bosch XF, Robles C, Diaz M, e al. HPV Fas e : b oadening he pe spec i es in he p e en ion o HPV ela ed cance s. Na u e Re Clin Oncol 2015;13:119–32. g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om ials h ee coho s om andomized ollow-up o egis y-based−−ce ical neoplasia end-poin accine e icacy agains he mos s ingen Ten-yea ollow-up o human papilloma i us Jo ma Paa onen, Ga y Dubin and Joakim Dillne Pe äjä, Ee o Pukkala, Ma i Sii a i-Ma ila, F ank S uy , Pekka Nieminen, TiinaAp e , Ka ja Ha jula, Ma jo Kuo i, Ka i Na unen, Johanna Palm o h, Ma i Leh inen, Camilla Lagheden, Tapio Luos a inen, Tiina E iksson, Dan doi: 10.1136/bmjopen-2017-015867 2017 7: BMJ Open h p://bmjopen.bmj.com/con en /7/8/e015867 Upda ed in o ma ion and se ices can be ound a : These include: Re e ences #BIBLh p://bmjopen.bmj.com/con en /7/8/e015867 This a icle ci es 23 a icles, 1 o which you can access o ee a : Open Access h p://c ea i ecommons.o g/licenses/by-nc/4.0/non-comme cial. See: p o ided he o iginal wo k is p ope ly ci ed and he use is non-comme cially, and license hei de i a i e wo ks on di e en e ms, pe mi s o he s o dis ibu e, emix, adap , build upon his wo k Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license, which This is an Open Access a icle dis ibu ed in acco dance wi h he C ea i e se ice Email ale ing box a he op igh co ne o he online a icle. Recei e ee email ale s when new a icles ci e his a icle. Sign up in he Collec ions Topic A icles on simila opics can be ound in he ollowing collec ions (430)Oncology (583)In ec ious diseases No es h p://g oup.bmj.com/g oup/ igh s-licensing/pe missions To eques pe missions go o: h p://jou nals.bmj.com/cgi/ ep in o m To o de ep in s go o: h p://g oup.bmj.com/subsc ibe/ To subsc ibe o BMJ go o: g oup.bmj.com on Oc obe 6, 2017 - Published by h p://bmjopen.bmj.com/Downloaded om