title: Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.
abstract: BACKGROUND
  Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of 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 randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681.
  
  
  RESULTS
  Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination.
  
  
  CONCLUSIONS
  PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer.
  
  
  BACKGROUND
  GlaxoSmithKline Biologicals.
authors.affiliation: University of Tampere, School of Public Health, Tampere, Finland. matti.lehtinen@uta.fi
authors.forename: Matti
authors.initials: M
authors.lastname: Lehtinen
authors.forename: Jorma
authors.initials: J
authors.lastname: Paavonen
authors.forename: Cosette M
authors.initials: CM
authors.lastname: Wheeler
authors.forename: Unnop
authors.initials: U
authors.lastname: Jaisamrarn
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Garland
authors.forename: Xavier
authors.initials: X
authors.lastname: Castellsagué
authors.forename: S Rachel
authors.initials: SR
authors.lastname: Skinner
authors.forename: Dan
authors.initials: D
authors.lastname: Apter
authors.forename: Paulo
authors.initials: P
authors.lastname: Naud
authors.forename: Jorge
authors.initials: J
authors.lastname: Salmerón
authors.forename: Song-Nan
authors.initials: SN
authors.lastname: Chow
authors.forename: Henry
authors.initials: H
authors.lastname: Kitchener
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Teixeira
authors.forename: James
authors.initials: J
authors.lastname: Hedrick
authors.forename: Genara
authors.initials: G
authors.lastname: Limson
authors.forename: Anne
authors.initials: A
authors.lastname: Szarewski
authors.forename: Barbara
authors.initials: B
authors.lastname: Romanowski
authors.forename: Fred Y
authors.initials: FY
authors.lastname: Aoki
authors.forename: Tino F
authors.initials: TF
authors.lastname: Schwarz
authors.forename: Willy A J
authors.initials: WA
authors.lastname: Poppe
authors.forename: Newton S
authors.initials: NS
authors.lastname: De Carvalho
authors.forename: Maria Julieta V
authors.initials: MJ
authors.lastname: Germar
authors.forename: Klaus
authors.initials: K
authors.lastname: Peters
authors.forename: Adrian
authors.initials: A
authors.lastname: Mindel
authors.forename: Philippe
authors.initials: P
authors.lastname: De Sutter
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Bosch
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: David
authors.forename: Dominique
authors.initials: D
authors.lastname: Descamps
authors.forename: Frank
authors.initials: F
authors.lastname: Struyf
authors.forename: Gary
authors.initials: G
authors.lastname: Dubin
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000536:Aluminum Hydroxide / Q000008:administration & dosage*; D001208:Asia; D001315:Australia; D004279:DNA, Viral / Q000032:analysis; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D052161:Human papillomavirus 18 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D060787:Neoplasm Grading; D009656:North America; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000517:prevention & control* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage*; D013020:South America; D013997:Time Factors; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000473:pathology / Q000517:prevention & control* / Q000821:virology
chemical_list: C532963:ASO4 mixture; D000276:Adjuvants, Immunologic; D004279:DNA, Viral; D008050:Lipid A; D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18; D000536:Aluminum Hydroxide