title: 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.
abstract: 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 randomly assigned (1:1) to HPV-16/18 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 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 populations 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 ClinicalTrials.gov, number NCT00122681.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  GlaxoSmithKline Biologicals.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. cwheeler@salud.unm.edu
authors.forename: Cosette M
authors.initials: CM
authors.lastname: Wheeler
authors.forename: Xavier
authors.initials: X
authors.lastname: Castellsagué
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Garland
authors.forename: Anne
authors.initials: A
authors.lastname: Szarewski
authors.forename: Jorma
authors.initials: J
authors.lastname: Paavonen
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: Dan
authors.initials: D
authors.lastname: Apter
authors.forename: Henry
authors.initials: H
authors.lastname: Kitchener
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Teixeira
authors.forename: S Rachel
authors.initials: SR
authors.lastname: Skinner
authors.forename: Unnop
authors.initials: U
authors.lastname: Jaisamrarn
authors.forename: Genara
authors.initials: G
authors.lastname: Limson
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: F Xavier
authors.initials: FX
authors.lastname: Bosch
authors.forename: Diane M
authors.initials: DM
authors.lastname: Harper
authors.forename: Warner
authors.initials: W
authors.lastname: Huh
authors.forename: Karin
authors.initials: K
authors.lastname: Hardt
authors.forename: Toufik
authors.initials: T
authors.lastname: Zahaf
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
authors.forename: Matti
authors.initials: M
authors.lastname: Lehtinen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000536:Aluminum Hydroxide / Q000008:administration & dosage*; D000956:Antigens, Viral / Q000276:immunology; D001208:Asia; D001315:Australia; D003429:Cross Reactions; 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*; D011230:Precancerous Conditions / Q000175:diagnosis / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; 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; D000956:Antigens, Viral; D004279:DNA, Viral; D008050:Lipid A; D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18; D000536:Aluminum Hydroxide