title: Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study.
abstract: BACKGROUND
  Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women.
  
  
  METHODS
  In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047.
  
  
  RESULTS
  The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination.
  
  
  CONCLUSIONS
  In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45.
  
  
  BACKGROUND
  GlaxoSmithKline Biologicals SA.
authors.affiliation: Vaccines Trials Group, Telethon Institute for Child Health Research, Perth, WA, Australia; Sydney University Discipline of Paediatrics and Child Health, Children's Hospital Westmead, Sydney, NSW, Australia. Electronic address: rachel.skinner@health.nsw.gov.au.
authors.forename: S Rachel
authors.initials: SR
authors.lastname: Skinner
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Szarewski
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Romanowski
authors.affiliation: Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Parkville, VIC, Australia; Department of Microbiology, The Royal Children's Hospital, Parkville, VIC, Australia; Murdoch Childrens Research Institute, Parkville, VIC, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Garland
authors.affiliation: Avenida Universidad S/N Jojutla, Morelos, Mexico.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lazcano-Ponce
authors.affiliation: Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Morelos, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Salmerón
authors.affiliation: Department of Obstetrics and Gynecology, San Pablo Colleges Medical Center, San Pablo City, Laguna, Philippines.
authors.forename: M Rowena
authors.initials: MR
authors.lastname: Del Rosario-Raymundo
authors.affiliation: Gynaecological Oncology and HumVac Research Group, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: René H M
authors.initials: RH
authors.lastname: Verheijen
authors.affiliation: Parkway Gynaecology Screening & Treatment Centre, Gleneagles Hospital, Singapore.
authors.forename: Swee Chong
authors.initials: SC
authors.lastname: Quek
authors.affiliation: Departmento de Ginecologia, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: da Silva
authors.affiliation: Women's Cancer Centre, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Kitchener
authors.affiliation: Department of Obstetrics and Gynaecology, Singapore General Hospital, Singapore.
authors.forename: Kah Leng
authors.initials: KL
authors.lastname: Fong
authors.affiliation: Clinique RSF, Québec, QC, Canada.
authors.forename: Céline
authors.initials: C
authors.lastname: Bouchard
authors.affiliation: Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada; The Women's Health Research Institute, Vancouver, BC, Canada.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Money
authors.affiliation: Division of Gynecologic Oncology, National University Hospital, Singapore.
authors.forename: Arunachalam
authors.initials: A
authors.lastname: Ilancheran
authors.affiliation: Division of Medical Education, University of Aberdeen, Aberdeen, UK.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Cruickshank
authors.affiliation: University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Myron J
authors.initials: MJ
authors.lastname: Levin
authors.affiliation: Department of Pediatrics, University of South Dakota Sanford School of Medicine, and Sanford Children's Specialty Clinics, Sioux Falls, SD, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Stapleton
authors.affiliation: Jersey Shore University Medical Center, Neptune, NJ, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Martens
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Quint
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: David
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Meric
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Hardt
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Descamps
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Brecht
authors.initials: B
authors.lastname: Geeraerts
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Struyf
authors.affiliation: GSK Vaccines, King of Prussia, PA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Dubin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D003429:Cross Reactions; D004279:DNA, Viral / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D052161:Human papillomavirus 18 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000517:prevention & control / Q000821:virology
chemical_list: D000276:Adjuvants, Immunologic; D004279:DNA, Viral; D053918:Papillomavirus Vaccines