S Rachel Skinner1, Anne Szarewski2, Barbara Romanowski3, Suzanne M Garland4, Eduardo Lazcano-Ponce5, Jorge Salmerón6, M Rowena Del Rosario-Raymundo7, René H M Verheijen8, Swee Chong Quek9, Daniel P da Silva10, Henry Kitchener11, Kah Leng Fong12, Céline Bouchard13, Deborah M Money14, Arunachalam Ilancheran15, Margaret E Cruickshank16, Myron J Levin17, Archana Chatterjee18, Jack T Stapleton19, Mark Martens20, Wim Quint21, Marie-Pierre David22, Dorothée Meric22, Karin Hardt22, Dominique Descamps22, Brecht Geeraerts22, Frank Struyf22, Gary Dubin23. 1. 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. 2. Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. 3. Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. 4. 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. 5. Avenida Universidad S/N Jojutla, Morelos, Mexico. 6. Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Morelos, Mexico. 7. Department of Obstetrics and Gynecology, San Pablo Colleges Medical Center, San Pablo City, Laguna, Philippines. 8. Gynaecological Oncology and HumVac Research Group, University Medical Center Utrecht, Utrecht, Netherlands. 9. Parkway Gynaecology Screening & Treatment Centre, Gleneagles Hospital, Singapore. 10. Departmento de Ginecologia, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal. 11. Women's Cancer Centre, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Manchester, UK. 12. Department of Obstetrics and Gynaecology, Singapore General Hospital, Singapore. 13. Clinique RSF, Québec, QC, Canada. 14. Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada; The Women's Health Research Institute, Vancouver, BC, Canada. 15. Division of Gynecologic Oncology, National University Hospital, Singapore. 16. Division of Medical Education, University of Aberdeen, Aberdeen, UK. 17. University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. 18. Department of Pediatrics, University of South Dakota Sanford School of Medicine, and Sanford Children's Specialty Clinics, Sioux Falls, SD, USA. 19. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA. 20. Jersey Shore University Medical Center, Neptune, NJ, USA. 21. DDL Diagnostic Laboratory, Rijswijk, Netherlands. 22. GSK Vaccines, Wavre, Belgium. 23. GSK Vaccines, King of Prussia, PA, USA.
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. FINDINGS: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. INTERPRETATION: 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. FUNDING: GlaxoSmithKline Biologicals SA.
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: GlaxoSmithKline Biologicals SA.
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