Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study - 21/09/16

Doi : 10.1016/S1473-3099(16)30120-7

Cosette M Wheeler, ProfPhD ^a,^⁎ , S Rachel Skinner, ProfPhD ^b,^c, M Rowena Del Rosario-Raymundo, MD ^d, Suzanne M Garland, ProfFRCPA ^e,^f,^g,^h, Archana Chatterjee, ProfMD ⁱ, Eduardo Lazcano-Ponce, ProfPhD ^j, Jorge Salmerón, ProfPhD ^k, Shelly McNeil, ProfMD ^l, Jack T Stapleton, ProfMD ^m, Céline Bouchard, FRCSC ⁿ, Mark G Martens, MD ^o, Deborah M Money, ProfMD ^p, Swee Chong Quek, MBBCh ^q, Barbara Romanowski, ProfMD ^r, Carlos S Vallejos, MD ^s, Bram ter Harmsel, PhD ^t, Vera Prilepskaya, PhD ^u, Kah Leng Fong, MRCOG ^v, Henry Kitchener, ProfMD ^w, Galina Minkina, ProfMD ^x, Yong Kuei Timothy Lim, MBBS ^y, Tanya Stoney, MBBS ^z, Nahida Chakhtoura, MD ^aa, Margaret E Cruickshank, ProfMD ^ab, Alevtina Savicheva, PhD ^ac, Daniel Pereira da Silva, MD ^ad, Murdo Ferguson, MD ^ae, Anco C Molijn, MSc ^af, Wim G V Quint, PhD ^af, Karin Hardt, PhD ^ag, Dominique Descamps, MD ^ag, Pemmaraju V Suryakiran, MSc ^ah, Naveen Karkada, MSc ^ah, Brecht Geeraerts, PhD ^ag, Gary Dubin, MD ^ai, Frank Struyf, MD ^ag
for the
VIVIANE Study Group^{^†}
Collaborators are listed at the end of the Article

^a Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

^b Vaccines Trials Group, Telethon Kids Institute, Perth, WA, Australia

^c Sydney University Discipline of Child and Adolescent Health, Children’s Hospital Westmead, Sydney, NSW, Australia

^d Department of Obstetrics and Gynecology, San Pablo Colleges Medical Center, San Pablo City, Laguna, Philippines

^e Department of Microbiology and Infectious Diseases, The Royal Women’s Hospital, Parkville, VIC, Australia

^f Department of Microbiology, The Royal Children’s Hospital, Parkville, VIC, Australia

^g Murdoch Childrens Research Institute, Parkville, VIC, Australia

^h Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC, Australia

ⁱ Department of Pediatrics, University of South Dakota, Sanford School of Medicine, Sanford Children’s Specialty Clinic, Sioux Falls, SD, USA

^j Research Centre on Public Health, National Institute of Public Health, Cuernavaca, Mexico

^k Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Morelos, Mexico

^l Canadian Center for Vaccinology, IWK Health Center and Nova Scotia Health Authority, Dalhousie University, Halifax, NS, Canada

^m Departments of Internal Medicine and Infectious Diseases, University of Iowa, Iowa City, IA, USA

ⁿ Department of Obstetrics and Gynaecology, Université Laval and Clinique RSF, Québec, QC, Canada

^o Department of Obstetrics and Gynaecology, Jersey Shore University Medical Center, Neptune, NJ, USA

^p Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada

^q Parkway Gynaecology Screening and Treatment Centre, Gleneagles Hospital, Singapore, Singapore

^r Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

^s Division de Investigacion, Oncosalud-AUNA, Lima, Peru

^t Roosevelt Kliniek, Leiden, Netherlands

^u Outpatient Department, Scientific Center of Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, Moscow, Russian

^v Singapore General Hospital, Singapore, Singapore

^w Department of Gynaecological Oncology, Women’s Cancer Centre, University of Manchester, St Mary’s Hospital, Manchester, UK

^x City Clinical Hospital, Moscow, Russian

^y Department of Gynaecologic Oncology, KK Women’s and Children’s Hospital, Singapore, Singapore

^z Vaccines Trials Group, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia

^aa Department of Obstetrics and Gynecology, Miler School of Medicine, University of Miami, Miami, FL, USA

^ab Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen, UK

^ac Laboratory of Microbiology, DO Ott Research Institute of Obstetrics and Gynecology, St Petersburg, Russia

^ad Departmento de Ginecologia, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal

^ae Department of Family Medicine and Emergency Medicine, Colchester Research Group, Colchester Regional Hospital, Dalhousie University, Truro, NS, Canada

^af DDL Diagnostic Laboratory, Rijswijk, Netherlands

^ag GSK Vaccines, Wavre, Belgium

^ah GSK Pharmaceuticals India Ltd, Bangalore, India

^ai GSK Vaccines, King of Prussia, PA, USA

^* Correspondence to: Prof Cosette M Wheeler, Departments of Pathology and Obstetrics and Gynecology, House of Prevention Epidemiology, MSC 02-1670 NE, 1 University of New Mexico, Albuquerque, NM 87131, USA Correspondence to: Prof Cosette M Wheeler Departments of Pathology and Obstetrics and Gynecology House of Prevention Epidemiology MSC 02-1670 NE 1 University of New Mexico Albuquerque NM 87131 USA

Summary

Background

Although the risk of human papillomavirus (HPV) infection is greatest in young women, women older than 25 years remain at risk. We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up.

Methods

In this phase 3, double-blind, randomised controlled trial, healthy women older than 25 years were enrolled (age stratified: 26–35 years, 36–45 years, and ≥46 years). Up to 15% in each age stratum had a history of HPV infection or disease. Women were randomly assigned (1:1) to receive HPV 16/18 vaccine or aluminium hydroxide control, with an internet-based system. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater (CIN1+) associated with HPV 16/18. We did analyses in the according-to-protocol cohort for efficacy and total vaccinated cohort. Data for the combined primary endpoint in the according-to-protocol cohort for efficacy were considered significant when the lower limit of the 96·2% CI around the point estimate was greater than 30%. For all other endpoints and cohorts, data were considered significant when the lower limit of the 96·2% CI was greater than 0%. This study is registered with ClinicalTrials.gov, number NCT00294047.

Findings

The first participant was enrolled on Feb 16, 2006, and the last study visit took place on Jan 29, 2014. 4407 women were in the according-to-protocol cohort for efficacy (n=2209 vaccine, n=2198 control) and 5747 women in the total vaccinated cohort (n=2877 vaccine, n=2870 control). At month 84, in women seronegative for the corresponding HPV type in the according-to-protocol cohort for efficacy, vaccine efficacy against 6-month persistent infection or CIN1+ associated with HPV 16/18 was significant in all age groups combined (90·5%, 96·2% CI 78·6–96·5). Vaccine efficacy against HPV 16/18-related cytological abnormalities (atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) and CIN1+ was also significant. We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 (65·8%, 96·2% CI 24·9–85·8) and HPV 45 (70·7%, 96·2% CI 34·2–88·4). In the total vaccinated cohort, vaccine efficacy against CIN1+ irrespective of HPV was significant (22·9%, 96·2% CI 4·8–37·7). Serious adverse events related to vaccination occurred in five (0·2%) of 2877 women in the vaccine group and eight (0·3%) of 2870 women in the control group.

Interpretation

In women older than 25 years, the HPV 16/18 vaccine continues to protect against infections, cytological abnormalities, and lesions associated with HPV 16/18 and CIN1+ irrespective of HPV type, and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up.

Funding

GlaxoSmithKline Biologicals SA.

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Vol 16 - N° 10

P. 1154-1168 - octobre 2016 Retour au numéro

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Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study - 21/09/16

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