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

Cosette M. Wheeler*, S. Rachel Skinner, M. Rowena Del Rosario-Raymundo, Suzanne M. Garland, Archana Chatterjee, Eduardo Lazcano-Ponce, Jorge Salmeron, Shelly McNeil, Jack T. Stapleton, Celine Bouchard, Mark G. Martens, Deborah M. Money, Swee Chong Quek, Barbara Romanowski, Carlos S. Vallejos, Bram ter Harmsel, Vera Prilepskaya, Kah Leng Fong, Henry Kitchener, Galina MinkinaYong Kuei Timothy Lim, Tanya Stoney, Nahida Chakhtoura, Margaret E. Cruickshank, Alevtina Savicheva, Daniel Pereira da Silva, Murdo Ferguson, Anco C. Molijn, Wim G. V. Quint, Karin Hardt, Dominique Descamps, Pemmaraju V. Suryakiran, Naveen Karkada, Brecht Geeraerts, Gary Dubin, Frank Struyf, VIVIANE Study Grp

*Corresponding author for this work

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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 signifi cant 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 signifi cant 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 signifi cance and low-grade squamous intraepithelial lesion) and CIN1+ was also signifi cant. We also noted signifi cant 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 signifi cant (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.

Original languageEnglish
Pages (from-to)1154-1168
Number of pages15
JournalLancet Infectious Diseases
Issue number10
Early online date28 Jun 2016
Publication statusPublished - Oct 2016



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