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 Minkina; Yong 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 Group

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

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 Group

^*Corresponding author for this work

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Research output: Contribution to journal › Article › peer-review

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Abstract

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 language	English
Pages (from-to)	1154-1168
Number of pages	15
Journal	Lancet Infectious Diseases
Volume	16
Issue number	10
Early online date	28 Jun 2016
DOIs	https://doi.org/10.1016/S1473-3099(16)30120-7
Publication status	Published - Oct 2016

Bibliographical note

Acknowledgments

The VIVIANE study was funded and coordinated by GlaxoSmithKline Biologicals SA, which also covered all costs associated with development and publication of this report. We thank all study participants and their families. We gratefully acknowledge the work of the central and local study coordinators, and staff members of the sites who participated in this study. Writing support services were provided by Mary Greenacre (An Sgriobhadair, Isle of Barra, UK), on behalf of GSK Vaccines; editing and publication coordination services were provided by Jérôme Leemans (Keyrus Biopharma, Lasne, Belgium), Stéphanie Delval (XPE Pharma and Science, Wavre, Belgium), and Matthieu Depuydt (Business Decision Life Sciences, Brussels, Belgium), on behalf of GSK Vaccines

Keywords

OF-STUDY ANALYSIS
INTRAEPITHELIAL NEOPLASIA
QUADRIVALENT VACCINE
SUSTAINED EFFICACY
CONTROLLED-TRIAL
HPV VACCINATION
CERVICAL-CANCER
PATRICIA TRIAL
BROAD-SPECTRUM
YOUNG-WOMEN

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wheeler, C. M., Skinner, S. R., Rowena Del Rosario-Raymundo, M., Garland, S. M., Chatterjee, A., Lazcano-Ponce, E., Salmeron, J., McNeil, S., Stapleton, J. T., Bouchard, C., Martens, M. G., Money, D. M., Quek, S. C., Romanowski, B., Vallejos, C. S., ter Harmsel, B., Prilepskaya, V., Fong, K. L., Kitchener, H., ... VIVIANE Study Group (2016). 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. Lancet Infectious Diseases, 16(10), 1154-1168. https://doi.org/10.1016/S1473-3099(16)30120-7

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. / Wheeler, Cosette M.; Skinner, S. Rachel; Rowena Del Rosario-Raymundo, M. et al.
In: Lancet Infectious Diseases, Vol. 16, No. 10, 10.2016, p. 1154-1168.

Research output: Contribution to journal › Article › peer-review

Wheeler, CM, Skinner, SR, Rowena Del Rosario-Raymundo, M, Garland, SM, Chatterjee, A, Lazcano-Ponce, E, Salmeron, J, McNeil, S, Stapleton, JT, Bouchard, C, Martens, MG, Money, DM, Quek, SC, Romanowski, B, Vallejos, CS, ter Harmsel, B, Prilepskaya, V, Fong, KL, Kitchener, H, Minkina, G, Lim, YKT, Stoney, T, Chakhtoura, N, Cruickshank, ME, Savicheva, A, da Silva, DP, Ferguson, M, Molijn, AC, Quint, WGV, Hardt, K, Descamps, D, Suryakiran, PV, Karkada, N, Geeraerts, B, Dubin, G, Struyf, F & VIVIANE Study Group 2016, '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', Lancet Infectious Diseases, vol. 16, no. 10, pp. 1154-1168. https://doi.org/10.1016/S1473-3099(16)30120-7

Wheeler CM, Skinner SR, Rowena Del Rosario-Raymundo M, Garland SM, Chatterjee A, Lazcano-Ponce E et al. 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. Lancet Infectious Diseases. 2016 Oct;16(10):1154-1168. Epub 2016 Jun 28. doi: 10.1016/S1473-3099(16)30120-7

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title = "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",

abstract = "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.",

keywords = "OF-STUDY ANALYSIS, INTRAEPITHELIAL NEOPLASIA, QUADRIVALENT VACCINE, SUSTAINED EFFICACY, CONTROLLED-TRIAL, HPV VACCINATION, CERVICAL-CANCER, PATRICIA TRIAL, BROAD-SPECTRUM, YOUNG-WOMEN",

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

note = "Acknowledgments The VIVIANE study was funded and coordinated by GlaxoSmithKline Biologicals SA, which also covered all costs associated with development and publication of this report. We thank all study participants and their families. We gratefully acknowledge the work of the central and local study coordinators, and staff members of the sites who participated in this study. Writing support services were provided by Mary Greenacre (An Sgriobhadair, Isle of Barra, UK), on behalf of GSK Vaccines; editing and publication coordination services were provided by J{\'e}r{\^o}me Leemans (Keyrus Biopharma, Lasne, Belgium), St{\'e}phanie Delval (XPE Pharma and Science, Wavre, Belgium), and Matthieu Depuydt (Business Decision Life Sciences, Brussels, Belgium), on behalf of GSK Vaccines",

year = "2016",

month = oct,

doi = "10.1016/S1473-3099(16)30120-7",

language = "English",

volume = "16",

pages = "1154--1168",

journal = "Lancet Infectious Diseases",

issn = "1473-3099",

publisher = "ELSEVIER APPL SCI PUBL LTD",

number = "10",

}

TY - JOUR

T1 - Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years

T2 - 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study

AU - Wheeler, Cosette M.

AU - Skinner, S. Rachel

AU - Rowena Del Rosario-Raymundo, M.

AU - Garland, Suzanne M.

AU - Chatterjee, Archana

AU - Lazcano-Ponce, Eduardo

AU - Salmeron, Jorge

AU - McNeil, Shelly

AU - Stapleton, Jack T.

AU - Bouchard, Celine

AU - Martens, Mark G.

AU - Money, Deborah M.

AU - Quek, Swee Chong

AU - Romanowski, Barbara

AU - Vallejos, Carlos S.

AU - ter Harmsel, Bram

AU - Prilepskaya, Vera

AU - Fong, Kah Leng

AU - Kitchener, Henry

AU - Minkina, Galina

AU - Lim, Yong Kuei Timothy

AU - Stoney, Tanya

AU - Chakhtoura, Nahida

AU - Cruickshank, Margaret E.

AU - Savicheva, Alevtina

AU - da Silva, Daniel Pereira

AU - Ferguson, Murdo

AU - Molijn, Anco C.

AU - Quint, Wim G. V.

AU - Hardt, Karin

AU - Descamps, Dominique

AU - Suryakiran, Pemmaraju V.

AU - Karkada, Naveen

AU - Geeraerts, Brecht

AU - Dubin, Gary

AU - Struyf, Frank

AU - VIVIANE Study Group

N1 - Acknowledgments The VIVIANE study was funded and coordinated by GlaxoSmithKline Biologicals SA, which also covered all costs associated with development and publication of this report. We thank all study participants and their families. We gratefully acknowledge the work of the central and local study coordinators, and staff members of the sites who participated in this study. Writing support services were provided by Mary Greenacre (An Sgriobhadair, Isle of Barra, UK), on behalf of GSK Vaccines; editing and publication coordination services were provided by Jérôme Leemans (Keyrus Biopharma, Lasne, Belgium), Stéphanie Delval (XPE Pharma and Science, Wavre, Belgium), and Matthieu Depuydt (Business Decision Life Sciences, Brussels, Belgium), on behalf of GSK Vaccines

PY - 2016/10

Y1 - 2016/10

N2 - 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.

AB - 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.

KW - OF-STUDY ANALYSIS

KW - INTRAEPITHELIAL NEOPLASIA

KW - QUADRIVALENT VACCINE

KW - SUSTAINED EFFICACY

KW - CONTROLLED-TRIAL

KW - HPV VACCINATION

KW - CERVICAL-CANCER

KW - PATRICIA TRIAL

KW - BROAD-SPECTRUM

KW - YOUNG-WOMEN

U2 - 10.1016/S1473-3099(16)30120-7

DO - 10.1016/S1473-3099(16)30120-7

M3 - Article

SN - 1473-3099

VL - 16

SP - 1154

EP - 1168

JO - Lancet Infectious Diseases

JF - Lancet Infectious Diseases

IS - 10

ER -