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Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial

BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c3493 (Published 20 July 2010) Cite this as: BMJ 2010;341:c3493
  1. The FUTURE I/II Study Group
  1. Correspondence to: J Dillner, Department of Medical Microbiology, Lund University, Malmö University Hospital, SE-20502 Malmö, Sweden joakim.dillner{at}med.lu.se
  • Accepted 29 April 2010

Abstract

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata).

Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up.

Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world.

Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy.

Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6.

Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied.

Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma.

Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up.

Trial registrations NCT00092521 and NCT00092534.

Footnotes

  • We thank Mary Anne Rutlowski and Carolyn Maass for statistical programming support, and Laurie Orloski for writing support.

  • Members of the FUTUREI/II Study Group who are authors of this paper: Joakim Dillner,1 Susanne K Kjaer,2 Cosette M Wheeler,3 Kristján Sigurdsson,4 Ole-Erik Iversen,5 Mauricio Hernandez-Avila,6 Gonzalo Perez,7 Darron R Brown,8 Laura A Koutsky,9 Eng Hseon Tay,10 Patricia García,11 Kevin A Ault,12 Suzanne M Garland,13 Sepp Leodolter,14 Sven-Eric Olsson,15 Grace WK Tang,16 Daron G Ferris,17 Jorma Paavonen,18 Matti Lehtinen,19 Marc Steben,20 F Xavier Bosch,21 Elmar A Joura,14 Slawomir Majewski,22 Nubia Muñoz,23 Evan R Myers,24 Luisa L Villa,25 Frank J Taddeo,26 Christine Roberts,26 Amha Tadesse,26 Janine T Bryan,26 Roger Maansson,26 Shuang Lu,26 Scott Vuocolo,26 Teresa M Hesley,26 Eliav Barr,26 Richard Haupt,26

  • Affiliations: 1Depatment of Laboratory Medicine, Lund University, Malmö, Sweden, and Departments of Laboratory Medicine, Medical Epidemiology and Biostatistics, Karolinska Institiutet, Stockholm, Sweden; 2Department of Virus, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society/Rigshospitalet, Copenhagen, Denmark; 3Departments of Molecular Genetics and Microbiology and Obstetrics and Gynecology, University of New Mexico, Albuquerque NM, USA; 4National Cancer Detection Clinic, Reykjavik, Iceland; 5Department of Clinical Medicine, University of Bergen and Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; 6Institute of Public Health, Cuernavaca, Morelos, Mexico; 7Universidad del Rosario, Bogotá, Colombia; 8Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA; 9Department of Epidemiology, University of Washington, Seattle WA, USA; 10KK Women’s and Children’s Hospital, Singapore; 11Epidemiology HIV and STD Unit, Universidad Peruana Cayetano Heredia, Lima Peru; 12Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA; 13Microbiology and Infectious Diseases Department, Royal Women’s Hospital and Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia; 14Department of Gynecology and Obstetrics, Medical University of Vienna, Vienna, Austria; 15Karolinska Institute at Danderyd Hospital, Stockholm, Sweden; 16Department of Obstetrics and Gynecology, University of Hong Kong, HKSAR; 17Department of Family Medicine and Obstetrics and Gynecology, Medical College of Georgia, Augusta, GA, USA; 18Department of Obstetric and Gynecology, University Central Hospital, Helsinki, Finland; 19School of Public Health, University of Tampere, Tampere, Finland; 20Direction Risques Biologiques, Environnementaux et Occupationnels, Institut National de Santé Publique du Québec, Montréal, Canada; 21Institut Catala d’Oncologia, IDIBELL, Barcelona, Spain; 22Department of Dermatology and Venereology, Center of Diagnostics and Treatment of Sexually Transmitted Diseases, Warsaw Medical University, Warsaw, Poland; 23National Institute of Cancer, Bogotá, Colombia; 24Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA; 25Department of Virology, Ludwig Institute for Cancer Research, Sao Paulo, Brazil; 26Merck Research Laboratories, West Point, PA, USA

  • Contributors: EB, RH, and TMH managed the sponsor’s operations. JD, CMW, KS, O-EI, MH-A, DRB, LAK, EHT, PG, KAA, SMG, SLe, S-EO, GWKT, DGF, JP, ML, MS, EAJ, GP, and SM set up study sites and enrolled participants into the studies. SKK, GP, NM, FXB, ERM, and LLV helped draft the protocols. JTB, FJT, CR, and AT managed the development of the PCR based assays for HPV types 6, 11, 16, and 18 as well as the execution of genital swab and biopsy sample testing using the assays. RM and SLu provided statistical expertise. JD and SV drafted the manuscript, to which all others contributed and approved before submission.

  • Funding: Merck Research Laboratories, a division of Merck & Company, funded these studies.

  • Role of the funding source: The studies were designed by the sponsor (Merck & Company) in collaboration with external investigators and an external data and safety monitoring board. The sponsor collated the data, monitored the conduct of the study, performed the statistical analysis, and coordinated the writing of the manuscript with all authors. The authors were actively involved in the collection, analysis, or interpretation of the data, the revising of the manuscript for intellectual content, and approved the final manuscript.

  • Competing interests: JD has received consultancy fees, lecture fees, and research grants from Merck & Company and Sanofi Pasteur MSD. SKK has received consultancy fees and has received funding through her institution to conduct HPV vaccine studies for Sanofi Pasteur MSD and Digene. SMG has received advisory board fees and grant support from Commonwealth Serum Laboratories and GlaxoSmithKline, lecture fees from Merck & Company, and funding through her institution to conduct HPV vaccine studies for GlaxoSmithKline. CMW has received funding through her institution to conduct HPV vaccine studies for GlaxoSmithKline, and has received reagents and equipment from Roche Molecular Systems for HPV genotyping studies. KS has received consultancy fees from Merck & Company. O-EI has received lecture fees from Merck & Company and GlaxoSmithKline. LLV has received lecture fees, advisory board fees, and consultancy fees from Merck & Company and Sanofi Pasteur MSD. KAA has received consultancy and advisory board fees. MH-A has received lecture fees and grant support from Merck & Company. GP has received lecture fees and consultancy fees from Merck & Company and Sanofi Pasteur MSD. DRB has received lecture fees, advisory board fees, and intellectual property fees. SLe has received lecture fees from Merck & Company and Sanofi Pasteur MSD. S-EO has received lecture fees from Merck & Company. DGF has received consultancy fees and funding through his institution to conduct HPV vaccine studies for GlaxoSmithKline, and lecture fees and consultancy fees from Merck & Company. JP has received consultancy fees, advisory board fees, and lecture fees from Merck & Company. MS has received lecture fees and grant support from Merck & Company. FXB has received lecture fees from Merck & Company and GlaxoSmithKline, and has received funding through his institution to conduct HPV vaccine studies for GlaxoSmithKline. EAJ has received lecture fees from Merck & Company, Sanofi Pasteur MSD, and GlaxoSmithKline. SM has received lecture fees, advisory board fees, and consultancy fees from Merck & Company and Sanofi Pasteur MSD. NM has received lecture fees, advisory board fees, and consultancy fees from Merck & Company and Sanofi Pasteur MSD. Additionally, S-EO, CMW, MH-A, LLV, O-EI, GWKT, FXB, JP, JD, EHT, SLe, EAJ, SKK, GP, DGF, KS, MS, LAK, and DRB have received funding through their institutions to conduct HPV vaccine studies for Merck & Company. FJT, CR, AT, JTB, RM, SV, TMH, RH, and EB are employees of Merck & Company and potentially own stock or stock options in the company.

  • Ethical approval: Studies were conducted in conformity with country or local requirements regarding ethics committee review, informed consent, and other statutes or regulations regarding the rights and welfare of human subjects participating in biomedical research.

  • Data sharing: Data sets are available from the corresponding author at joakim.dillner@med.lu.se.

  • Answer CME questions related to this article.

  • Accepted 29 April 2010

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