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

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.

Conflict of interest statement

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.