Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial

Abstract

Background: A community-based randomized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine (NCT00128661). The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease (CIN2+) associated with incident HPV-16/18 cervical infections. Secondary objectives were to evaluate efficacy against CIN2+ associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18. Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated.

Methods: We randomized (3727 HPV arm; 3739 control arm), vaccinated (HPV-16/18 or Hepatitis A) and followed (median 53.8 months) 7466 healthy women aged 18-25 years. 5312 women (2635 HPV arm; 2677 control arm) were included in the according to protocol analysis for efficacy. The full cohort was evaluated for safety. Immunogenicity was considered on a subset of 354 (HPV-16) and 379 (HPV-18) women. HPV type was assessed by PCR on cervical specimens. Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays. Disease outcomes were histologically confirmed. Vaccine efficacy and 95% confidence intervals (95%CI) were computed.

Results: Vaccine efficacy was 89.8% (95% CI: 39.5-99.5; N=11 events total) against HPV-16/18 associated CIN2+, 59.9% (95% CI: 20.7-80.8; N=39 events total) against CIN2+ associated with non-HPV-16/18 oncogenic HPVs and 61.4% (95% CI: 29.5-79.8; N=51 events total) against CIN2+ irrespective of HPV type. The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses.

Conclusions: Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types. These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial.

Trial registration: Registered with clinicaltrials.gov: NCT00128661.

Keywords: Cervical neoplasia; Clinical trial; Human papillomaviruses; Prevention; Vaccination.

Conflict of interest statement

Conflicts of interest: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf. F.S., G.C. and G.D. are employees of the GlaxoSmithKline group of companies. G.D. and F.S. receive stock options/restricted shares from the GlaxoSmithKline group of companies, and G.D. has previously received patent royalties from Wyeth Vacines. The other authors declare that they have no conflicts of interest. The NCI receives licensing fees for HPV vaccines.

Published by Elsevier Ltd.

Figures

Figure 1. Consort Diagram - Analytic Cohort for Efficacy Analyses

Figure 2A. Distribution of CIN2+ Outcomes by HPV Type (a-priori) and Vaccination Arm – According to Protocol Cohort for Efficacy – Costa Rica HPV-16/18 Vaccine Triala

a CIN2+ = Cervical intraepithelial lesion or more severe disease; HPV type attribution for a-priori outcome defined based on HPV type(s) detected in the cytology specimen that led to colposcopy referral. b Only non-oncogenic incident HPV types were detected for three women, positivity for uncharacterized HPV types was observed for two women, and no HPV was detectable for two women.

Figure 2B. Distribution of CIN2+ Outcomes by HPV Type (exploratory) and Vaccination Arm – According to Protocol Cohort for Efficacy – Costa Rica HPV-16/18 Vaccine Triala

a CIN2+ = Cervical intraepithelial lesion or more severe disease; HPV type attribution for exploratory outcome defined considering evidence of HPV persistence preceding colposcopy when multiple HPV types were present in the cytology specimen that led to colposcopy referral. b Only non-oncogenic incident HPV types were detected for three women, positivity for uncharacterized HPV types was observed for two women, and no HPV was detectable for two women.

Figure 3A. Kinetics of HPV-16 Antibody Response by Vaccination Arma. (ELISA Assay) – Immunogenicity Subcohort – Costa Rica HPV-16/18 Vaccine Trial (CVT)

a HPV Arm plotted irrespective of entry serostatus. Control Arm plotted separately by entry serostatus.

Figure 3B. Kinetics of HPV-18 Antibody Response by Vaccination Arma. (ELISA Assay) – Immunogenicity Subcohort – Costa Rica HPV-16/18 Vaccine Trial (CVT)

a HPV Arm plotted irrespective of entry serostatus. Control Arm plotted separately by entry serostatus.

Figure 3C. Kinetics of HPV-16 Antibody Response by Vaccination Arma. (V5 – EIA Assay) – Immunogenicity Subcohort – Costa Rica HPV-16/18 Vaccine Trial (CVT)

a HPV Arm plotted irrespective of entry serostatus. Control Arm plotted separately by entry serostatus.

Figure 3D. Kinetics of HPV-18 Antibody Response by Vaccination Arm*. (J4 - EIA Assay) – Immunogenicity Subcohort – Costa Rica HPV-16/18 Vaccine Trial (CVT)

a HPV Arm plotted irrespective of entry serostatus. Control Arm plotted separately by entry serostatus