title: 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.
  
  
  BACKGROUND
  Registered with clinicaltrials.gov: NCT00128661.
authors.affiliation: National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, 9609 Medical Center Drive, Bethesda, MD 20892, United States. Electronic address: hildesha@exchange.nih.gov.
authors.forename: Allan
authors.initials: A
authors.lastname: Hildesheim
authors.affiliation: National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, 9609 Medical Center Drive, Bethesda, MD 20892, United States. Electronic address: wacholds@exchange.nih.gov.
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.affiliation: GlaxoSmithKline Vaccines, Avenue Fleming 20, B-1300 Wavre, Belgium. Electronic address: gregory.x.catteau@gsk.com.
authors.forename: Gregory
authors.initials: G
authors.lastname: Catteau
authors.affiliation: GlaxoSmithKline Vaccines, Avenue Fleming 20, B-1300 Wavre, Belgium. Electronic address: frank.struyf@gsk.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Struyf
authors.affiliation: GlaxoSmithKline SA, 2301 Renaissance 22 Boulevard, RN0220, King of Prussia, PA 19406, United States. Electronic address: Gary.O.Dubin@gsk.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Dubin
authors.affiliation: Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, Solarium Bldg., Liberia, Costa Rica. Electronic address: HerreroR@iarc.fr.
authors.forename: Rolando
authors.initials: R
authors.lastname: Herrero
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D003364:Costa Rica; D004311:Double-Blind Method; D005260:Female; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D030361:Papillomavirus Infections / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000627:therapeutic use*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000517:prevention & control*
chemical_list: D000914:Antibodies, Viral; D053918:Papillomavirus Vaccines
keywords: Cervical neoplasia; Clinical trial; Human papillomaviruses; Prevention; Vaccination