Safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in adolescents aged 12-15 years: Interim analysis of a large community-randomized controlled trial

Hum Vaccin Immunother. 2016 Dec;12(12):3177-3185. doi: 10.1080/21645515.2016.1183847.


This community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12-15 y in 33 communities in Finland ( NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0-82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2-91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03-1.24] and 0.16 [95% CI: 0.03-0.55], respectively).

Keywords: HPV-16/18 AS04-adjuvanted vaccine; Human papillomavirus (HPV); adolescents; autoimmune disease; insulin-dependent diabetes mellitus; safety.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aluminum Hydroxide / administration & dosage
  • Aluminum Hydroxide / adverse effects*
  • Autoimmune Diseases / chemically induced
  • Autoimmune Diseases / epidemiology
  • Child
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Finland
  • Hepatitis B Vaccines / administration & dosage
  • Hepatitis B Vaccines / adverse effects
  • Humans
  • Lipid A / administration & dosage
  • Lipid A / adverse effects
  • Lipid A / analogs & derivatives*
  • Male
  • Papillomavirus Infections / prevention & control*
  • Papillomavirus Vaccines / administration & dosage
  • Papillomavirus Vaccines / adverse effects*


  • ASO4 mixture
  • Hepatitis B Vaccines
  • Lipid A
  • Papillomavirus Vaccines
  • Aluminum Hydroxide

Associated data