To evaluate safety and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in a large prospective, community-based controlled study (HPV-040, NCT00534638).
In this phase III/IV, cluster-randomized, partially blind trial, adolescents aged 12–15 years (y) born 1992–1995, from 33 communities in Finland, received HPV-16/18 (12399 girls, 2438 boys) or hepatitis B virus (HBV) vaccine (8119 girls, 9219 boys), at months (m) 0-1-6. Subjects were followed-up until they reached ~18.5y of age. Active safety surveillance was performed until m12 in a subset of boys. Passive safety surveillance was performed by linkage of the Registry of Vaccinated Individuals (total vaccinated cohort: 32175 subjects) to a national hospital patient register (HILMO; occurrence of new onset of autoimmune disorders [NOADs] and pregnancy-related outcomes) and to the Birth Registry (pregnancy-related outcomes). Spontaneous reporting of related serious adverse events (SAEs) and pregnancy outcomes was recorded throughout the study period. Blood samples were collected at m0, m7 and at age ~18.5y; anti-HPV-16/18 antibody responses were assessed by ELISA (immunogenicity subset: 764 girls and 225 boys).
Active safety surveillance results were previously reported, at interim analysis. Overall, passive surveillance results were similar between groups. The most commonly reported NOADs were inflammatory bowel diseases (incidence per 100,000 person-years: 47.9 [HPV], 59.8 [HBV]) and coeliac disease (16.0 [HPV], 21.8 [HBV]), type-1 diabetes mellitus (22.4 [HPV], 38.1 [HBV]), and juvenile idiopathic arthritis (14.4 [HPV], 16.3 [HBV]). The respective incidence rates for SAEs possibly related to vaccination, throughout the study, were comparable between groups (39.1 [HPV] and 39.8 [HBV]). There were 1252 pregnancies (728 in HPV group, 524 in HBV group); of these, 31.9% (HPV) and 30.7% (HBV) resulted in live infant outcomes, 59.2% (HPV) and 59.9% (HBV) ended up in elective termination, 8.0% (HPV) and 7.8% (HBV) in spontaneous abortion, all with no apparent congenital anomalies. Anti-HPV-16 geometric mean titre (GMT) was 2588 (95% CI: 2433, 2753) vs 2735 (95% CI: 2420, 3091) and anti-HPV-18 GMT was 878 (95% CI: 818; 942) vs 838 (95% CI: 731, 962) in girls vs boys, respectively.
The HPV-16/18 AS04-adjuvanted vaccine was well tolerated and outcomes were in line with the known safety profile of this vaccine. Immunogenicity results at age ~18.5 years were similar in girls and boys. Health registries contributed an important number of NOAD and pregnancy cases and play a major role in long-term post-vaccination safety surveillance.
Funding: GlaxoSmithKline Biologicals SA