Safety of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine in adolescents aged 12–15 years: end-of-study results from a community-randomized study up to 6.5 years

Abstract

This manuscript discloses end-of-study safety data of a community-randomized controlled trial in Finland (NCT00534638), assessing the effectiveness of two vaccination strategies (gender-neutral versus females only) using the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18) vaccine. The total vaccination cohort included 32,175 adolescents aged 12-15 y at vaccination of whom 14,837 received the AS04-HPV-16/18 vaccine and 17,338 received the hepatitis-B virus vaccine (control). Spontaneous reporting of serious adverse events (SAEs) combined with surveillance using nation-wide health registries showed an acceptable safety profile of the AS04-HPV-16/18 vaccine. During the study period (up to 6.5 y), the incidences (per 100,000 person-years) of reported SAEs considered as possibly related to vaccination were 39.1 (95% confidence interval [CI]: 25.3-57.7) and 39.8 (95%CI: 26.8-56.8) in the HPV and control groups, respectively. The most frequently reported new-onset autoimmune diseases (NOADs) were ulcerative colitis (incidence rates of 28.2 and 33.1 per 100,000 person-years in the HPV and control groups, respectively), insulin-dependent diabetes mellitus (21.9 and 37.1), Crohn's disease (15.6 and 22.5), celiac disease (15.6 and 21.2), and juvenile idiopathic arthritis (14.1 and 15.9). Of 1,344 pregnancies reported (777 and 567 in the HPV and control groups, respectively), most resulted in elective termination (58.4% and 58.6%), birth of a live infant (32.7% and 32.3%), or in spontaneous abortion (8.0% and 7.9%). No major, registered congenital anomalies were identified. The incidence rates of NOADs and pregnancy outcomes were generally balanced between groups. No specific safety signals were identified in the populationbased health registry surveillance. Plain Language SummaryWhat is the context?• Since first licensure in 2007 of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine (Cervarix, GSK), large quantity of safety data has been collected and confirmed its safety profile. This study provides further unique, population-based safety data from vaccinated Finnish adolescents monitored via health registries up to 6.5 y of follow-up.What is new?• The vaccine has shown an acceptable safety profile in girls and boys. The risk of new-onset autoimmune diseases (NOADs) was similar between the HPV vaccine group and the control group and in line with the expectations for the studied population. • The study supports that safety surveillance via national health registries is in general more sensitive than the conventional safety reporting, notably for monitoring specific chronic diseases, e.g. autoimmune disorders.

Effectiveness of various human papillomavirus vaccination strategies: A community randomized trial in Finland

“…Safety of the vaccine in this study has been reported elsewhere in detail, but no new safety concerns were identified and safety was similar in boys and girls. 11 Strengths of the study have been described previously, 10 and include the large sample size, 8-year duration, uniform enrollment of girls and boys by school year, birth cohort, and community, and little movement between communities. HPV mass vaccination was introduced in Finland in 2013 for girls born from 1998, and there was therefore no confounding in our study from the national immunization plan.…”

“…Safety of the vaccine in this study has been reported elsewhere in detail, but no new safety concerns were identified and safety was similar in boys and girls. 11 …”

“…A polymerase chain reaction (PCR) assay and multiplex type-specific (MPTS) PCR Luminex assay were used to test cervical samples for DNA of 14 oncogenic types (HPV- 16,18,31,33,35,39,45,51,52,56,58,59, 66, and 68) and 11 non-oncogenic types 11,34,40,42,43,44,53,54, 70, and 74), as previously described. 13 The Bethesda 2001 system was used to report cervical cytology diagnoses.…”

“… 10 Data from the trial on vaccine safety and its effectiveness in reducing oropharyngeal HPV infections have been previously reported. 11 , 12 We now report the analyses of overall effectiveness measurements against cervical infections in vaccinated and unvaccinated adolescent girls.…”

Risk of Guillain–Barré syndrome after vaccination against human papillomavirus: a systematic review and meta-analysis, 1 January 2000 to 4 April 2020

“…The 25 included studies (Table 1) were conducted between 1999 and 2017. Twelve studies were conducted in Europe [13,[23][24][25][26][27][28][29][30][31][32][33] and 12 studies were conducted in North America [34][35][36][37][38][39][40][41][42][43][44][45]. One study reported pooled RCT outcomes [46] without reporting the study location(s).…”