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

INTRODUCTION: We conducted a community-randomized trial (NCTBLINDED) in Finland to assess gender-neutral and girls-only vaccination strategies with the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18)vaccine. METHODS: Girls and boys (12-15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04-HPV-16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04-HPV-16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV-16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04-HPV-16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co-primary objectives were overall effectiveness following gender-neutral or girls-only vaccination. RESULTS: Of 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: -19.0, 51.1; P = 0.232) with gender-neutral vaccination. Following girls-only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04-HPV-16/18 vaccine was high in both sexes. CONCLUSIONS: This study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.

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.

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 population-based health registry surveillance. Plain Language Summary What 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. What is the impact? ● This study highlights the importance of health registries in long-term vaccination safety surveillance. The population-based safety data reported in this study further support the routine administration of the HPV vaccine to girls and boys.

Effectiveness of the AS04-adjuvanted HPV-16/18 vaccine in reducing oropharyngeal HPV infections in young females-Results from a community-randomized trial.

We studied effectiveness of the AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) vaccine against human papillomavirus (HPV) oropharyngeal infections associated with the increase of head/neck cancers in western countries. All 38,631 resident adolescents from 1994 to 1995 birth cohorts of 33 Finnish communities were invited in this community-randomized trial (NCT00534638). During 2008-2009, 11,275 girls and 6,129 boys were enrolled in three arms of 11 communities each. In Arm A, 90% of vaccinated girls/boys, and in Arm B, 90% of vaccinated girls received AS04-HPV-16/18 vaccine. Other Arm A/B and all Arm C vaccinated participants received control vaccine. All Arm A participants and Arm B female participants were blinded to vaccine allocation. Oropharyngeal samples were analyzed from 4,871 18.5-year-old females who attended follow-up visit 3-6 years postvaccination. HPV DNA prevalence was determined by SPF-10 LiPA and Multiplex type-specific PCR. Total vaccine effectiveness (VE) was defined as relative reduction of oropharyngeal HPV prevalence in pooled Arms A/B HPV-vaccinated females vs. all Arm C females. VE against oropharyngeal HPV-16/18, HPV-31/45 and HPV-31/33/45 infections were 82.4% (95% confidence intervals [CI]: 47.3-94.1), 75.3% (95%CI: 12.7-93.0) and 69.9% (95% CI: 29.6-87.1), respectively. In conclusion, the AS04-HPV-16/18 vaccine showed effectiveness against vaccine and nonvaccine HPV-types oropharyngeal infections in adolescent females up to 6 years postvaccination.

Decennial administration of a reduced antigen content diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults.

BACKGROUND: Booster vaccination against tetanus and diphtheria at 10-year intervals is commonly recommended. Reduced antigen content diphtheria and tetanus toxoids and acellular pertussis (dTpa) vaccines developed for booster vaccination of preschool children, adolescents, and adults are licensed for once-in-a-lifetime use in most countries. Objective. To evaluate decennial administration of a dTpa vaccine. Methods. Young adults vaccinated with dTpa or diphtheria and tetanus toxoids followed by acellular pertussis (DT+ap) 1 month later in a clinical trial 10 years previously received 1 dTpa dose. Blood samples were taken before and 1 month after vaccination. Antibody concentrations against vaccine antigens were measured by enzyme-linked immunosorbent assay. Solicited and unsolicited symptoms and serious adverse events were recorded. RESULTS: Eighty-two individuals were enrolled in the study. In the 75 individuals who had received the dTpa vaccine 10 years previously, prevaccination seroprotection or seropositivity rates were 98.8% (diphtheria), 97.5% (tetanus), 64.6% (pertussis toxoid), 100% (filamentous hemagglutinin), and 96.3% (pertactin). One month after the second booster, all study participants were seroprotected or seropositive against all vaccine antigens. Antibody concentrations increased by a similar magnitude as 10 years previously. During the 4-day follow-up, 9.9% of participants recorded grade 3 pain; 17.3% and 18.5% recorded redness and swelling of 50 mm or larger, respectively; and 8.6% recorded fever (temperature, 37.5 degrees C). No serious adverse events were considered causally related to the vaccine. CONCLUSIONS: A second dTpa booster was highly immunogenic and well tolerated in this population of young adults. This study supports the use of this vaccine as a decennial booster. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00610168 .

Immunogenicity and reactogenicity of two diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccines administered at 3, 5 and 11-12 months of age.

The use of combination vaccines in the routine childhood program reduces distress to the recipients and is likely to improve uptake rates and timeliness of vaccination but requires careful evaluation and surveillance. The aim of this study was to evaluate the immunogenicity and reactogenicity of two commercial diphtheria-tetanus- acellular pertussis-hepatitis b-inactivated polio virus-Haemophilus influenzae type b (DTaP-HBV-IPV/Hib) combination vaccines when administered to infants at 3, 5 and 11-12 months of age. A total of 494 infants were randomized to receive three doses of either Infanrix hexa (GlaxoSmithKline Biologicals; N = 246) or Hexavac (Sanofi Pasteur MSD; N = 248) in 10 centers in Italy, Finland and Sweden. After the third dose, antibodies to diphtheria, tetanus, polio and Hib were at the protective level in nearly all infants in both groups whereas the proportion of subjects who had achieved the protective concentration of >or=10 mIU/ml to hepatitis B surface antigen was 99.1% (95% CI 96.7-99.9) in the Infanrix hexa group as compared to 94.4% (95% CI 90.4.97.1) in the Hexavac group. Antibody titers to all three polio antigens were highest in Italy and lowest in Finland. Clinically relevant general reactions (such as fever of >39.5 degrees C) were mostly reported in less than 5% of the vaccinees. Three doses of DTaP-HBV-IPV/Hib combination vaccines produced sufficient immune responses in nearly all vaccinees.