Matti Lehtinen

Oncogenic non‐vaccine human papillomavirus (HPV) types may conceivably fill the vacated ecological niche of the vaccine types. The likelihood of this may differ by the risk of acquiring HPV infections. We examined occurrence of HPV types among vaccinated and unvaccinated subgroups of 1992–1994 birth cohorts with differing acquisition risks up to 9 years post‐implementation of HPV vaccination in 33 Finnish communities randomized to: Arm A (gender‐neutral HPV16/18 vaccination), Arm B (girls‐only HPV16/18 vaccination and hepatitis B‐virus (HBV) vaccination of boys), and Arm C (gender‐neutral HBV vaccination). Out of 1992–1994 born resident boys (31,117) and girls (30,139), 8,618 boys and 15,615 girls were vaccinated, respectively, with 20–30% and 50% coverage in 2007–2009. In 2010–2013, 8,868 HPV16/18 and non‐HPV vaccinated females, and in 2014–2016, 5,574 originally or later (2010–2013) HPV16/18 vaccinated females attended two cervical sampling visits, aged 18.5 and 22‐years. The samples were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68 using PCR followed by MALDI‐TOF MS. HPV prevalence ratios (PR) between Arms A/B vs. C were calculated for Chlamydia trachomatis positives (core‐group), and negatives (general population minus core group). At both visits the vaccine‐protected HPV type PRs did not significantly differ between the core‐group and non‐core group. Among the vaccinated 18‐year‐olds, HPV51 occurrence was overall somewhat increased (PR_core = 1.4, PR_non‐core. = 1.4) whereas the HPV52 occurrence was increased in the core‐group only (PR_core = 2.5, PR_non‐core = 0.8). Among the non‐HPV vaccinated 18‐year‐olds, the HPV51/52 PRs were higher in the core‐group (PR_core = 3.8/1.8, PR_non‐core = 1.2/1.1). The 22‐year‐olds yielded no corresponding observations. Monitoring of the sexual risk‐taking core‐group may detect early tendencies for HPV type replacement.

With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective effectiveness (PE) against high‐risk HPV infections by HPV type and vaccination strategy in a community‐randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender‐neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (Arm B) and gender‐neutral HBV vaccination (Arm C). Entire 1992–1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20–30% and 45% coverage in 2007–2010. During 2010–2014, 11,396 cervicovaginal samples were collected from 13,545 18.5‐year‐old attendees. HPV typing was performed by a high‐throughput PCR. VE was calculated for HPV vaccinated women and HE for non‐HPV‐vaccinated women, using the HBV vaccinated, for HE all non‐HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate‐weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86–94% and 30–66%, respectively. Only the gender‐neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort—increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender‐neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender‐neutral vaccination‐enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.

Efficacy of human papillomavirus (HPV) vaccines promises to control HPV infections. However, HPV vaccination programs may lay bare an ecological niche for non‐vaccine HPV types. We evaluated type‐replacement by HPV type and vaccination strategy in a community‐randomized trial executed in HPV vaccination naïve population. Thirty‐three communities were randomized to gender‐neutral vaccination with AS04‐adjuvanted HPV16/18 vaccine (Arm A), HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (Arm B) and gender‐neutral HBV vaccination (Arm C). Resident 1992‐95 born boys (40,852) and girls (39,420) were invited. 11,662 boys and 20,513 girls were vaccinated with 20–30% and 45–48% coverage, respectively. HPV typing of 11,396 cervicovaginal samples was performed by high throughput PCR. Prevalence ratios (PR) between arms and ranked order of HPV types and odds ratio (OR) for having multiple HPV types in HPV16 or 18/45 positive individuals were calculated. The ranked order of HPV types did not significantly differ between arms or birth cohorts. For the non‐HPV vaccinated 1992–1993 birth cohorts increased PR, between the gender‐neutral intervention versus control arms for HPV39 (PR_A 1.84, 95% CI 1.12–3.02) and HPV51 (PR_A 1.56, 95% CI 1.11–2.19) were observed. In the gender‐neutral arm, increased clustering between HPV39 and the vaccine‐covered HPV types 16 or 18/45 (OR_A16 = 5.1, OR_A18/45 = 11.4) was observed in the non‐HPV vaccinated 1994–1995 birth cohorts. Comparable clustering was seen between HPV51 and HPV16 or HPV18/45 (OR_B16 = 4.7, OR_B18/45 = 4.3), in the girls‐only arm. In conclusion, definitively consistent postvaccination patterns of HPV type‐replacement were not observed. Future occurrence of HPV39 and HPV51 warrant investigation.

Population‐based Finnish Maternity Cohort (FMC) comprises 2M first trimester sera collected from 1M women during 33 years. Informed consent is by the opt‐out principle, and linkages with cancer and population registries provide a base for over time and over generation studies. Follow‐up for 17M person‐years by the end of 2014 can identify 39,700 cases of invasive cancer and 18,900 cases of premalignant breast and cervix lesions, and basal cell carcinoma diagnosed after serum sampling. For women with multiple pregnancies, serial samples taken before cancer diagnosis are available. Offspring of the women have developed more than 4000 cancers. For 100,000 individuals, samples taken during the pregnancies of both their mothers and grandmothers enable familial cancer studies. FMC continues to collect samples, and surveillance of exposures or interventions like vaccination programs is feasible. In summary, the FMC is a unique, accessible biobank for epidemiological, biomarker, and surveillance studies on cancer.

Human papillomavirus (HPV) vaccine is efficacious but the real‐life effectiveness of gender‐neutral and girls‐only vaccination strategies is unknown. We report a community‐randomized trial on the protective effectiveness [(PE) = vaccine efficacy (VE) + herd effect (HE)] of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender‐neutral vaccination with AS04‐adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (11 communities) or Arm C) gender‐neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992‐95 were invited in 2007–09. Virtually all (99%) 12‐ to 15‐year‐old participating males (11,662) and females (20,513) received three doses resulting in uniform 20–30% male and 50% female vaccination coverage by birth cohort. Four years later (2010–14) 11,396 cervicovaginal samples obtained from 18.5 year‐old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non‐vaccine types consistent with cross‐protection were highest in those born 1994–95 for HPV45 (VE_A 82.8%; VE_B 86.1%) and for HPV31 (VE_A 77.6%, VE_B 84.6%). The HEs in the non HPV‐vaccinated were statistically significant in those born 1994–95 for HPV18 (HE_A 51.0%; 95% CI 8.3–73.8, HE_B 47.2%; 6.5–70.2) and for HPV31/33 in arm A (HE_A 53.7%; 22.1–72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PE_A 58.1%; 45.1–69.4; PE_B 55.7%; 42.9–66.6). PE estimates against HPV31/33 were higher by the gender‐neutral vaccination (PE_A 60.5%; 43.6–73.4; PE_B 44.5%; 24.9–60.6). In conclusion, while gender‐neutral strategy enhanced the effectiveness of HPV vaccination for cross‐protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638

We assessed human papillomavirus (HPV) prevalence among HPV-16/18–vaccinated and unvaccinated Finnish male adolescents participating in chlamydia screening 4 years after vaccination with AS04-adjuvanted HPV-16/18 vaccine in 2007–2009. Previously vaccinated (n = 395) or unvaccinated (n = 149) male adolescents were enrolled in 12 municipalities. First-void urine samples were tested for HPV types 6, 11, 16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 66, and 68, and prevalence rates for HPV-16/18, and HPV-11/16/18/31/33/45 were reduced profoundly (0% vs 2.1% [P = .02] and 0.8% vs 5.3 [P = .002], respectively). Overall HPV DNA prevalence was also significantly reduced among HPV-16/18–vaccinated (4.1%) compared with unvaccinated subjects (10.1%) (P = .01). In this post hoc study, a highly significant reduction in HPV prevalence 4 years after vaccination suggests that the bivalent HPV-16/18 vaccine has protective efficacy in men.

Objective Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+). Methods We report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials’ end. Results During the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88). Conclusions Ten years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects. Trial registration number NCT01393470.

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 (ClinicalTrials.gov 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).