Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial

Abstract

Background: Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial.

Methods and findings: In 2007-2010, the 1992-1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005-2010) and post-vaccination era (2011-2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005-2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR16 = 0.64, 95% CI 0.10-0.85; PR18 = 0.72, 95% CI 0.22-0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR16 = 0.64, 95% CI 0.50-0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR31/33/35/45 = 0.88, 95% CI 0.81-0.97) were replicated in Arm C (PR31/33/35/45 = 0.79, 95% CI 0.69-0.90).

Conclusions: In this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels.

Trial registration: ClinicalTrials.gov number NCT00534638, https://clinicaltrials.gov/ct2/show/NCT00534638.

Fig 1. Lexis diagrams depicting the community-level exposure of the adolescent population to direct and indirect effects of the cluster-randomized human papillomavirus vaccination trial by birth cohort and study arm.

hite bars represent the birth cohorts with no vaccination, and the purple (trial vaccination) and orange (national vaccination) bars represent post-vaccination birth cohorts. The blue dashed lines indicate the sampling years and ages of this study. The colored fill of the symbols indicates the proportion of each type of vaccination that took place at that time point and age per birth cohort.

Fig 2. Flow chart of the cross-sectional cohort study nested in the Finnish community randomized human papillomavirus (HPV) vaccination trial with stepwise subsequent exclusions.

¹The arms are the trial arms from the cluster (community) randomized trial of HPV vaccination strategy, conducted in 2007–2010.²Includes all females aged 3–22 years who were resident in the communities specified as of the 31 December 2005 (data extracted from Statistics Finland).

Fig 3. Type-specific human papillomavirus (HPV) and herpes simplex virus type 2 (HSV-2) seroprevalence (%) among unvaccinated females under the age of 23 years by intervention strategy: Gender-neutral vaccination (Arm A), girls-only vaccination (Arm B), and control vaccination (Arm C).

Type-specific seroprevalence is stratified by time period of sample donation (pre-vaccination era, 2005–2010; post-vaccination era, 2011–2016).

Fig 4. Evaluation of human papillomavirus (HPV) vaccination coverage in the study population: Community-specific birth-cohort-weighted vaccination coverage of the consecutive community-randomized trial and national girls-only vaccination program.

Exposure to the indirect effects of HPV16/18 vaccination is defined as residing at the time of sample donation in one of the community-randomized HPV vaccination trial communities. Each row represents a trial community, and each column a year of the follow-up period. The community-specific vaccination coverage is calculated for pregnant females under the age of 23 years and includes vaccination of 12- to 15-year-old males and females in 2007–2010, and the national girls-only vaccination program launched in late 2013.

Fig 5. Ratio of human papillomavirus (HPV) seroprevalence ratios (PRs) comparing Arm A/B to Arm C.

Arm-specific PRs comprise post-vaccination to pre-vaccination-era HPV PRs among pregnant unvaccinated Finnish females, aged under 23 years, and adjusted for community-level maternal smoking. RPR, ratio of seroprevalence ratios.