Penelope Gray

Controlled trial of cervical cancer screening frequency among human‐papillomavirus‐vaccinated women

Abstract Cervical screening frequency has not been studied in vaccinees. As the major risk factor, oncogenic human papillomavirus (HPV) is declining due to vaccination. We report a trial to assess the effectiveness of cervical screening frequency among women HPV‐vaccinated as early adolescents (NCT02149030). In 2013, 5626 1992‐1995‐born women, who had received three doses of the HPV16/18 vaccine at ages 12–15 between 2007 and 2010 in a community‐randomized vaccination trial (NCT00534638), were allocated at age 22 into high‐intensity cytology‐based cervical screening by even birth date (Arm A1) or into low‐intensity cytology‐based cervical screening by odd birth date (Arm A2). One thousand three hundred thirty‐three women who received HPV16/18 vaccination at age 18 attended a safety of low intensity‐screening arm (Arm A3). Low‐intensity screening, where low‐grade cytological abnormalities were not revealed for 6 years, was compared to the standard high‐intensity screening used in Finland at the time. The prevalence of cytological and HPV findings was calculated at ages 22/25/28. The hazard ratio of histopathologically confirmed immediate cervical cancer precursors (HSIL/CIN2+) among participants was compared between low‐ and high‐intensity screening arms. The overall occurrence of CIN2+ was comparable in Arms A1, 0.70% and A2, 0.66%, with the corresponding hazard ratio at age 28 being 0.97 (95% confidence intervals, 0.50–1.88). By age 28, the occurrence of vaccine‐HPV types 16/18 was reduced up to 88% in the 12‐to‐15 compared to 18‐year‐old HPV‐vaccinated women. In conclusion, the risk of CIN2+ was similar for HPV‐vaccinated women who attended low‐intensity cervical screening compared to high‐intensity screening most likely due to the decline of oncogenic HPVs.

Population-Based Age-Period-Cohort Analysis of Declining Human Papillomavirus Prevalence

Abstract Background Most countries in the world have launched human papillomavirus (HPV) vaccination programs, and declining HPV prevalences are reported. We aimed to disentangle the influences of calendar time, birth cohort, and age by analyzing HPV prevalences in the population-based cervical screening program using age-period-cohort modeling. Methods All 813 882 primary HPV-based cervical screening tests from women aged 23–64 years between 2014 and 2023 in the capital region of Sweden were identified in the Swedish National Cervical Screening Registry. The odds ratio (OR) of HPV-16/18 infection was estimated comparing birth cohorts to the unvaccinated 1984-born using an age-period-cohort model. The impact of changing HPV prevalences on the number needed to screen (NNS) to detect and prevent 1 cervical cancer case was calculated. Results HPV vaccination coverage was 82%–83% among women born in 1999–2000. Before 2019, the HPV-16/18 prevalence was highest among the youngest women. During 2020–2023 the prevalence consistently decreased among the birth cohorts offered organized school-based vaccination. There was a 98% decline in HPV-16 prevalence (OR, 0.02 [95% confidence interval {CI}, .01–.04]) and a 99% decline in HPV-18 prevalence (OR, 0.01 [95% CI, .00–.04]) among the 2000-born compared to the 1984-born. The declining HPV-16/18 prevalences resulted in major increases in the NNS to detect and to prevent 1 case of cervical cancer. Conclusions The declines of HPV-16/18 were considerably larger than the vaccination coverage, suggesting herd immunity. The changing epidemiology of HPV types impacts screening needs, necessitating updated screening programs.

Low methylation marker levels among human papillomavirus‐vaccinated women with cervical high‐grade squamous intraepithelial lesions

AbstractCervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)‐vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false‐positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case–control study, 9242 women who received the three‐dose HPV16/18‐vaccine at ages 12–15 or 18 in a community‐randomized trial were included. Subsequently, they were re‐randomized for either frequent or infrequent cervical cancer screening trials. Over a 15‐year post‐vaccination follow‐up until 2022, 17 high‐grade squamous intraepithelial lesion (HSIL) and 15 low‐grade (LSIL) cases were identified at the 25‐year screening round, alongside 371 age and community‐matched HPV16/18‐vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host‐cell genes (EPB41L3, FAM19A4, and miR124‐2) was measured, along with HPV‐genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV‐genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host‐cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV‐vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV‐vaccinated women and its implications for management.

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

BackgroundCervical 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 findingsIn 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).ConclusionsIn 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 registrationClinicalTrials.gov numberNCT00534638,https://clinicaltrials.gov/ct2/show/NCT00534638.

Scientific approaches toward improving cervical cancer elimination strategies

AbstractAt the 2023 EUROGIN workshop scientific basis for strategies to accelerate the elimination of cervical cancer and its causative agent, human papillomavirus (HPV) were reviewed. Although some countries have reached key performance indicators toward elimination (>90% of girls HPV vaccinated and >70% of women HPV screened), most are yet to reach these targets, implying a need for improved strategies. Gender‐neutral vaccination, even with moderate vaccination coverage was highlighted as a strategy to achieve elimination more rapidly. It is more resilient against major disturbances in vaccination delivery, such as what happened during the coronavirus pandemic. Further, an analysis of ethical/legal issues indicated that female‐restricted vaccination is problematic. Extended catch‐up of vaccination with concomitant screening, and outreach to vulnerable groups were highlighted. Although birth cohorts with high coverage of HPV vaccination at school are protected against HPV, and HPVs have a very low reproductive rate in women above age 35, adult women below age 30 have inadequate direct protection. In addition to herd protection from gender‐neutral vaccination, this group can be protected by offering concomitant catch‐up HPV vaccination and HPV screening. Furthermore, hepatitis B vaccination experiences indicate that elimination cannot be achieved without prioritizing vulnerable/migrant populations. The long‐lasting durability of vaccination‐induced antibody responses suggests prolonged protection with HPV vaccines when adequately administrated. Finally, cost‐effectiveness modelling suggests that high‐coverage HPV vaccination in multiple population segments will be resource‐saving due to reduced need for screening. In summary, the workshop found that strategically optimal deployment of vaccination will accelerate elimination of HPV and cervical cancer.

Effectiveness, Safety and Immunogenicity of GSK Biologicals' HPV Vaccine GSK580299 (Cervarix) Administered in Healthy Adolescents

Genital infections with oncogenic human papillomaviruses (HPV) are common in both men and women. The most important disease associated with oncogenic HPV infection is cervical cancer, currently the second leading cause of cancer-related death among women globally. The current study is designed to evaluate the overall impact of HPV immunization in adolescents 12-15 years of age.