Ville N. Pimenoff

Predicting optimal impact interventions in the post‐ HPV vaccination world

Abstract Prophylactic vaccination is a powerful tool that changes exposure to infections and associated morbidity of preventable diseases. We discuss the impact of pneumococci and human papillomavirus (HPV) vaccination on the population biology of the two micro‐organisms and related public health effects. Data on HPV type‐replacement in communities where vaccine‐covered HPVs are almost eliminated, and interactions of the remaining HPV types on the risk of cervical cancer are reviewed. Results of comprehensive models for European country‐specific conduction of cervical screening among HPV‐vaccinated and unvaccinated women, assuming different HPV‐vaccination coverage and strategies, are discussed in our policy‐oriented review. An acceptable balance of benefits and harms of cervical cancer screening in HPV vaccinated populations requires an understanding of cancer risks in differently vaccinated birth cohorts. Finally, the challenges are complex but can be met if strategies are applied that (i) as fast as possible achieve herd effect and (ii) use a risk‐based design of HPV screening.

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.

Assessing the risk of cervical neoplasia in the post‐HPV vaccination era

AbstractThis review is based on the recent EUROGIN scientific session: “Assessing risk of cervical cancer in the post‐vaccination era,” which addressed the demands of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesion (SIL) triage now that the prevalence of vaccine‐targeted oncogenic high‐risk (hr) human papillomaviruses (HPVs) is decreasing. Change in the prevalence distribution of oncogenic HPV types that follows national HPV vaccination programs is setting the stage for loss of positive predictive value of conventional but possibly also new triage modalities. Understanding the contribution of the latter, most notably hypermethylation of cellular and viral genes in a new setting where most oncogenic HPV types are no longer present, requires studies on their performance in vaccinated women with CIN/SIL that are associated with nonvaccine HPV types. Lessons learned from this research may highlight the potential of cervical cells for risk prediction of all women's cancers.

Ecological diversity profiles of non-vaccine-targeted HPVs after gender-based community vaccination efforts

The long-term effect of population-level human papillomavirus (HPV) vaccination on the viral ecology of the untargeted HPVs is poorly understood. We performed an 8-year follow-up of 33 communities randomized to gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and control communities without HPV vaccination. The 1992/93 and 1994 birth cohorts were invited in school years 2007/8 and 2008/9. Follow-up cervico-vaginal sampling at 18 and 22 years of age, 4 and 8 years post-vaccination, respectively, were attended by 11,396 and 5,602 participants. HPV types 6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68 were genotyped and used for the community-level ecological diversity estimations. Gender-neutral vaccination communities with a stronger herd immunity than girls-only vaccination communities show a significantly increased HPV α-diversity (p = 1.1 × 10