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Cervical 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. [ABSTRACT FROM AUTHOR]

Introduction: We report head-to-head comparison of the bivalent and quadrivalent HPV vaccine efficacies against immediate precursors of cervical cancer from 15 years' country-wide cancer registry follow-up of phase III trial cohorts and an age-aligned cohort of unvaccinated women. Methods: These individually and/or clusterrandomized cohorts of HPV6/11/16/18- and HPV16/18-vaccinated and unvaccinated women were enrolled, respectively, in 2002, 2004, and 2003/2005. The trial cohorts comprised initially 16- to 17-yearold HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866) and HPV16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2,465), and 16,526 initially 16- to 19-year-old unvaccinated controls. After active 4-year clinical follow-up, passive, country-wide Finnish Cancer Registry (FCR) follow-up for cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) was based on consented use of unique personal identifiers and started 6 months after the end of the FUTURE II and PATRICIA trials in 2007 and 2009, and ended at the end of 2019. The follow-up with altogether 229,020 follow-up years was age-aligned to ensure that similarly aged cohorts were passively followed up for 15 years post=vaccination for the intention-to-treat analyses of vaccine efficacy. Results: Overall, we identified 5 and 16 CIN3 (no AIS) cases in the HPV6/11/16/18 and HPV16/18 cohorts, respectively, during the FCR-based follow-up. In the unvaccinated cohort, we identified 281 CIN3 cases, 20 AIS cases, and 13 cases with invasive cervical cancer. Vaccine efficacies against CIN3+ were 68.4% and 64.5% for the quadrivalent and the bivalent vaccines, respectively, with overlapping confidence intervals. Discussion: Long-term follow-up of randomized, initially adolescent HPVvaccinated and unvaccinated cohorts shows, in this head-to-head setting, that the bivalent and quadrivalent HPV vaccines are equally effective against immediate precursors of cervical cancer. [ABSTRACT FROM AUTHOR]

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 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., Author(s): Penelope Gray 1,*, Hanna Kann 2, Ville N. Pimenoff 2,3,4, Tiina Eriksson 5, Tapio Luostarinen 6, Simopekka Vänskä 7, Heljä-Marja Surcel 8,9, Helena Faust 2, Joakim Dillner 2, Matti [...]

HPV16 E6-antibody associated risk of oropharyngeal cancer increases by calendar-time: A nested case-control study Abbreviations CL confidence limits FMC Finnish Maternity Cohort HPV human papillomavirus ICD 10 International Classification of Diseases, Tenth Revision MFI median fluorescence intensity OPC oropharyngeal cancer OPSCC oropharyngeal squamous cell carcinoma OR odds ratio RR relative risk During the last 40 years the incidence of oropharyngeal cancer (OPC), especially that of oropharyngeal squamous cell carcinoma (OPSCC) has increased in many Western countries.[1] This is mostly due to the human papillomavirus type 16 epidemic[2] which, in the absence of preventive measures against OPC has resulted in its incidence now exceeding that of cervical cancer.[3] Depending on calendar-time and ethnicity, HPV16 E6 antibodies are associated with 20- to 270-fold relative risk (RR) of OPSCC.[4] Among OPSCC cases prediagnostic HPV16 E6 antibodies became two to three times more prevalent between the early 1990s and 2010.[4] The highest E6 seropositivity among OPSCC cases of 68% was observed in cases with <5 years lead time between serum sampling and an OPSCC diagnosis made after the year 2005.[4] Sensitivity/specificity of HPV16 E6 antibodies in the identification of overt, HPV-driven OPSCC are excellent and exceed 90% and 95%.[5] In a number of OPSCC cases E6 antibodies are positive up to three decades before diagnosis.[4] However, for fertile-aged women affected by the silent HPV16 epidemic since the late 1980s[2] data on the E6 antibody-specific risks are scarce. The firm association between HPV16 and oropharyngeal squamous cell carcinoma will eventually be alleviated by gender-neutral HPV vaccination.[1] In the meantime, middle-aged birth cohorts which are beyond prophylactic vaccination age may be screened for oropharyngeal cancer using HPV16 E6 antibodies. [Extracted from the article]

For head-to-head comparison of human papillomavirus (HPV) antibody levels induced by different vaccines, 25-year-old vaccine-naive women were given either the bivalent (n = 188) or the nonavalent HPV vaccine (n = 184). Six months after vaccination antibodies against pseudovirions from 17 different HPV types (HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68/73) were measured. Antibodies against HPV16/18 were higher after bivalent HPV vaccination (mean international units [IU] 1140.1 and 170.5 for HPV16 and 18, respectively) than after nonavalent vaccination (265.1 and 22.3 IUs, respectively). The bivalent vaccine commonly induced antibodies against the nonvaccine HPV types 31/33/35/45 or 58. The nonavalent vaccine induced higher antibodies against HPV6/11/31/33/45/52/58 and 35. [ABSTRACT FROM AUTHOR]

Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life‐years. We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992–1994 birth‐cohorts (30,139 females) were invited to a community‐randomized HPV16/18‐vaccination trial. A total of 9,482 female trial participants received HPV16/18‐vaccination in 2007–2009 at age of 13–15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014–2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high‐risk HPV types were: 0.5% (53/1,000 follow‐up years, 104) and 25% (2,530/104) in the frequently screened Arm 1; 0.2% (23/104) and 24% (2,413/104) in the infrequently screened Arm 2; and 3.1% (304/104) and 23% (2,284/104) in the safety Arm 3. Corresponding prevalence of HSIL/ASC‐H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former. What's new? As the first generation of girls vaccinated against HPV reach adulthood, it's time to re‐evaluate screening recommendations. Reducing the frequency of screenings could save money without increasing cervical cancer incidence. Here, the authors collected baseline data on the safety of less frequent cervical cancer screenings. They conducted a randomized trial of Finnish women born in 1992‐1994 and vaccinated against HPV16/18, in which participants are screened either once or three times by age 28. At baseline and the first safety interim analyses they found no difference in the incidence of HSIL/CIN3 lesions between the two groups, suggesting that infrequent screening for HPV‐vaccinated women does not compromise safety. [ABSTRACT FROM AUTHOR]

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 (PRcore = 1.4, PRnon‐core. = 1.4) whereas the HPV52 occurrence was increased in the core‐group only (PRcore = 2.5, PRnon‐core = 0.8). Among the non‐HPV vaccinated 18‐year‐olds, the HPV51/52 PRs were higher in the core‐group (PRcore = 3.8/1.8, PRnon‐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. What's new? Oncogenic non‐vaccine human papillomavirus (HPV) types may conceivably fill the vacated ecological niche of the vaccine types‐‐a phenomenon which could undermine national HPV vaccination programs and warrants surveillance. The high sexual activity core‐group, which is permissive for faster transmission dynamics, may be more susceptible to HPV type replacement. Here, the authors report that in the core‐group defined by Chlamydia trachomatis positivity, among non‐HPV vaccinated women high‐risk HPV51 and HPV52 were increased four years post‐vaccination. In the core‐group of HPV16/18 vaccinated women HPV52 only was increased. Monitoring of the sexual risk‐taking core‐group may detect early tendencies for HPV type replacement. [ABSTRACT FROM AUTHOR]

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 (PRA 1.84, 95% CI 1.12–3.02) and HPV51 (PRA 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 (ORA16 = 5.1, ORA18/45 = 11.4) was observed in the non‐HPV vaccinated 1994–1995 birth cohorts. Comparable clustering was seen between HPV51 and HPV16 or HPV18/45 (ORB16 = 4.7, ORB18/45 = 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. [ABSTRACT FROM AUTHOR]

Background: Most countries in the world have launched human papillomavirus (HPV) vaccination programmes and declining prevalences of HPV are reported. We aimed to disentangle the influences of calendar time, birth cohort and age by analysing HPV prevalences in the population-based cervical screening programme using age-period-cohort modelling., Methods: All 836,314 primary HPV-based cervical screening tests from women aged 23-64 between 2014-2023 in the capital region of Sweden were identified in the Swedish National Cervical Screening Registry. The odds ratio of HPV16/18 infection was estimated comparing each birth cohort to the unvaccinated 1984-born using an age-period-cohort model. The impact of changing HPV prevalences on the numbers needed to screen (NNS) to detect and prevent 1 cervical cancer case were calculated., Results: HPV vaccination coverage was 82-83% among women born in 1999-2000. Before 2019 the HPV16/18 prevalence was highest among the youngest women in the screening program. During 2020-2023 the prevalence consistently decreased among the birth cohorts offered organised school-based vaccination. There was a 98% decline in HPV16 prevalence (odds ratio=0.02 [95% CI 0.01-0.04]) and a 99% decline in HPV18 prevalence (odds ratio=0.01 [0.00-0.04]) among the 2000-born compared to the HPV unvaccinated 1984-born. The declining HPV16/18 prevalences resulted in major increases in the NNS to detect and to prevent 1 case of cervical cancer., Conclusions: The declines of HPV16/18 were considerably larger than the vaccination coverage, suggesting herd immunity effects. The changing epidemiology of HPV types impacts screening needs, necessitating updated screening programs., (© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)