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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-year-old 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 HPV-vaccinated 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., Competing Interests: DA, JD, ML, and JPaa have received grants for their HPV vaccination studies from Merck&Co. Inc. DA, JD, ML, and JPaa and GSK Biologicals DA, ML, JPaa. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lehtinen, Gray, Luostarinen, Eriksson, Apter, Bly, Harjula, Heikkilä, Hokkanen, Kuortti, Nieminen, Nummela, Paavonen, Palmroth, Petäjä, Pimenoff, Pukkala and Dillner.)

Objective: We assessed the relationship between Chlamydia trachomatis infection, duration of oral contraceptive (OC) use and cervical atypia among young adult Finnish women., Design: A longitudinal study., Setting and Participants: Women who were included in this study participated in a community-randomised trial on the effectiveness of human papillomavirus (HPV) vaccination and C. trachomatis screening at ages 18.5 and 22 years in Finland. They completed questionnaires on both visits about sexual behaviours. The cytology test results at age 18.5 and 22 years were also available for those women. The total number of participants in this study at 18.5 years of age were 11 701 and at 22 years of age were 6618., Main Outcome Measure: ORs with 95% CIs using univariable and multivariable logistic regression were used to assess the association between C. trachomatis infection, duration of OC and squamous intraepithelial lesions (SIL)., Results: There were 940 cytological SIL cases at the first screening visit and 129 cytological SIL cases at the second screening visit. Among the 22 years old, more than fourfold adjusted risk of SIL was associated with C. trachomatis positivity. The HPV16/18, condom use, smoking and number of sexual partners adjusted joint effect of prolonged OC use and C. trachomatis was significantly increased (OR 4.7, 95% CI 1.7 to 12.8) in the 22-year-old women. This observed joint effect was 1.6 times higher than expected on a multiplicative scale. On additive scale, the observed relative excess risk from interaction was 1.8., Conclusion: The risk of SIL in HPV vaccinated women is significantly increased if they are C. trachomatis positive and have used OC for 5 or more years. The biological basis may be lack of condom facilitated protection against sexually transmitted diseases., Trial Registration Number: NCT00534638., Competing Interests: Competing interests: ML and DA have grants from Merck & Co Inc and GSK for HPV vaccination trials through their employers (Tampere University, ML; Family Federation Finland, DA)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Human papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that vaccination provides HPV-type-specific protection against invasive cancer., Methods: Individually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002-2005. HPV vaccine cohorts comprised originally 16-17 year-old HPV 16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18-19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts., Findings: During a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p<0.05)., Interpretation: Vaccination is effective against invasive HPV-positive cancer., Trial Registration Number: NCT00122681, Post-results; NCT00169494, Post-results; NCT00092534, Post-results., Competing Interests: Competing interests: We declare that ML, DA, JD and JPaa have received grants from Merck & Co. Inc. and/or from the GSK group of companies through their respective employers. GSK Biologicals SA was provided the opportunity to review this manuscript but the authors are solely responsible for final content and interpretation., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: M.L. has previously received grants from Merck & Co. and GSK Biologicals through his employers the Finnish Institute of Health and Welfare (THL) and the University of Tampere for HPV vaccination studies.

Background: Human papillomavirus (HPV) vaccination of girls with very high (>90%) coverage has the potential to eradicate oncogenic HPVs, but such high coverage is hard to achieve. However, the herd effect (HE) depends both on the HPV type and the vaccination strategy., Methods: We randomized 33 Finnish communities into gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and hepatitis B virus vaccination arms. In 2007-2010, 11 662 of 20 513 of 40 852 of 39 420 resident boys/girls from 1992 to 1995 birth cohorts consented. In 2010-2014, cervicovaginal samples from vaccinated and unvaccinated girls at age 18.5 years were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Vaccine efficacy for vaccinated girls, HE for unvaccinated girls, and the protective effectiveness (PE) for all girls were estimated. We extended the community-randomized trial results about vaccination strategy with mathematical modeling to assess HPV eradication., Results: The HE and PE estimates in the 1995 birth cohort for HPV18/31/33 were significant in the gender-neutral arm and 150% and 40% stronger than in the girls-only arm. Concordantly, HPV18/31/33 eradication was already predicted in adolescents/young adults in 20 years with 75% coverage of gender-neutral vaccination. With the 75% coverage, eventual HPV16 eradication was also predicted, but only with the gender-neutral strategy., Conclusions: Gender-neutral vaccination is superior for eradication of oncogenic HPVs., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

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., (© 2019 UICC.)

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., (© 2018 UICC.)

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., (© 2018 UICC.)

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., (© 2017 UICC.)

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., Competing Interests: Competing interests: DA, ML, JP and JD have received grants from GSK group of companies and/or Merck & Co. Inc. through their employers (DA, Family Federation Finland; ML; University of Tampere; JP and PN University of Helsinki; JD and ML, Karolinska Institute) for HPV vaccination studies. GD was and FS is employee of GSK group of companies. FS has received shares and stock options from the GSK group of companies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Cutaneous human papillomavirus (HPV) types have been associated with non-melanoma skin cancer (NMSC), including a previous nested case-control study using HPV serology with bacterially derived fusion proteins with the major HPV capsid protein L1 (GST-L1). However, HPV serology using conformationally intact pseudovirions has been shown to correlate better with natural infection. Prospective studies using a more valid marker of infection are therefore warranted., Methods: Cancer registry follow-up of large Nordic biobanks identified prediagnostic serum samples from 633 subjects who later developed SCC, 1,990 subjects who developed basal cell carcinoma (BCC). The samples from cases and matched controls were tested for IgG to pseudovirions to 16 different HPV types (3, 5, 6, 11, 15: , 16, 18, 31, 32, 33, 38: , 45, 52, 58, 68, and 76: ) and two polyomaviruses (MCPyV and JCPyV)., Results: Baseline seropositivity was not associated with SCC risk, and there were only weak associations with BCC risk [HPV-5 (OR, 1.1; 95% confidence interval [CI], 1.0-1.3), HPV-15 (OR, 1.2; 95% CI, 1.0-1.4), HPV-38 (OR, 1.2; 95% CI, 1.0-1.3), and MCPyV (OR, 1.1; 95% CI, 1.0-1.3)]. Acquisition of HPV-5 seropositivity during follow-up was associated with SCC risk (OR, 3.2; 95% CI, 1.3-7.6). Persistent seropositivity for HPV-15 was weakly associated with BCC (OR, 1.4; 95% CI, 1.0-1.9) and HPV-6 antibody persistence was weakly associated with SCC (OR, 2.2; 95% CI, 1.0-4.8)., Conclusion: Considering the large number of viruses tested, the weak associations found do not support any strong links between studied HPV and NMSC, with the possible exception of HPV-5 seroconversion and SCC., Impact: Known alpha and beta papillomaviruses do not appear to be risk factors for NMSC. Cancer Epidemiol Biomarkers Prev; 25(4); 721-4. ©2016 AACR., (©2016 American Association for Cancer Research.)

Genital high-risk human papillomaviruses (HPVs) cause cervical cancer and are also found in a small proportion of nonmelanoma skin cancers (NMSCs). We used cancer registry linkages to follow the 856,000 serum donors included in the Southern Sweden Microbiology Biobank or the Janus Biobank in Norway, for incident skin cancers occurring up to 30 years after serum donation. Serum samples taken before diagnosis of squamous cell carcinoma (SCC) (N = 633), basal cell carcinoma (BCC) (N = 1990) or other NMSC (N = 153) and matched samples from control donors were tested for antibodies to the genital HPV types 16 and 18. Both HPV 16 and 18 were associated with increased risk for SCC [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.6 and OR 1.7, 95% CI 1.1-2.5, respectively] and other NMSC (OR 2.3, 95% CI 1.0-5.2 and OR 3.5, 95% CI 1.4-8.7, respectively), but not for BCC. Tumor blocks from HPV16 or 18 seropositive cases were tested with real-time polymerase chain reaction for presence of HPV16 or 18 DNA. No HPV18 DNA was found and only four of 79 SCC cases (two of which were from the perineum/perianal area), one of 221 BCC cases and zero of five cases with other NMSC contained HPV16 DNA. In conclusion, we found prospective evidence that HPV16 and 18 antibodies associate with SCC and other NMSC risk, but not with BCC risk. As only a small proportion of seropositive subjects had evidence of the corresponding HPV DNA in the tumor, most of this excess risk is likely to be due to confounders associated with genital HPV infection., (Copyright © 2013 UICC.)

Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high-grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16-adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk., (© 2013 UICC.)

Cutaneous human papillomaviruses (HPVs) have been associated with squamous cell carcinoma (SCC) in case-control studies, but there are limited data from prospective studies assessing whether virus exposure predicts risk of future cancer development. Two major biobanks, the Southern Sweden Microbiology Biobank (1971-2003) and the Janus Biobank (1973-2003) in Norway, containing samples from 850,000 donors, were searched for incident skin cancer for up to 30 years using registry linkages. Altogether, 2,623 donors with samples taken before diagnosis of SCC or basal cell carcinoma (BCC) of the skin were identified. Prediagnostic samples and samples from 2,623 matched controls were tested for antibodies against 33 types of HPV. Baseline seropositivity to HPV types in genus β species 2 was associated with SCC risk (odds ratio = 1.3, 95% confidence interval: 1.1, 1.7); this was also the case for samples taken more than 18 years before diagnosis (odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). Type-specific persistent seropositivity entailed elevated point estimates for SCC risk for 29 HPV types and decreased point estimates for only 3 types. After multiple hypothesis adjustment, HPV 76 was significantly associated with SCC risk and HPV 9 with BCC risk. In summary, seropositivity for certain HPV types was associated with an increased risk for future development of SCC and BCC.

Background: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects., Methods: Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI., Results: Exposure to HPV16 was the strongest risk factor for cervical cancer [OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3)., Conclusions: A large prospective study has assessed the role of different STIs in cervical cancer., Impact: Prospective evidence supports cofactor role of some STI in cervical cancer.

Background: Attendance in screening is an important determinant of cervical cancer. Previous experience on high-risk human papillomavirus (hrHPV) DNA testing on patient-obtained samples suggests a good effect among nonattendees of screening. We assessed the effects of self-sampling on attendance in the Finnish screening program., Methods: Nonattendees after the primary invitation in one municipality (Espoo) were randomized to receive either a self-sampling kit (2,397 women) or an extra invitation (6,302 women). One fourth (1,315 women) of reminder letter arm nonattendees also received a self-sampling kit as a third intervention. Main outcomes were increases in screening attendance and coverage., Results: The adjusted relative risk for participation by self-sampling as a second intervention in comparison to a reminder letter arm was 1.21 (95% CI: 1.13-1.30). Total attendance increased from 65% to 76% by self-sampling and from 65% to 74% with a reminder letter. Combining the interventions (reminder letter and then self-sampling) increased total attendance from 63% to 78%. One fifth of the participants in all three groups increased screening coverage (previous Pap smear ≥5 years ago or never). Self-obtained samples were more often HPV positive than provider-obtained ones (participants after primary invitation and reminder letter), 12% to 13% versus 7%., Conclusions: Self-sampling is a feasible option in enhancing the attendance at organized screening, particularly as an addition to a reminder letter., Impact: If self-sampling is used as a third intervention after two written invitations, the overall attendance in Finland could most likely reach the desired 80% to 85%.

Purpose: Human papillomavirus (HPV) has been linked to oropharyngeal carcinomas, but its role in laryngeal squamous cell carcinoma (LSCC) is not clear. A prospective multicenter study based on known tumor-cell percentage of fresh frozen carcinoma biopsies was established to determine the HPV prevalence. Moreover risk factors such as smoking, alcohol abuse, chronic laryngitis and gastroesophageal reflux disease (GERD) were evaluated, Methods: Fresh-frozen laryngeal cancer biopsies from 108 patients in Finland, Norway, and Sweden were investigated. Patients whose biopsy samples contained at least 20% tumor tissue (N = 69) entered the study. HPV DNA was determined with MY09/11 and GP5+/6+ nested PCR and SPF10 PCR hybridization assay. Patients were examined by an ENT specialist and an extensive questionnaire concerning risk factors was filled in., Results: Only three patients (4.4%) harbored HPV DNA in their carcinoma sample. Heavy alcohol drinking was associated with an increased risk of death, advanced-stage disease, and younger age at diagnosis. Chronic laryngitis, GERD, and orogenital sex contacts were rare. Poor oral hygiene was not associated with survival, although it correlated with heavy drinking., Conclusion: In our series HPV was not important in LSCC. Heavy drinking led to major mortality in LSCC and promoted early carcinogenesis.

Human papillomaviruses (HPVs, most notably types 16 and 18) cause cervical carcinoma, the second most common cancer among women. Vaccination of adolescents against HPV16/18 might prevent large proportion of cervical and other anogenital cancers. However, because of ethical reasons this cannot be proven by clinical studies. To determine the long-term vaccine efficacy (VE) of HPV16/18 virus-like-particle (VLP) vaccine against cervical carcinoma in situ (CIS+) and invasive cervical carcinoma, the following three population-based cohorts of adolescent women have been enrolled: (1) women vaccinated with the HPV vaccine; (2) women vaccinated with hepatitis A control vaccine; and (3) unvaccinated control women. These cohorts will be passively followed for cumulative incidence of CIS+ endpoints by population-based cancer registry. Overall 24,046 16- to 17-year-old adolescent women from 18 cities in Finland were invited between May 2004 and June 2005 to participate in a phase III trial with bivalent HPV16/18 VLP vaccine. A total of 58,996 18- to 19-year-old women were invited in May 2005 to participate as unvaccinated controls. Women who reported their willingness to participate in an HPV vaccination trial had they been 1-2 years younger were eligible. Cumulative incidence (CI) of CIS+ in our cohorts over 15 years is approximately 0.45%. VE of 70% against CIS+ with 80% power requires 3357-3189 HPV16/18 vaccine recipients, 3357-3189 other vaccine recipients, and 6714-9567 unvaccinated controls. We have now enrolled 2404 HPV16/18 vaccine recipients, 2404 hepatitis A-vaccine recipients, and 5130 unvaccinated controls. This enrolment in addition to our earlier enrolment in another phase III trial guarantees enough power so that by 2020 we can ultimately provide data on the efficacy of HPV16/18 vaccination against CIS+.

Epidemiologic evidence of sexual history has emerged as a consistently found risk factor for prostate cancer. Some studies have reported an association between human papillomavirus (HPV) infections and prostate cancer. We did a nested case-control study within cohorts of more than 200,000 men enrolled in three Nordic biobanking projects. Follow-up using cancer registry linkages identified 804 prospectively occurring prostate cancer cases. Four control subjects per case were randomly selected from eligible sets of matched subjects that were alive and free of cancer at the time of diagnosis of the corresponding case and were matched to cases on biobank cohort, age (+/-2 years), county of residence, and date of blood sampling (+/-2 months in the Finnish and Swedish cohorts, +/-6 months in the Norwegian cohort). The serum samples were analyzed by standard ELISAs for the presence of immunoglobulin G antibodies against HPV types 16, 18, and 33. The joint HPV-16/HPV-18/HPV-33 seroprevalence in the joint cohort was 13.4% (107 of 799) among cases and 14.0% (363 of 2,596) among controls (odds ratio, 0.94; 95% confidence interval, 0.74-1.19). There were no noteworthy differences when the data were analyzed by different HPV type, country, or antibody levels. Our data do not support an association between serologic markers of HPV-16, HPV-18, and HPV-33 infections and risk of prostate cancer.