Human papillomavirus (HPV) assays vary regarding the minimum amount of virus they detect. We investigated analytical thresholds of HPV detection and cervical screening sensitivity and specificity. One hundred cervical intraepithelial neoplasia grade 2 or worse (CIN2+) cases and 200 matched population-based controls were obtained at the Swedish National HPV Reference Laboratory and analyzed by 10 laboratories across 10 countries. Cumulative sensitivity (weighted according to the global HPV type distribution in invasive cervical cancer (ICC)) and specificity were estimated at varying analytical detection thresholds. Consensus results found HPV in 99/100 CIN2+ cases and 52/200 controls. HPV16 prevalence declined in HPV-vaccinated birth cohorts, among both cases and controls. Line plots of 1-specificity and ICC-weighted sensitivity found optimal analytical detection thresholds as 3 International Units (IU)/µl for HPV16/18, 25 IU/µl for HPV31/33/35/45/52/58 and 100 genome equivalents (GE)/µl for HPV 39/51/56/59 resulting in 92.00% cumulative specificity and 90.08% ICC-weighted sensitivity. Thresholds defined using virus amounts per 104 human cells gave similar results. Comparator assay testing using manufacturer-defined thresholds achieved high ICC-weighted sensitivity (96.61%) but low specificity (82.50%). This international collaborative study has identified HPV analytical detection thresholds optimizing the sensitivity and specificity of cervical screening.

The HPValidate study evaluated vaginal HPV self-sampling in the English NHS cervical screening programme. Here we report a secondary objective to examine pre-analytical and analytical technical factors across five workflows, addressing the absence of standardised testing protocols. The workflows included Roche cobas HPV DNA and Hologic APTIMA HPV mRNA assays with Rovers Evalyn® Brush, Copan FLOQSwabs®, and the Hologic Multitest kit. Self-collected samples were compared with clinician-collected samples as the reference standard to establish technical baselines. Outcomes assessed were: (1) sample acceptance; (2) invalid test rates and potential sources of interference (blood, bacterial or fungal growth, participant age, and time from collection to resuspension in 5 ml Hologic ThinPrep® PreservCyt®); and (3) sample stability. Time from self-sample collection to resuspension was identified as a potential determinant of invalid HPV results, with one workflow demonstrating an invalid rate of 5.6% (56/1010) for self-collected samples, compared with no invalid results in matched clinician-collected samples. Following resuspension, samples showed high stability, with reproducibility ranging from (89.4%-100%). These data support the optimisation of laboratory workflows, acceptance criteria, and standardised HPV self-sampling protocols.

BACKGROUND:The clearance of high-risk oncogenic human papillomaviruses (hrHPV) and related cervical lesions is associated with the development of a robust T-cell response. Therapeutic vaccination that induces HPV antigen-specific T cells is a promising approach. METHOD:A 2-vector dosing strategy using Chimpanzee Adenovirus Oxford 1-HPV and Modified Vaccinia virus Ankara-HPV, both encoding the same multiantigen HPV cassette was given on a 0/28-day schedule to participants with persistent cervical hrHPV and a history of low-grade cervical lesions. An open-label lead-in was followed by a randomized, blinded, placebo-controlled main phase. The primary endpoint was the safety of the different dose regimens; secondary endpoints included immunogenicity, and clearance of hrHPV and associated lesions at 12 months. Nine participants were enrolled in the lead-in and 99 were randomized 67:32 to 5 active dose arms or placebo, respectively. RESULTS:The regimens were well-tolerated with no grade 3-related treatment emergent adverse events or serious adverse reactions. All dosing regimens generated antigen-specific CD4+ and CD8+ T-cell responses. There was no difference in hrHPV clearance between the pooled active groups and placebo (20/64 [31.3%] versus 10/30 [33.3%]; P > .99), nor in lesion clearance. A trend toward higher hrHPV clearance (60%) was observed with the highest Chimpanzee Adenovirus Oxford 1-HPV doses. No association between the peripheral immune response and clearance was demonstrated. CONCLUSIONS:A heterologous, multiantigenic HPV 2-component immunotherapy regimen was well-tolerated and immunogenic but did not result in a statistically significant clearance of either hrHPV or the associated cervical lesions in women with persistent high-risk HPV infections. TRIAL REGISTRATION:EudraCT 2019-001890-98; NCT04607850.

AIMS:Given the increasing adoption of self-sampling in cervical cancer screening, it is essential to evaluate the performance of human papillomavirus (HPV) tests in this context. The aim of the present work was to assess the accuracy of the Papilloplex high-risk (HR)-HPV test on self-taken samples. METHODS:Women provided a clinician-taken cervical sample (CS), a urine sample and a vaginal swab according to the VALidation of HUman papillomavirus assays and collection Devices for Self-samples and urine samples protocol. Relative sensitivity and specificity for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) of the Papilloplex HR-HPV assay on self-taken samples versus CS were assessed. Additionally, type-specific concordance and viral load signals (expressed in Ct (crossing thershold) values) between the two self-taken sample types and the CS were evaluated. RESULTS:At the manufacturers' cut-off, the assay showed a relative clinical sensitivity and specificity for CIN2+of 0.95 (95% CI 0.88 to 1.03) and 0.95 (95% CI 0.88 to 1.03) for urine versus CS. Corresponding values for vaginal samples versus CS were 1.05 (95% CI 1.01 to 1.09) and 0.81 (95% CI 0.74 to 0.89). Cut-off optimisation led to relative sensitivity and specificity that included unity for vaginal swabs. Median Ct values were lower in vaginal swabs versus CS, although higher in urine versus CS samples. No relationship between mean Ct values and disease outcome was observed. CONCLUSIONS:The clinical sensitivity of the Papilloplex HR-HPV test was similar on self-collected vaginal swabs and urine compared with CS; clinical specificity on urine was similar to CS yet lower on vaginal samples. Cut-off optimisation resulted in a similar assay specificity on vaginal swabs and CS with no significant detriment to sensitivity.

Background and objectives Gay, bisexual and other men who have sex with men (GBMSM) are at increased risk of anal human papillomavirus (HPV) infection and subsequent development of anal cancer. An opportunistic HPV vaccination programme for GBMSM and those at similar risk for HPV infection was launched in Scotland in July 2017 using the quadrivalent vaccine. We aimed to evaluate the impact of the HPV vaccination programme for GBMSM by monitoring changes in the prevalence of HPV types. Methods A repeated cross-sectional study was undertaken collecting and HPV typing rectal swab samples from men in a city centre sexual health clinic. A baseline sample and three subsequent samples were taken for the 4 years following the introduction of the programme. Results Overall, HPV prevalence was high across all sample years, particularly in 2019/2020. Prevalence of quadrivalent vaccine targeted types decreased by 23% (PR 0.77, 95% CI 0.70 to 0.86, p<0.001) in the most recent sample taken in 2021 compared with the baseline. Other high-risk HPV types increased in each sample year and were 25% higher (PR 1.25, 95% CI 1.12 to 1.40, p<0.001) in the 2021 sample compared with baseline. Conclusions Reductions in vaccine targeted types are encouraging and may reflect direct protection offered by the GBMSM vaccination programme or a combination of direct and modest indirect protection from the routine programme. These findings support HPV vaccination as an effective method of anal cancer prevention.

Vaccination against high-risk HPV has been shown to reduce significantly the incidence of pre-invasive and invasive cervical disease. Clinical trials show immunity and vaccine effectiveness for over 12 years but real-life longitudinal data are lacking. Vaccination with the bivalent vaccine (3 dose schedule) for women aged 12-18 years began in Scotland in 2008; immunised women entered screening in 2010. Women immunised at age12-13 years entered screening in 2015. Linked data from ≤12 years of routine screening activity shows adjusted VE against CIN2+ at age 12-13 of 72·6% (95%CI: 67.7-76.8) and at age 14-16 of 63·2 (CI 60·4-65·8), and against CIN3+ of 81·7 (CI 76·2-78·6; age 12-13) and 68·1 (CI 64·1-71·6; age 14-16) after 3 doses or two doses 5 months apart. Adjusted VE following two doses 1 month apart or one dose only at age14 was 20.5 (95%CI: 6.1-32.6) for CIN2+ and 34.9 (95%CI:17.0-48.9) for CIN3+. No benefit was seen with vaccination over the age of 18 years. The most deprived women showed the highest incidence of CIN2+ and CIN3+, and the greatest reduction in CIN2+ and CIN3+ following complete immunisation. Herd protection is seen in all immunised cohorts. This population based analysis confirms the long-term effectiveness of the bivalent HPV vaccine, greatest in women from the most deprived areas and reinforces the importance of ensuring high vaccine uptake rates at an early age.

Cervical cancer screening is vital for achieving global elimination of this preventable disease. Vaginal self-sampling (VSS) for human papillomavirus (HPV) has the potential to increase screening uptake, particularly among individuals who may be underserved by clinician collection. Expanding self-sampling options with accurate, acceptable collection devices is essential. The Daye diagnostic tampon (DDT) offers an innovative approach, utilizing a tampon for HPV-based detection. This study assessed the diagnostic accuracy of DDT in detecting high-risk HPV infections, using vaginal clinician-collected swabs (CCS) as the reference standard. In this UK-based study, 260 participants provided CCS and VSS (with Copan FLOQSwabs) and DDT samples for HPV testing. Samples were analyzed using the Aptima HPV assay, which detects 14 high-risk HPV types. The sensitivity, specificity, positive predictive value, and negative predictive value of the DDT were evaluated against the CCS. Invalidity rates-HPV-negative results with negative internal controls-were compared across sampling methods. The DDT showed a sensitivity of 82.9% [95% confidence interval (CI): 72.4%-89.9%], specificity of 91.6% (CI: 86.4%-94.9%), and overall accuracy of 89.0% (CI: 84.4%-92.4%) relative to CCS. McNemar's test showed no significant difference between CCS and DDT results (P = 0.845). Valid result rates were highest for DDT (99.2%), followed by VSS (95.4%) and CCS (90.8%). The DDT demonstrates comparable accuracy to CCS for detecting high-risk HPV. This novel device shows promise as a self-sampling method. Furthermore, complementary research should focus on assessing DDT's clinical performance in detecting HPV associated with cervical disease endpoints.IMPORTANCECervical cancer remains a leading preventable cause of cancer death globally, with persistent disparities in screening access. Self-sampling for HPV has emerged as a critical tool to improve screening uptake, particularly among underserved populations, yet device acceptability and diagnostic reliability remain barriers to equitable implementation. This study demonstrates that the Daye diagnostic tampon (DDT), a novel, tampon-based self-sampling method, achieves diagnostic accuracy comparable to clinician-collected swabs (sensitivity 82.9% and specificity 91.6%) while yielding fewer invalid results (0.8%) than conventional swabs. By aligning with a familiar menstrual product, the DDT addresses usability concerns that hinder confidence in existing self-sampling devices, as evidenced by 70.5% participant preference in focus groups. These findings advance progress toward World Health Organisation (WHO) cervical cancer elimination targets by validating a culturally resonant, high-performance alternative to clinic-based sampling. The DDT's potential to expand screening access, especially in low-resource settings or among individuals avoiding pelvic exams, could transform preventive care landscapes, reducing disparities in a disease rooted in healthcare inequity.

Relative test accuracy of human papillomavirus (HPV) testing on self vs. clinician-collected samples may depend on the specific combination of a self-sampling device and HPV assay. Five self-sampling workflows were studied within the routine English cervical screening programme; the cobas HPV DNA and APTIMA HPV mRNA assays with the Evalyn brush, Self Vaginal FLOQSwabs (FLOQSwabs) and the Multitest kit. To study test sensitivity, women were recruited at routine colposcopy appointments; to study test specificity, women were recruited at routine screening appointments. The estimated conditional relative sensitivity for high-grade cervical intraepithelial neoplasia (CIN2+) was 0.90 (90% CI: 0.84–0.94) for the Evalyn + cobas workflow, 0.94 (0.90–0.97) for FLOQSwabs + cobas, 0.77 (0.69–0.83) for Evalyn + APTIMA, 0.92 (0.85–0.96) for FLOQSwabs+APTIMA and 0.92 (0.86–0.96) for Multitest+APTIMA. The estimates of the relative specificity were 0.96 (0.95-0.98), 0.91 (0.90-0.93), 0.99 (0.97–1.01), 0.89 (0.87–0.92) and 0.87 (0.85–0.89), respectively. The specificity estimates were sensitive to the inclusion of certain subgroups of women. HPV detection rates were higher for all self-sample than clinician-sample workflows. The relative test sensitivity of four self-sampling workflows including both DNA and mRNA HPV assays was relatively close to that associated with clinician-collected samples.

High risk human papillomaviruses (hrHPVs) cause most cervical cancers. Cervical screening programmes aim to identify precancerous disease using detection of hrHPV nucleic acid using clinician-taken liquid-based cytology (LBC) samples, or increasingly, self-taken samples (STSs). However, STSs are incompatible with traditional cytology triage. Therefore, development of novel triage tests is essential. Quantification of cellular and viral mRNA biomarkers is one option, but little is known about mRNA quality in STSs. We extracted RNA from two sets of STSs (reflecting separate sampling devices) from the Scottish HPV Archive (SHA) and the Swedish Cervical Cytology Biobank (SCCB). We investigated whether the ACTB, GAPDH and p16 RNAs could be amplified by reverse transcription quantitative PCR (RT-qPCR). RNA was degraded in both sets of samples, but samples from the Scottish HPV Archive were generally suitable for RT-qPCR analysis, while samples from the SCCB were mostly unsuitable. Genomic DNA contamination was detected in 11.6% of samples. The quantity and quality of RNA derived from STSs was unaffected by storage of the original sample at -70°C for a period of 1 year. These data suggest that feasibility of utilising STSs for mRNA expression work is device-dependent and that optimisation of collection and storage systems is warranted.

Background: Human Papillomavirus (HPV) vaccination and HPV-based cervical cancer screening are central pillars of the World Health Organization (WHO) global cervical cancer elimination strategy. The WHO HPV Laboratory Manual, published in 2009, has provided essential guidance to promote an internationally comparable quality of HPV testing for many years. As the development in this area is rapid, the Global Network of National HPV Reference Laboratories considered that there is a need for an updated HPV Laboratory e-Manual to serve as a comprehensive and interactive resource for professionals engaged in quality-assured HPV testing for research and/or HPV-based cancer control. Content: The HPV Laboratory e-Manual covers key areas, including laboratory quality assurance, HPV taxonomy and risk association, collection and handling of specimens, nucleic acid extraction, HPV detection and typing, HPV serology, data management, and the use of international standards. It provides up-to-date protocols and best practices to enhance accuracy and reliability of HPV testing. Interactive features allow for real-time updates, making it a dynamic resource for laboratories worldwide. The e-Manual is freely available at: https://www. hpvcenter.se/hpv-laboratory-manual/. Collaborators: The e-Manual has been developed by international experts from 11 countries, including contrib-utors from the International HPV Reference Center (IHRC, Sweden), the CDC's Global HPV Reference Laboratory (USA), and multiple National HPV Reference Laboratories (NRLs). The standard procedure for writing a chapter was that 2 NRLs authored the chapter and 1 other NRL reviewed it. Conclusion: The HPV Laboratory e-Manual represents a step toward global harmonization in laboratory meth-odologies for HPV testing, underpinning both research and cervical cancer control efforts.

Persistent infection with high-risk human papillomavirus (hrHPV) causes almost all cases of cervical cancer. Despite the success of cervical screening in reducing cervical cancer incidence, novel tests are required to identify patients with HPV infection who do not have clinically significant disease, minimising unnecessary diagnosis and inappropriate treatment. Digital PCR (dPCR) is a technology that can support the identification and validation of mRNA biomarkers as it allows quantification with high precision. In gene expression studies, the use of reference genes is essential for accurate quantification of the target molecule. We investigated the suitability of a panel of eight reference genes (ACTB, GAPDH, RPP30, HPRT1, HMBS, MT-ATP6, UBE2D2 and GUSB) for normalisation of dPCR gene expression data in liquid-based cytology (LBC) samples representing low (CIN1) and high-grade (CIN3) cervical disease. To identify stable candidates, reference genes were compared using geNorm and NormFinder. Results of geNorm analysis indicated that inclusion of the four best performing reference genes (GAPDH, ACTB, GUSB and MT-ATP6) is optimal. GAPDH and ACTB were the most stable genes overall but were expressed at very high levels. Therefore, they may not be suitable for normalisation of dPCR data of putative biomarkers where expression levels are consistently much lower. Instead, we recommend the use of GUSB and HMBS as a stable reference gene pair. These are expressed at a suitable level for accurate normalisation of biomarker expression using dPCR.

The Venus HPV assay (VenusHPV) is a real-time PCR-based human papillomavirus (HPV) test that is widely used in China but lacks extensive clinical validation. The VALidation of HPV GENotyping Tests (VALGENT) framework is an established protocol for evaluating HPV genotyping assays against a standard comparator test. This study aimed to assess the clinical accuracy and reproducibility of the VenusHPV assay following international validation criteria. The clinical performance of VenusHPV was evaluated against the GP5+/6+ PCR-based enzyme immunoassay (GP-EIA) using the VALGENT-4 panel, which included 998 consecutive routine screening samples enriched with 297 samples with abnormal cytology from the Danish cervical cancer screening program. Cases were defined as women diagnosed with histologically confirmed cervical intraepithelial neoplasia 2 or more (CIN2+), while two consecutive negative cytology results served as a proxy for nondisease. Intra- and interlaboratory reproducibility was assessed on 500 samples. Using the manufacturer-recommended cutoff, VenusHPV demonstrated noninferior sensitivity for detection of CIN2+, but its specificity for ≤ CIN1 was inferior to that of GP-EIA. Applying an optimized a posteriori cutoff improved the specificity, yielding relative specificity of 1.02 (95% CI [CI], 1.00-1.03; p noninferiority [pn.inf] < 0.0001), while maintaining a noninferior sensitivity (of 1.02; CI, 1.00-1.08; pn.inf < 0.0001). The intra- and interlaboratory reproducibility was excellent (95.2%, CI, 93.3-97.1%, Kappa [κ] = 0.87 and 94.0%, CI, 92.0%-96.0%, κ = 0.85, respectively). Notably, the reproducibility criteria were met consistently, regardless of whether the unadjusted or optimized cutoff was applied. The VenusHPV was as sensitive as the GP-EIA for detecting cervical precancer using the unadjusted cutoff but less specific. However, after cutoff optimization, VenusHPV met the international accuracy criteria for cervical cancer screening. Additionally, the assay demonstrated excellent reproducibility.

BACKGROUND:Human papillomavirus (HPV) is a common infection of the anogenital tract. Although most infections clear, persistent infections with oncogenic types can predispose to cancer. While the natural history of anogenital HPV infection in cisgendered women is relatively well understood, there are significant knowledge gaps regarding HPV prevalence and clinical implications of genital HPV infection in transgender women (TGW) with neovagina(s). METHODS:A systematic review, including meta-analysis, of studies available in the literature with data on HPV prevalence in TGW with neovaginas was performed. Additionally, a narrative analysis of the clinical manifestations of genital HPV infections in TGW with neovagina(s) was performed. RESULTS:21 studies were included; six focused on the prevalence of HPV in TGW, and data were pooled in a meta-analysis of prevalence; 15 were case reports/series, which were included in a narrative analysis of clinical implications. The meta-analysis showed the prevalence of genital HPV in TGW with neovaginas was 15% (95% CI 9% to 21%). The most frequently detected HPV type was HPV 16. 18 TGW were included in case reports/series and the median age was 42; 12 presented with condylomata acuminata and six had squamous carcinoma. CONCLUSION:Data on genital HPV prevalence in TGW with neovaginas are sparse, with many studies having small denominators. We report higher HPV prevalence compared with cisgendered women. Symptomatic genital HPV infection in TGW with neovaginas was largely associated with benign condylomata, although some carcinoma was detected. Future longitudinal studies are required to elucidate the clinical impact of genital HPV infection and examine its implications in TGW with neovaginas in order to inform prevention and management strategies.

The introduction of self-sampling in cervical cancer screening has raised the importance of HPV test validation on self-collected samples. This study aimed to evaluate the clinical accuracy of the OncoPredict HPV Screening (SCR) assay on self-collected vaginal and first-void urine (FVU) samples, relative to cervical specimens, using the VALHUDES Framework. FVU and vaginal self-samples followed by a clinician-collected cervical brushing were collected from 500 women referred to colposcopy and tested using OncoPredict HPV SCR assay. The assay demonstrated clinical sensitivity to detect cervical intraepithelial neoplasia grade 2 or worse (≥ CIN2) similar to cervical samples in FVU (ratio: 0.95, [95% CI: 0.88-1.02]) and vaginal self-samples (ratio: 0.96 [95% CI: 0.90-1.02]). The clinical specificity for < CIN2 was lower in vaginal (ratio: 0.90 [95% CI: 0.84-0.96]) but not in FVU samples (ratio: 1.03 [95% CI: 0.96-1.12) when compared to cervical samples. However, the relative specificity improved following cut-off optimization (ratio: 0.94, 95% CI: [0.88-1.01]). Moderate to excellent agreement in HPV detection between self-collected and cervical samples was demonstrated (Kappa values: 0.53-1.00). To conclude, OncoPredict HPV SCR assay demonstrated similar accuracy on FVU and cervical samples. On vaginal compared to cervical samples sensitivity was similar with a lower specificity, which improved with cut-off optimization.

Biobanks of cervical screening (LBC) samples annotated with disease status are an invaluable resource to support the development of tools for the risk stratification of disease. Although there is growing interest in the assessment of RNA-based biomarkers, little is known on the suitability and durability of stored clinical samples (commonly used in cervical screening) to support RNA-based research. RNA was extracted from 260 stored LBC samples. Storage at -80°C or -25°C allowed isolation of sufficient RNA for further analysis. RNA was found to be substantially degraded according to Agilent Bioanalyser data. Despite this, RT-qPCR was successful in 95% samples tested. These data suggest that biobanked LBC samples are suitable for RNA-based assessment even if stored for up to 14 years.

To suit the needs of the human papillomaviruses (HPV) community comprehensively, a range of commercial HPV tests with different performance characteristics are required. Four periodic inventories of commercial HPV molecular tests present in the global market were published previously in 2010, 2012, 2015 and 2020. For the fifth inventory, data were retrieved from internal files and a detailed search using the main bibliographic databases as well as general internet search without period or language restrictions was performed in December 2023. At least 264 distinct HPV tests (and 511 test variants) were available globally in December 2023. A small 2020-2023 net increase in total numbers was observed, but with a strong introduction/withdrawal dynamic: 86 new distinct HPV tests (and 141 variants) were introduced and 76 tests (and 55 variants) were withdrawn from the market in the last four years. Although quality improvement of some tests was recorded, half of all HPV tests are still without a single peer-reviewed publication, and 79% of tests are without published evidence that demonstrate performance characteristics are in line with requirements agreed in the HPV community. Only a relatively small pool of tests fulfill the operational/performance characteristics required to meet the global cervical cancer screening challenge. Although clinical and analytical performance characteristics of many commercial HPV tests are largely unknown, such tests are used worldwide in daily clinical practice and research, with potentially deleterious consequences. Due to this long-lasting unfavorable situation, significant scope for improvement persists for both manufacturers of HPV tests and the HPV community.

Background High-risk human papillomavirus causes cervical cancer. Vaccines have been developed that significantly reduce the incidence of preinvasive and invasive disease. This population-based observational study used linked screening, immunization, and cancer registry data from Scotland to assess the influence of age, number of doses, and deprivation on the incidence of invasive disease following administration of the bivalent vaccine.Methods Data for women born between January 1, 1988, and June 5, 1996, were extracted from the Scottish cervical cancer screening system in July 2020 and linked to cancer registry, immunization, and deprivation data. Incidence of invasive cervical cancer per 100 000 person-years and vaccine effectiveness were correlated with vaccination status, age at vaccination, and deprivation; Kaplan Meier curves were calculated.Results No cases of invasive cancer were recorded in women immunized at 12 or 13 years of age irrespective of the number of doses. Women vaccinated at 14 to 22 years of age and given 3 doses of the bivalent vaccine showed a significant reduction in incidence compared with all unvaccinated women (3.2/100 000 [95% confidence interval (CI) = 2.1 to 4.6] vs 8.4 [95% CI = 7.2 to 9.6]). Unadjusted incidence was significantly higher in women from most deprived (Scottish Index of Multiple Deprivation 1) than least deprived (Scottish Index of Multiple Deprivation 5) areas (10.1/100 000 [95% CI = 7.8 to 12.8] vs 3.9 [95% CI = 2.6 to 5.7]). Women from the most deprived areas showed a significant reduction in incidence following 3 doses of vaccine (13.1/100 000 [95% CI = 9.95 to 16.9] vs 2.29 [95% CI = 0.62 to 5.86]).Conclusion Our findings confirm that the bivalent vaccine prevents the development of invasive cervical cancer and that even 1 or 2 doses 1 month apart confer benefit if given at 12-13 years of age. At older ages, 3 doses are required for statistically significant vaccine effectiveness. Women from more deprived areas benefit more from vaccination than those from less deprived areas.