Prevention of Human Papillomavirus Infection. Beyond Cervical Cancer: A Brief Review.

INTRODUCTION: Human papillomavirus is responsible for almost all cases of cervical cancer, an important portion of anogenital and oropharyngeal invasive and preinvasive lesions, as well as genital warts (condyloma acuminatum) and recurrent respiratory papillomatosis. Currently, three prophylactic vaccines against high-risk Human papillomavirus are commercialized in many countries worldwide. METHODS: To this non-systematic review the authors searched in MEDLINE/PubMed for systematic reviews, meta-analysis and randomized controlled trials, published in the last six years, using the terms "HPV", "non-cervical cancer" and "vaccine". Non-cervical cancers caused by human papillomavirus are less common lesions. However, its incidence has been increasing, while cervical cancer has declined, due mainly to highly effective screening programs. There are no formal screening programs for non-cervical cancers, so universal vaccination could have an important impact. The preventive effect of the vaccine is mainly studied and established in relation to cervical cancer, although it has also been demonstrated in the development of vulvar and vaginal lesions. To date, the efficacy in preventing anal and oropharyngeal diseases related with human papillomavirus is uncertain due to scarce supporting data and low vaccination coverage in men. The prevalence of injuries and subsequent absolute benefit of vaccination is lower in men, but it provides an additional benefit to the herd immunity achieved with the vaccination of women. CONCLUSION: The total fraction of malignant and pre-malignant lesions attributed to Human papillomavirus genotypes contained in the nonavalent vaccine is significant in both women and men, which turns this vaccine into a great asset in terms of Public Health.

Introdução: O vírus do papiloma humano é responsável por quase todos os casos de cancro do colo do útero, de uma importante fração de lesões anogenitais e orofaríngeas pré-invasivas e invasivas bem como de condilomas genitais e da papilomatose respiratória recorrente. Atualmente existem três vacinas profiláticas contra o vírus do papiloma humano de alto risco comercializadas em vários países do mundo. Métodos: Para esta revisão não-sistemática, os autores pesquisaram na MEDLINE/PubMed revisões sistemáticas, metanálises e ensaios clínicos randomizados, publicados nos últimos seis anos, utilizando os termos "HPV", "cancro não cervical" e "vacina". Os cancros não cervicais causados pelo vírus do papiloma humano são lesões menos comuns. Contudo, a sua incidência tem aumentado, a par de uma diminuição do cancro do colo do útero, devido principalmente à implementação de programas de rastreio altamente eficazes. Uma vez que não existem programas oficiais de rastreio para cancros não cervicais, a vacinação universal pode ter um impacto importante. O efeito preventivo da vacina é principalmente estudado e estabelecido em relação ao cancro do colo do útero, embora também tenha sido demonstrado no desenvolvimento de lesões vulvares e vaginais. Até ao momento, a eficácia na prevenção de doenças anais e orofaríngeas relacionadas com o vírus do papiloma humano é incerta, devido à escassez de dados na literatura e baixa cobertura de vacinação em homens. A prevalência de lesões e o consequente benefício absoluto da vacinação é inferior nos homens, porém proporciona um benefício adicional à imunidade de grupo alcançada com a vacinação de mulheres. Conclusão: A fração total de lesões malignas e pré-malignas atribuídas aos genótipos de vírus do papiloma humano contidos na vacina nonavalente é significativa tanto em mulheres quanto em homens, o que confere a essa vacina um grande potencial em termos de Saúde Pública.

Prophylactic vaccination against human papillomaviruses to prevent vulval and vaginal cancer and their precursors.

Introduction: Safety and efficacy of prophylactic HPV vaccines against HPV infection and associated cervical cancers and precursors is well documented in the literature; however, their efficacy against vulval and vaginal endpoints has not been previously assessed.Areas covered: Published results of trials involving licensed HPV vaccines were included. Main efficacy outcomes were histologically confirmed high-grade vulval and vaginal precancer distinguishing those associated with vaccine HPV types and any vulval and vaginal precancerous lesions. Exposure groups included women aged 15-26 or 24-45 years being initially negative for high-risk HPV (hrHPV), negative for the HPV vaccine types, and women unselected by HPV status.Expert opinion: Our results show that the HPV vaccines are equally highly efficacious against vulval/vaginal disease as previously noted for cervical disease. The vaccines demonstrated excellent protection against high-grade vulval and vaginal lesions caused by vaccine-related HPV types among young women who were not initially infected with hrHPV types or types included in the vaccines (vaccine efficacies more than 90%). No protection against high-grade vulval and vaginal lesions associated with HPV16/18 was observed for mid-adult women. Trials were not powered to address protection against invasive cancers.

The Potential Role of Medicinal Mushrooms in the Prevention and Treatment of Gynecological Cancers: A Review.

A review of scientific information about the potential role of medicinal mushrooms in the prevention and treatment of gynecological cancers, human immunodeficiency virus, and human papillomavirus infections is reported here. The results of in vivo and in vitro experiments on 16 different species of Basidiomycetes and three Ascomycetes, which possess chemopreventive potential and are effective in clinical application in combination with chemotherapy, are also discussed. Medicinal mushroom extracts confirm an evident efficacy on the reduction of tumor cell proliferation and side effects in patients with gynecological tumors who are undergoing chemotherapy treatments. This review, the first on the use of medicinal mushrooms in the prevention and treatment of gynecological cancers, aims to highlight the remarkable potential of mushrooms in integrated oncology.

Systematic review and evidence synthesis of non-cervical human papillomavirus-related disease health system costs and quality of life estimates.

BACKGROUND: Many economic evaluations of human papillomavirus vaccination should ideally consider multiple disease outcomes, including anogenital warts, respiratory papillomatosis and non-cervical cancers (eg, anal, oropharyngeal, penile, vulvar and vaginal cancers). However, published economic evaluations largely relied on estimates from single studies or informal rapid literature reviews. METHODS: We conducted a systematic review of articles up to June 2016 to identify costs and utility estimates admissible for an economic evaluation from a single-payer healthcare provider's perspective. Meta-analyses were performed for studies that used same utility elicitation tools for similar diseases. Costs were adjusted to 2016/2017 US$. RESULTS: Sixty-one papers (35 costs; 24 utilities; 2 costs and utilities) were selected from 10 742 initial records. Cost per case ranges were US$124-US$883 (anogenital warts), US$6912-US$52 579 (head and neck cancers), US$12 936-US$51 571 (anal cancer), US$17 524-34 258 (vaginal cancer), US$14 686-US$28 502 (vulvar cancer) and US$9975-US$27 629 (penile cancer). The total cost for 14 adult patients with recurrent respiratory papillomatosis was US$137 601 (one paper).Utility per warts episode ranged from 0.651 to 1 (12 papers, various utility elicitation methods), with pooled mean EQ-5D and EQ-VAS of 0.86 (95% CI 0.85 to 0.87) and 0.74 (95% CI 0.74 to 0.75), respectively. Fifteen papers reported utilities in head and neck cancers with range 0.29 (95% CI 0.0 to 0.76) to 0.94 (95% CI 0.3 to 1.0). Mean utility reported ranged from 0.5 (95% CI 0.4 to 0.61) to 0.65 (95% CI 0.45 to 0.75) (anal cancer), 0.59 (95% CI 0.54 to 0.64) (vaginal cancer), 0.65 (95% CI 0.60 to 0.70) (vulvar cancer) and 0.79 (95% CI 0.74 to 0.84) (penile cancer). CONCLUSIONS: Differences in values reported from each paper reflect variations in cancer site, disease stages, study population, treatment modality/setting and utility elicitation methods used. As patient management changes over time, corresponding effects on both costs and utility need to be considered to ensure health economic assumptions are up-to-date and closely reflect the case mix of patients.

HPV vaccine in the treatment of usual type vulval and vaginal intraepithelial neoplasia: a systematic review.

BACKGROUND: HPV DNA is found in almost 80% of VIN/VaIN. Current management is inadequate, with high recurrence rates. Our objective was to review the literature regarding the role of HPV vaccine in secondary prevention and treatment of VIN/VaIN. METHODS: Database searches included Ovid Medline, Embase, Web of Science, The Cochrane Library and Clinicaltrials.gov . Search terms included HPV vaccine AND therapeutic vaccine* AND VIN OR VAIN, published in English with no defined date limit. Searches were carried out with a UCL librarian in March 2018. We included any type of study design using any form of HPV vaccine in the treatment of women with a histologically confirmed diagnosis of VIN/VaIN. We excluded studies of other lower genital tract disease, vulval/vaginal carcinoma and prophylactic use of vaccines. The outcome measures were lesion response to vaccination, symptom improvement, immune response and HPV clearance. RESULTS: We identified 93 articles, 7 studies met our inclusion criteria; these were uncontrolled case series. There were no RCTs or systematic reviews identified. Reduction in lesion size was reported by all 7 studies, symptom relief by 5, HPV clearance by 6, histological regression by 5, and immune response by 6. CONCLUSIONS: This review finds the evidence relating to the use of HPV vaccine in the treatment of women with VIN/VaIN is of very low quality and insufficient to guide practice. Further longitudinal studies are needed to assess its use in prevention of progression to cancer.

Epidemiological dynamic modeling of human papillomavirus-related diseases to assess vaccination strategies in Argentina.

Our objective was to develop and test a dynamic simulation model of human papillomavirus (HPV)-related diseases to assess rational vaccination strategies in Argentina. A dynamic stochastic transmission model for hetero- and homosexual transmission of HPV oncogenic and low-risk oncogenic types among females and males was developed. The model included HPV transmission and vaccination, the natural history of HPV-related diseases, disease outcomes, and cervical cancer screening. Considering all cervical cancers, covered or not by the current quadrivalent vaccine, the existing coverage rate would lead to 60% reduction in the global incidence of cervical cancer at 25 years, and to 79% at 50 years. Isolated current female vaccination without a screening program would need around 100 years to eliminate cervical cancer from the local population. Current coverage rate would lead to 59% reduction of vulvar cancer, 76% of vaginal cancer, 85% of anal cancer, and 87% of oropharyngeal cancer, estimated over a 25-year time prospect. Female HPV vaccination within the context of current cervical cancer screening should reach a minimum long-term mean coverage of 60% of girls, receiving at least a two-dose vaccine schedule, to significantly reduce or virtually eliminate cervical cancer at 50 years. Including vaccination to boys to improve herd immunity did not influence the incidence of cervical cancer over time, as long as female coverage did not fall below 50%. Regarding vulvar, vaginal, anal, penile, and some oropharyngeal cancers, current girls-only based vaccination could virtually eliminate these cancer types after 35-40 years, both in women and men.

Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice.

Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long-peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NP) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV+ cancers. Immunization of TC-1 tumor-bearing mice with a single dose of NP-conjugated E7LP (NP-E7LP) generated a larger pool of E7-specific CD8+ T cells with increased effector functions than unconjugated free E7LP. At the tumor site, NP-E7LP prompted a robust infiltration of CD8+ T cells that was not accompanied by concomitant accumulation of regulatory T cells (Tregs), resulting in a higher CD8+ T-cell to Treg ratio. Consequently, the amplified immune response elicited by the NP-E7LP formulation led to increased regression of large, well-established tumors, resulting in a significant percentage of complete responses that were not achievable by immunizing with the non-NP-conjugated long-peptide. The partial responses were characterized by distinct phases of regression, stable disease, and relapse to progressive growth, establishing a platform to investigate adaptive resistance mechanisms. The efficacy of NP-E7LP could be further improved by therapeutic activation of the costimulatory receptor 4-1BB. This NP-E7LP formulation illustrates a "solid-phase" antigen delivery strategy that is more effective than a conventional free-peptide ("liquid") vaccine, further highlighting the potential of using such formulations for therapeutic vaccination against solid tumors. Cancer Immunol Res; 6(11); 1301-13. ©2018 AACR.

Ten Years of Human Papillomavirus Vaccination in the United States.

Since human papillomavirus (HPV) vaccine was first introduced for females in the United States in 2006, vaccination policy has evolved as additional HPV vaccines were licensed and new data became available. The United States adopted a gender neutral routine HPV immunization policy in 2011, the first country to do so. Vaccination coverage is increasing, although it remains lower than for other vaccines recommended for adolescents. There are various reasons for low coverage, and efforts are ongoing to increase vaccine uptake. The safety profile of HPV vaccine has been well established from 10 years of postlicensure monitoring. Despite low coverage, the early effects of the HPV vaccination program have exceeded expectations.

Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage.

BACKGROUND: Estonia has high cervical cancer incidence and low screening coverage. We modelled the impact of population-based bivalent, quadrivalent or nonavalent HPV vaccination alongside cervical cancer screening. METHODS: A Markov cohort model of the natural history of HPV infection was used to assess the cost-effectiveness of vaccinating a cohort of 12-year-old girls with bivalent, quadrivalent or nonavalent vaccine in two doses in a national, school-based vaccination programme. The model followed the natural progression of HPV infection into subsequent genital warts (GW); premalignant lesions (CIN1-3); cervical, oropharyngeal, vulvar, vaginal and anal cancer. Vaccine coverage was assumed to be 70%. A time horizon of 88years (up to 100years of age) was used to capture all lifetime vaccination costs and benefits. Costs and utilities were discounted using an annual discount rate of 5%. RESULTS: Vaccination of 12-year-old girls alongside screening compared to screening alone had an incremental cost-effectiveness ratio (ICER) of €14,007 (bivalent), €14,067 (quadrivalent) and €11,633 (nonavalent) per quality-adjusted life-year (QALY) in the base-case scenario and ranged between €5367-21,711, €5142-21,800 and €4563-18,142, respectively, in sensitivity analysis. The results were most sensitive to changes in discount rate, vaccination regimen, vaccine prices and cervical cancer screening coverage. CONCLUSION: Vaccination of 12-year-old girls alongside current cervical cancer screening can be considered a cost-effective intervention in Estonia. Adding HPV vaccination to the national immunisation schedule is expected to prevent a considerable number of HPV infections, genital warts, premalignant lesions, HPV related cancers and deaths. Although in our model ICERs varied slightly depending on the vaccine used, they generally fell within the same range. Cost-effectiveness of HPV vaccination was found to be most dependent on vaccine cost and duration of vaccine immunity, but not on the type of vaccine used.

Design of a long-term follow-up effectiveness, immunogenicity and safety study of women who received the 9-valent human papillomavirus vaccine.

The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16-26years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare.

Second-generation prophylactic HPV vaccines: current options and future strategies for vaccines development.

Two vaccines focused on the prevention of HPV-related diseases have been introduced in the last decade, the quadrivalent vaccine Gardasil and the bivalent vaccine Cervarix. They are targeted to prevent precancerous and cancerous lesions not only of the cervix, but also of the vulva, vagina, anal and head-neck region. Furthermore, the protection of the quadrivalent vaccine Gardasil includes also genital warts and recurrent respiratory Papillomatosis, two benign conditions with high socio-economic impact. Although their efficacy in reducing the burden of HPV-related pathologies has been already documented, second-generation HPV vaccines are being developed in order to overcome major limitations, above all the cost of production, distribution and acceptance, thus promoting an easier access to vaccination, especially in developing countries. Recently a new multivalent VLP vaccine active against nine HPV subtypes, called Gardasil 9 (Merck & Co., Inc., Whitehouse Station, NJ, USA), has been approved, showing promising preliminary results. In this article, we outline the strategies adopted for second-generation HPV vaccine engineering, the latest HPV vaccines available at this time, as well as those currently in development.

Reduced dose human papillomavirus vaccination: an update of the current state-of-the-art.

Human papillomavirus (HPV) infection is the primary cause of genital warts, some oropharyngeal cancers and anogenital cancers, including cervical, vagina, vulvar, anal and penile cancers. Primary prevention of cervical cancer requires the prevention of high-risk HPV infections, particularly HPV genotypes 16 and 18. Both Gardasil® and Cervarix® vaccines when administered by a three-dose schedule have been demonstrated to be effective against cervical, vulva, and vaginal cancer precursors from vaccine genotypes in phase III clinical trials, and post-marketing studies; Gardasil® vaccine also offers additional protection against anal cancer precursors. However, high costs of HPV vaccines and the logistics of delivering a three-dose schedule over 6 months are challenging in countries with limited resources. Several studies have demonstrated non-inferiority in antibody response between adolescents (9-15 years old) who received two doses (6 months apart) and women (>15 years old) who received the standard three-dose schedule. These studies provided evidence for the World Health Organization and European Medical Association to revise its recommendation to give two instead of three doses of HPV vaccine to adolescents below 15 years of age, provided the 2nd dose is given 6 months apart. Although reduced dose schedules can alleviate costs and logistics associated with HPV vaccination, especially in resource-poor countries, there are still gaps in this area of research, particularly regarding long-term protection. This review discusses the findings on antibody response and clinical outcomes in studies evaluating reduced dose HPV schedules, and highlights the important considerations of its implementation. In addition, other important immunological biomarkers that may be associated with long-term protection are highlighted and discussed.

Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions.

OBJECTIVE: Human papillomavirus (HPV) vaccines can potentially control cervical cancer and help to reduce other HPV-related cancers. We aimed to estimate the relative contribution (RC) of the nine types (HPVs 16/18/31/33/45/52/58/6/11) included in the recently approved 9-valent HPV vaccine in female anogenital cancers and precancerous lesions (cervix, vulva, vagina and anus). METHODS: Estimations were based on an international study designed and coordinated at the Catalan Institute of Oncology (Barcelona-Spain), including information on 10,575 invasive cervical cancer (ICC), 1709 vulvar, 408 vaginal and 329 female anal cancer cases and 587 Vulvar Intraepitelial Neoplasia grade 2/3 (VIN2/3), 189 Vaginal Intraepitelial Neoplasia grade 2/3 (VaIN2/3) and 29 Anal Intraepitelial Neoplasia grade 2/3 (AIN2/3) lesions. Consecutive histologically confirmed paraffin-embedded cases were obtained from hospital pathology archives from 48 countries worldwide. HPV DNA-detection and typing was performed by SPF10-DEIA-LiPA25 system and RC was expressed as the proportion of type-specific cases among HPV positive samples. Multiple infections were added to single infections using a proportional weighting attribution. RESULTS: HPV DNA prevalence was 84.9%, 28.6%, 74.3% and 90.0% for ICC, vulvar, vaginal and anal cancers, respectively, and 86.7%, 95.8% and 100% for VIN2/3, VaIN2/3 and AIN2/3, respectively. RC of the combined nine HPV types was 89.5% (95% confidence interval (CI): 88.8-90.1)-ICC, 87.1% (83.8-89.9)-vulvar, 85.5% (81.0-89.2)-vaginal, 95.9% (93.0-97.9)-female anal cancer, 94.1% (91.7-96.0)-VIN2/3, 78.7% (71.7-84.2)-VaIN2/3 and 86.2% (68.3-96.1)-AIN2/3. HPV16 was the most frequent type in all lesions. Variations in the RC of HPVs 31/33/45/52/58 by cancer site were observed, ranging from 7.8% (5.0-11.4)-female anal cancer to 20.5% (16.1-25.4)-vaginal cancer. CONCLUSIONS: The addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines (HPV16/18) could prevent almost 90% of HPV positive female anogenital lesions worldwide. Taking into account that most HPV-related cancers are ICC ones, the 9-valent HPV vaccine could potentially avoid almost 88% of all female anogenital cancers.

[AN HPV-ASSOCIATED DISEASES AND CERVICAL CANCER AND PROPHYLACTIC HUMAN PAPILLOMAVIRUS (HPV) VACCINES].

Human papillomavirus (HPV) infection is the central cause of invasive cervical cancer (ICC) and its precursor lesions. Both vaccines can prevent most cases of cervical cancer. In addition, both can prevent vaginal and vulvar cancer in women, and HPV-related cancers. HPV4 can prevent genital warts in women and men. Routine vaccination of 12-year-old girls with HPV4 vaccine appears to be cost-effective in addition to providing both short-term and long-term health gains.

Adjuvant vaginal brachytherapy decreases the risk of vaginal recurrence in patients with stage I non-invasive uterine papillary serous carcinoma. A multi-institutional study.

OBJECTIVES: To investigate the impact of adjuvant vaginal brachytherapy on vaginal recurrence in stage I non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a retrospective multi-institutional study from 2000-2012. 103 patients who underwent surgical treatment with non-invasive stage IA UPSC were included. RESULTS: 85% and 55% underwent staging lymphadenectomy and omentectomy respectively. 28.2% (29/103) developed recurrence. Vaginal, pelvic and extra-pelvic recurrences developed in 7.8% (8/103), 3.9% (4/103) and 16.5% (17/103) respectively. Among patients who were observed or received only chemotherapy, the rate of vaginal recurrence was 10.9% (7/64) compared to 2.6% (1/39) among those who received vaginal brachytherapy +/- chemotherapy (p=0.035). The rate of vaginal recurrence was not different between those who were observed and those who received only chemotherapy (9.3% vs. 14.3%, p=0.27). The 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 88.3% and 90.6%. Patients who underwent surgical staging had longer PFS (p=0.001) and OS (p=0.0005) compared to those who did not. In multivariable analysis controlling for age, histology, chemotherapy, brachytherapy, and staging lymphadenectomy, only lymphadenectomy was an independent predictor of PFS (HR 0.28, 95% CI 0.11-0.71, p=0.0037) and OS (HR 0.27, 95% CI 0.10-0.71, p=0.0035). Neither chemotherapy nor brachytherapy were predictors of PFS or OS. CONCLUSIONS: This is the largest study reported in stage I non-invasive UPSC. The majority of recurrences were extra-pelvic. Vaginal brachytherapy has a significant role in reducing the risk of vaginal recurrence and surgical staging was the only predictor of outcome. Therefore, both should be considered in these patients.

[Nine-valent HPV vaccine - new generation of HPV vaccine]. / Nonavalentní HPV vakcína - nová generace ockování proti HPV.

OBJECTIVE: To evaluate current knowledge about new generation of HPV vaccine - nine-valent vaccine Gardasil9. DESIGN: Review article. RESULTS: The nine-valent vaccine against HPV 6/11/16/18/31/33/45/52/58 could improve efficacy of quadrivalent vaccine from 70 to 90 percent for cervical cancer. In addition this vaccine has covered around85-90% of HPV-related vulvar, vaginal and anal cancers. Efficacy and immunogenicity against HPV 6/11/16/18 is the same as for quadrivalent vaccine. Efficacy against HPV 31/33/45/52/58 associated lesions is 97%.

Targeting human papillomavirus to reduce the burden of cervical, vulvar and vaginal cancer and pre-invasive neoplasia: establishing the baseline for surveillance.

BACKGROUND: Infection with high-risk human papillomavirus (HPV) is causally related to cervical, vulvar and vaginal pre-invasive neoplasias and cancers. Highly effective vaccines against HPV types 16/18 have been available since 2006, and are currently used in many countries in combination with cervical cancer screening to control the burden of cervical cancer. We estimated the overall and age-specific incidence rate (IR) of cervical, vulvar and vaginal cancer and pre-invasive neoplasia in Denmark, Iceland, Norway and Sweden in 2004-2006, prior to the availability of HPV vaccines, in order to establish a baseline for surveillance. We also estimated the population attributable fraction to determine roughly the expected effect of HPV16/18 vaccination on the incidence of these diseases. METHODS: Information on incident cervical, vulvar and vaginal cancers and high-grade pre-invasive neoplasias was obtained from high-quality national population-based registries. A literature review was conducted to define the fraction of these lesions attributable to HPV16/18, i.e., those that could be prevented by HPV vaccination. RESULTS: Among the four countries, the age-standardised IR/105 of cervical, vaginal and vulvar cancer ranged from 8.4-13.8, 1.3-3.1 and 0.2-0.6, respectively. The risk for cervical cancer was highest in women aged 30-39, while vulvar and vaginal cancers were most common in women aged 70+. Age-standardised IR/105 of cervical, vulvar and vaginal pre-invasive neoplasia ranged between 138.8-183.2, 2.5-8.8 and 0.5-1.3, respectively. Women aged 20-29 had the highest risk for cervical pre-invasive neoplasia, while vulvar and vaginal pre-invasive neoplasia peaked in women aged 40-49 and 60-69, respectively. Over 50% of the observed 47,820 incident invasive and pre-invasive cancer cases in 2004-2006 can be attributed to HPV16/18. CONCLUSION: In the four countries, vaccination against HPV 16/18 could prevent approximately 8500 cases of gynecological cancer and pre-cancer annually. Population-based cancer and vaccination registries are essential to assess the predicted public health effects of HPV vaccination.