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Background: Given the accumulating evidence that one-dose vaccination could provide high and sustained protection against human papillomavirus (HPV) infection and related diseases, we examined the population-level effectiveness and efficiency of one-dose HPV vaccination of girls compared with two-dose vaccination, using mathematical modelling., Methods: In this mathematical modelling study, we used HPV-ADVISE LMIC, an individual-based transmission-dynamic model independently calibrated to four epidemiologically diverse low-income and middle-income countries (LMICs; India, Nigeria, Uganda, and Viet Nam). We parameterised and calibrated the model using sexual behaviour and epidemiological data identified from international population-based datasets and the literature. All base-case vaccination scenarios start in 2023 with the nonavalent vaccine and assumed 80% vaccination coverage with one or two doses. We assumed that two doses of vaccine provide 100% efficacy against vaccine-type infections and a lifelong duration of protection. We examined a non-inferior vaccination scenario for one dose compared with two doses, pessimistic scenarios of lower one-dose vaccine efficacy (85%) or a shorter duration of protection (ie, 20 or 30 years), and the effectiveness of a mitigation scenario in which schedules would switch from one dose to two doses. We also did sensitivity analyses by varying vaccination coverage. We used three outcomes: the relative reduction in cervical cancer incidence, the number of cervical cancers averted, and the number of vaccine doses needed to prevent one cervical cancer., Findings: Assuming non-inferior vaccine characteristics for one dose compared with two doses, the model projections show that two-dose or one-dose routine vaccination of girls aged 9 years (with a multi-age cohort vaccination of girls aged 10-14 years) would avert 12·0 million (80% UI 9·5-14·5) cervical cancers in India, 4·7 million (3·4-5·8) in Nigeria, 2·3 million (1·9-2·6) in Uganda, and 0·4 million (0·2-0·5) in Viet Nam over 100 years. Under pessimistic assumptions of lower one-dose efficacy (85%) or a shorter duration of protection (ie, 30 years), one-dose routine vaccination would avert 69% (61-80) to 94% (92-96) of the cervical cancers averted with two-dose routine vaccination. However, when assuming a duration of protection of 20 years, one-dose routine vaccination would avert substantially fewer cervical cancers (ie, 35% [26-44] to 69% [65-71] of the cervical cancers averted with two-dose routine vaccination). A switch from one-dose to two-dose routine vaccination of girls aged 9 years, with a one-dose catch-up of girls aged 10-14 years, 5 years after the start of the vaccination programme, could mitigate potential losses in cervical cancer prevention from a short one-dose duration of protection (averting 92% [83-98] to 99% [97-100]) of the cervical cancers averted with two-dose routine vaccination). One-dose routine vaccination would result in fewer doses needed to prevent one cervical cancer than two-dose routine vaccination, even if the duration of protection is as low as 20 years. Finally, for countries with two-dose routine vaccination, adding one-dose multi-age cohort vaccination in the first year would provide similar benefits as a two-dose multi-age cohort vaccination, and would be more efficient even under the pessimistic assumptions of lower one-dose vaccine efficacy or duration of protection., Interpretation: One-dose routine vaccination could avert most of the cervical cancers averted with two-dose vaccination while being more efficient, provided the duration of one-dose protection is greater than 20-30 years (depending on the LMIC). The doses saved by introducing one-dose routine vaccination could offer the opportunity to vaccinate girls before they age out of the vaccination window of 9-14 years and, potentially, to vaccinate boys or older age groups., Funding: Fonds de recherche du Québec-Santé, Digital Research Alliance of Canada, Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests MB, MD, and MJ are members of the Single-Dose HPV Vaccine Evaluation Consortium, which is funded by the Bill & Melinda Gates Foundation. M-CB acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council and the UK Foreign, Commonwealth & Development Office, under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the EU. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: To eliminate cervical cancer as a public health problem, the World Health Organization had recommended routine vaccination of adolescent girls with two doses of the human papillomavirus (HPV) vaccine before sexual initiation. However, many countries have yet to implement HPV vaccination because of financial or logistical barriers to delivering two doses outside the infant immunisation programme., Methods: Using three independent HPV transmission models, we estimated the long-term health benefits and cost-effectiveness of one-dose versus two-dose HPV vaccination, in 188 countries, under scenarios in which one dose of the vaccine gives either a shorter duration of full protection (20 or 30 years) or lifelong protection but lower vaccine efficacy (e.g. 80%) compared to two doses. We simulated routine vaccination with the 9-valent HPV vaccine in 10-year-old girls at 80% coverage for the years 2021-2120, with a 1-year catch-up campaign up to age 14 at 80% coverage in the first year of the programme., Results: Over the years 2021-2120, one-dose vaccination at 80% coverage was projected to avert 115.2 million (range of medians: 85.1-130.4) and 146.8 million (114.1-161.6) cervical cancers assuming one dose of the vaccine confers 20 and 30 years of protection, respectively. Should one dose of the vaccine provide lifelong protection at 80% vaccine efficacy, 147.8 million (140.6-169.7) cervical cancer cases could be prevented. If protection wanes after 20 years, 65 to 889 additional girls would need to be vaccinated with the second dose to prevent one cervical cancer, depending on the epidemiological profiles of the country. Across all income groups, the threshold cost for the second dose was low: from 1.59 (0.14-3.82) USD in low-income countries to 44.83 (3.75-85.64) USD in high-income countries, assuming one dose confers 30-year protection., Conclusions: Results were consistent across the three independent models and suggest that one-dose vaccination has similar health benefits to a two-dose programme while simplifying vaccine delivery, reducing costs, and alleviating vaccine supply constraints. The second dose may become cost-effective if there is a shorter duration of protection from one dose, cheaper vaccine and vaccination delivery strategies, and high burden of cervical cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The WHO Strategic Advisory Group of Experts recommended that an extended interval of 3-5 years between the two doses of the human papillomavirus (HPV) vaccine could be considered to alleviate vaccine supply shortages. However, three concerns have limited the introduction of extended schedules: girls could be infected between the two doses, the vaccination coverage for the second dose could be lower at ages 13-14 years than at ages 9-10 years, and identifying girls vaccinated with a first dose to give them the second dose could be difficult. Using mathematical modelling, we examined the potential effect of these concerns on the population-level impact and efficiency of extended dose HPV vaccination schedules., Methods: We used HPV-ADVISE, an individual-based, transmission-dynamic model of multitype HPV infection and disease, calibrated to country-specific data for four low-income and middle-income countries (India, Viet Nam, Uganda, and Nigeria). For the extended dose scenarios, we varied the vaccination coverage of the second dose among girls previously vaccinated, the one-dose vaccine efficacy, and the one-dose vaccine duration of protection. We also examined a strategy in which girls aged 14 years were vaccinated irrespective of their previous vaccination status. We used a scenario of girls-only two-dose vaccination at age 9 years (vaccine=9 valent, vaccine-type efficacy=100%, duration of protection=lifetime, and coverage=80%) as our comparator. We estimated two outcomes: the relative reduction in the age-standardised cervical cancer incidence (population-level impact) and the number of cervical cancers averted per 100 000 doses (efficiency)., Findings: Our model projected substantial reductions in cervical cancer incidence over 100 years with the two-dose schedule (79-86% depending on the country), compared with no vaccination. Projections for the 5-year extended schedule, in which the second dose is given only to girls previously vaccinated at age 9 years, were similar to the current two-dose schedule, unless vaccination coverage of the second dose is very low (reductions in cervical cancer incidence of 71-78% assuming 30% coverage at age 14 years among girls vaccinated at age 9 years). However, when the dose at age 14 years is given to girls irrespective of vaccination status and assuming high vaccination coverage, the model projected a substantially greater reduction in cervical cancer incidence compared with the current two-dose schedule (reductions in cervical cancer incidence of 86-93% assuming 70% coverage at age 14 years, irrespective of vaccination status). Efficiency of the extended schedule was greater than the two-dose schedule, even with a drop in vaccination coverage., Interpretation: The three concerns are unlikely to have a substantial effect on the population-level impact of extended dose schedules. Hence, extended dose schedules will likely provide similar cervical cancer reductions as two-dose schedules, while reducing the number of doses required in the short-term, providing a more efficient use of scarce resources, and offering a 5-year time window to reassess the necessity of the second dose., Funding: WHO, Canadian Institute of Health Research Foundation, Fonds de recherche du Québec-Santé, Digital Research Alliance of Canada, and Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests MB, MD, and MJ are members of the Single-Dose HPV Vaccine Evaluation Consortium. EB, J-FL, KP, and M-CB declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Human papillomavirus (HPV) vaccines were first licensed as a three-dose series. Two doses are now widely recommended in some age groups; there are data suggesting high efficacy with one dose. We updated a systematic literature review of HPV vaccine effectiveness by number of doses in observational studies., Methods: We searched Medline and Embase databases from January 1, 2007, through September 29, 2021. Data were extracted and summarized in a narrative synthesis. We also conducted quality assessments for bias due to selection, information, and confounding., Results: Overall, 35 studies were included; all except one were conducted within the context of a recommended three-dose schedule. Evaluations were in countries that used bivalent HPV vaccine (seven), quadrivalent HPV vaccine (27) or both (one). Nine evaluated effectiveness against HPV infection, ten anogenital warts, and 16 cervical abnormalities. All studies were judged to have moderate or serious risk of bias. The biases rated as serious would likely result in lower effectiveness with fewer doses. Investigators attempted to control for or stratify by potentially important variables, such as age at vaccination. Eight studies evaluated impact of buffer periods (lag time) for case counting and 10 evaluated different intervals between doses for two-dose vaccine recipients. Studies that stratified by vaccination age found higher effectiveness with younger age at vaccination, although differences were not all formally tested. Most studies found highest estimates of effectiveness with three doses; significant effectiveness was found among 28/29 studies that evaluated three doses, 19/29 that evaluated two doses, and 18/30 that evaluated one dose. Some studies that adjusted or stratified analyses by age at vaccination found similar effectiveness with three, two and one doses., Conclusion: Observational studies of HPV vaccine effectiveness have many biases. Studies examining persons vaccinated prior to sexual activity and using methods to reduce sources of bias are needed for valid effectiveness estimates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. LM, MD, MJ, JMB, GO, ARK, and MB are members of the Single-Dose HPV vaccine evaluation consortium., (Published by Elsevier Ltd.)

Background: Introduction of human papillomavirus (HPV) vaccination has been slow in low-income and middle-income countries (LMICs) because of resource constraints and worldwide shortage of vaccine supplies. To help inform WHO recommendations, we modelled various HPV vaccination strategies to examine the optimal use of limited vaccine supplies and best allocation of scarce resources in LMICs in the context of the WHO global call to eliminate cervical cancer as a public health problem., Methods: In this mathematical modelling analysis, we developed HPV-ADVISE LMIC, a transmission-dynamic model of HPV infection and diseases calibrated to four LMICs: India, Vietnam, Uganda, and Nigeria. For different vaccination strategies that encompassed use of a nine-valent vaccine (or a two-valent or four-valent vaccine assuming high cross-protection), we estimated three outcomes: reduction in the age-standardised rate of cervical cancer, number of doses needed to prevent one case of cervical cancer (NNV; as a measure of efficiency), and the incremental cost-effectiveness ratio (ICER; in 2017 international $ per disability-adjusted life-year [DALY] averted). We examined different vaccination strategies by varying the ages of routine HPV vaccination and number of age cohorts vaccinated, the population targeted, and the number of doses used. In our base case, we assumed 100% lifetime protection against HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58; vaccination coverage of 80%; and a time horizon of 100 years. For the cost-effectiveness analysis, we used a 3% discount rate. Elimination of cervical cancer was defined as an age-standardised incidence of less than four cases per 100 000 woman-years., Findings: We predicted that HPV vaccination could lead to cervical cancer elimination in Vietnam, India, and Nigeria, but not in Uganda. Compared with no vaccination, strategies that involved vaccinating girls aged 9-14 years with two doses were predicted to be the most efficient and cost-effective in all four LMICs. NNV ranged from 78 to 381 and ICER ranged from $28 per DALY averted to $1406 per DALY averted depending on the country. The most efficient and cost-effective strategies were routine vaccination of girls aged 14 years, with or without a later switch to routine vaccination of girls aged 9 years, and routine vaccination of girls aged 9 years with a 5-year extended interval between doses and a catch-up programme at age 14 years. Vaccinating boys (aged 9-14 years) or women aged 18 years or older resulted in substantially higher NNVs and ICERs., Interpretation: We identified two strategies that could maximise efforts to prevent cervical cancer in LMICs given constraints on vaccine supplies and costs and that would allow a maximum of LMICs to introduce HPV vaccination., Funding: World Health Organization, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, PATH, and The Bill & Melinda Gates Foundation., Translations: For the French and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The WHO Director-General has issued a call for action to eliminate cervical cancer as a public health problem. To help inform global efforts, we modelled potential human papillomavirus (HPV) vaccination and cervical screening scenarios in low-income and lower-middle-income countries (LMICs) to examine the feasibility and timing of elimination at different thresholds, and to estimate the number of cervical cancer cases averted on the path to elimination., Methods: The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), which consists of three independent transmission-dynamic models identified by WHO according to predefined criteria, projected reductions in cervical cancer incidence over time in 78 LMICs for three standardised base-case scenarios: girls-only vaccination; girls-only vaccination and once-lifetime screening; and girls-only vaccination and twice-lifetime screening. Girls were vaccinated at age 9 years (with a catch-up to age 14 years), assuming 90% coverage and 100% lifetime protection against HPV types 16, 18, 31, 33, 45, 52, and 58. Cervical screening involved HPV testing once or twice per lifetime at ages 35 years and 45 years, with uptake increasing from 45% (2023) to 90% (2045 onwards). The elimination thresholds examined were an average age-standardised cervical cancer incidence of four or fewer cases per 100 000 women-years and ten or fewer cases per 100 000 women-years, and an 85% or greater reduction in incidence. Sensitivity analyses were done, varying vaccination and screening strategies and assumptions. We summarised results using the median (range) of model predictions., Findings: Girls-only HPV vaccination was predicted to reduce the median age-standardised cervical cancer incidence in LMICs from 19·8 (range 19·4-19·8) to 2·1 (2·0-2·6) cases per 100 000 women-years over the next century (89·4% [86·2-90·1] reduction), and to avert 61·0 million (60·5-63·0) cases during this period. Adding twice-lifetime screening reduced the incidence to 0·7 (0·6-1·6) cases per 100 000 women-years (96·7% [91·3-96·7] reduction) and averted an extra 12·1 million (9·5-13·7) cases. Girls-only vaccination was predicted to result in elimination in 60% (58-65) of LMICs based on the threshold of four or fewer cases per 100 000 women-years, in 99% (89-100) of LMICs based on the threshold of ten or fewer cases per 100 000 women-years, and in 87% (37-99) of LMICs based on the 85% or greater reduction threshold. When adding twice-lifetime screening, 100% (71-100) of LMICs reached elimination for all three thresholds. In regions in which all countries can achieve cervical cancer elimination with girls-only vaccination, elimination could occur between 2059 and 2102, depending on the threshold and region. Introducing twice-lifetime screening accelerated elimination by 11-31 years. Long-term vaccine protection was required for elimination., Interpretation: Predictions were consistent across our three models and suggest that high HPV vaccination coverage of girls can lead to cervical cancer elimination in most LMICs by the end of the century. Screening with high uptake will expedite reductions and will be necessary to eliminate cervical cancer in countries with the highest burden., Funding: WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, National Health and Medical Research Council Australia Centre for Research Excellence in Cervical Cancer Control., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aimed to systematically review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants., Methods: Medline, EMBASE, Global Health Database and Cochrane Central Register of Controlled Trials were searched for publications and conference abstracts (dated January 1999-August 2018) using MeSH and non-MeSH terms for human papillomavirus AND vaccines AND (immunogenicity OR efficacy/effectiveness) AND dosage. Search results were screened against pre-specified eligibility criteria. Data were extracted from included articles, and a narrative synthesis conducted on efficacy against HPV16/18 infection and humoral immunogenicity., Results: Seven of 6,523 unique records identified were included in the review. Six were nested observational studies of participants randomised to receive two or three doses in three large HPV vaccine trials, in which some participants did not complete their allocated schedules. One small pilot study prospectively allocated participants to receive one or no vaccine dose. Frequency of HPV16/18 infection was low (e.g. <1% for 12-month-persistent infection) in all vaccinated participants up to seven years post vaccination and did not significantly differ by number of doses (p > 0.05 in all cases). Frequency of infection was significantly lower in one-dose recipients compared to unvaccinated controls (p < 0.01 for all infection endpoints in each study). HPV16/18 seropositivity rates were high in all HPV vaccine recipients (100% in three of four studies reporting this endpoint), though antibody levels were lower with one compared to two or three doses., Conclusions: This review supports the premise that one HPV vaccine dose may be as effective in preventing HPV infection as multi-dose schedules in healthy young women. However, it also highlights the paucity of available evidence from purpose-designed, prospectively-randomised trials. Results from ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination compared to currently-recommended schedules are awaited., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

Background: In the United States, the routine age for human papillomavirus (HPV) vaccination is 11 to 12 years, with catch-up vaccination through age 26 years for women and 21 years for men. U.S. vaccination policy on use of the 9-valent HPV vaccine in adult women and men is being reviewed., Objective: To evaluate the added population-level effectiveness and cost-effectiveness of extending the current U.S. HPV vaccination program to women aged 27 to 45 years and men aged 22 to 45 years., Design: The analysis used HPV-ADVISE (Agent-based Dynamic model for VaccInation and Screening Evaluation), an individual-based transmission dynamic model of HPV infection and associated diseases, calibrated to age-specific U.S. data., Data Sources: Published data., Target Population: Women aged 27 to 45 years and men aged 22 to 45 years in the United States., Time Horizon: 100 years., Perspective: Health care sector., Intervention: 9-valent HPV vaccination., Outcome Measures: HPV-associated outcomes prevented and cost-effectiveness ratios., Results of Base-Case Analysis: The model predicts that the current U.S. HPV vaccination program will reduce the number of diagnoses of anogenital warts and cervical intraepithelial neoplasia of grade 2 or 3 and cases of cervical cancer and noncervical HPV-associated cancer by 82%, 80%, 59%, and 39%, respectively, over 100 years and is cost saving (vs. no vaccination). In contrast, extending vaccination to women and men aged 45 years is predicted to reduce these outcomes by an additional 0.4, 0.4, 0.2, and 0.2 percentage points, respectively. Vaccinating women and men up to age 30, 40, and 45 years is predicted to cost $830 000, $1 843 000, and $1 471 000, respectively, per quality-adjusted life-year gained (vs. current vaccination)., Results of Sensitivity Analysis: Results were most sensitive to assumptions about natural immunity and progression rates after infection, historical vaccination coverage, and vaccine efficacy., Limitation: Uncertainty about the proportion of HPV-associated disease due to infections after age 26 years and about the level of herd effects from the current HPV vaccination program., Conclusion: The current HPV vaccination program is predicted to be cost saving. Extending vaccination to older ages is predicted to produce small additional health benefits and result in substantially higher incremental cost-effectiveness ratios than the current recommendation., Primary Funding Source: Centers for Disease Control and Prevention.

Background: More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination., Methods: In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks., Findings: We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5-8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0·17, 95% CI 0·11-0·25) among girls aged 13-19 years, and decreased significantly by 66% (RR 0·34, 95% CI 0·23-0·49) among women aged 20-24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0·46, 95% CI 0·33-0·66) among girls aged 13-19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0·33, 95% CI 0·24-0·46) among girls aged 15-19 years, decreased significantly by 54% (RR 0·46, 95% CI 0.36-0.60) among women aged 20-24 years, and decreased significantly by 31% (RR 0·69, 95% CI 0·53-0·89) among women aged 25-29 years. Among boys aged 15-19 years anogenital wart diagnoses decreased significantly by 48% (RR 0·52, 95% CI 0·37-0·75) and among men aged 20-24 years they decreased significantly by 32% (RR 0·68, 95% CI 0·47-0·98). After 5-9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0·49, 95% CI 0·42-0·58) among screened girls aged 15-19 years and decreased significantly by 31% (RR 0·69, 95% CI 0·57-0·84) among women aged 20-24 years., Interpretation: This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects., Funding: WHO, Canadian Institutes of Health Research, Fonds de recherche du Québec - Santé., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Human papillomavirus (HPV) vaccines were first licensed as a three-dose series; a two-dose series is now recommended in some age groups and there is interest in possible one-dose vaccination., Methods: We conducted a systematic literature review of HPV vaccine effectiveness by number of doses, including assessment of biases and impact of varying buffer periods (time between vaccination and outcome counting)., Results: Of 3787 articles identified, 26 full articles were assessed and 14 included in our review. All studies were conducted within the context of recommended three-dose schedules of bivalent (3) or quadrivalent HPV vaccine (11). Two evaluated effectiveness for prevention of HPV prevalence, six anogenital warts, and six abnormal cervical cytology or histology. Many studies found differences between three-, two- and one-dose vaccine recipients, indicating possible differences in HPV exposure prior to vaccination or in risk behavior. Adjusted or stratified analyses were conducted to control for potential confounding. All studies found significant vaccine effectiveness with three doses, 11 with two doses at various intervals, and six with one dose. Most studies showed a relationship (not always statistically significant) between effectiveness and number of doses, with greater decreases in HPV-related outcomes with three, followed by two and one dose(s). Few studies conducted formal comparisons of three vs fewer doses. Three of four studies that examined buffer periods found higher effectiveness and a smaller difference by number of doses with longer periods., Conclusion: Most post-licensure studies report highest effectiveness with three doses; some found no statistically significant difference between two and three doses. Additionally, almost half found some effectiveness with one dose. Several biases impact estimates, with most biasing two- and one-dose results away from showing effectiveness. Future effectiveness studies, examining persons vaccinated prior to sexual activity and using methods to reduce potential sources of bias, can help inform vaccination policy., (Published by Elsevier Ltd.)

We used transmission-dynamic modeling to estimate the added effectiveness of vaccinating multiple cohorts of females (12-26 years) in Australia compared with the theoretical introduction of routine-only (12-13 years) vaccination. Our results suggest that vaccinating multiple cohorts produced markedly faster direct/herd effects, and it added benefits that last for 20-70 years. Furthermore, the number needed to vaccinate to prevent 1 anogential warts (AGW) case or cervical cancer (CC) was similar for routine + catch-up (AGW = 9.9, CC = 678) and routine-only vaccination (AGW = 9.9, CC = 677), thus providing similar levels of efficiency per person vaccinated., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: Previous HPV models have only included genital transmission, when evidence suggests that transmission between several anatomical sites occurs. We compared model predictions of population-level HPV vaccination effectiveness against genital HPV16 infection in women, using a 1) uni-site (genital site), and a 2) multi-site model (genital and one extragenital site)., Methods: We developed a uni-site and a multi-site deterministic HPV transmission model, assuming natural immunity was either site-specific or systemic. Both models were calibrated to genital HPV16 prevalence (5%-7.5%), whilst the multi-site model was calibrated to HPV16 prevalence representative of oral (0%-1%) and anal (1%-7.5%) sites. For each model, we identified 2500 parameter sets that fit endemic genital and extragenital prevalences within pre-specified target ranges. In the Base-case analysis, vaccination was girls-only with 40% coverage. Vaccine efficacy was 100% for all sites with lifetime protection. The outcome was the relative reduction in genital HPV16 prevalence among women at post-vaccination equilibrium (RRprev). RRprev was stratified by extragenital prevalence pre-vaccination., Results: Under assumptions of site-specific immunity, RRprev with the multi-site model was generally greater than with the uni-site model. Differences between the uni-site and multi-site models were greater when transmission from the extragenital site to the genital site was high. Under assumptions of systemic immunity, the multi-site and uni-site models yielded similar RRprev in the scenario without immunity after extragenital infection. In the scenario with systemic immunity after extragenital infection, the multi-site model yielded lower predictions of RRprev than the uni-site model., Conclusions: Modelling genital-site only transmission may overestimate vaccination impact if extragenital infections contribute to systemic natural immunity or underestimate vaccination impact if a high proportion of genital infections originate from extragenital infections. Under current understanding of heterosexual HPV transmission and immunity, a substantial bias from using uni-site models in predicting vaccination effectiveness against genital HPV infection is unlikely to occur., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination., Methods: We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RR prev ) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI])., Findings: 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RR prev of HPV 16 among women and men was 0·53 (80% UI 0·46-0·68) and 0·36 (0·28-0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RR prev of HPV 16 among women and men was 0·93 (0·90-1·00) and 0·83 (0·75-1·00), respectively. Vaccinating boys in addition to girls increased the RR prev of HPV 16 among women and men by 0·18 (0·13-0·32) and 0·35 (0·27-0·39) for 40% coverage, and 0·07 (0·00-0·10) and 0·16 (0·01-0·25) for 80% coverage, respectively. The RR prev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RR prev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years)., Interpretation: Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time., Funding: Canadian Institutes of Health Research., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

We analyzed human papillomavirus (HPV) prevalences during prevaccination and postvaccination periods to consider possible changes in nonvaccine HPV genotypes after introduction of vaccines that confer protection against 2 high-risk types, HPV16 and HPV18. Our meta-analysis included 9 studies with data for 13,886 girls and women ≤19 years of age and 23,340 women 20-24 years of age. We found evidence of cross-protection for HPV31 among the younger age group after vaccine introduction but little evidence for reductions of HPV33 and HPV45. For the group this same age group, we also found slight increases in 2 nonvaccine high-risk HPV types (HPV39 and HPV52) and in 2 possible high-risk types (HPV53 and HPV73). However, results between age groups and vaccines used were inconsistent, and the increases had possible alternative explanations; consequently, these data provided no clear evidence for type replacement. Continued monitoring of these HPV genotypes is important.

A recent clinical trial using the 9-valent human papillomavirus virus (HPV) vaccine has shown that antibody responses after 2 doses are noninferior to those after 3 doses, suggesting that 2 and 3 doses may have comparable vaccine efficacy. We used an individual-based transmission-dynamic model to compare the population-level effectiveness and cost-effectiveness of 2- and 3-dose schedules of 9-valent HPV vaccine in the United States. Our model predicts that if 2 doses of 9-valent vaccine protect for ≥20 years, the additional benefits of a 3-dose schedule are small as compared to those of 2-dose schedules, and 2-dose schedules are likely much more cost-efficient than 3-dose schedules., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Human papillomavirus (HPV) vaccination programs have been implemented in more than 50 countries. These programs offer tremendous promise of reducing HPV-related disease burden. However, failure to achieve high coverage among high-risk groups may mitigate program success and increase inequalities. We examined sociodemographic inequalities in HPV vaccination coverage in 4 Canadian provinces (Quebec (QC), Ontario (ON), Manitoba (MB), British Columbia (BC))., Methods: We obtained annual HPV vaccination coverage of pre-adolescent girls at provincial and regional levels, from the start of programs to 2012/2013. Regions refer to administrative areas responsible for vaccine implementation and monitoring (there are 18/36/10/16 regions in QC/ON/MB/BC). We obtained regions' sociodemographic characteristics from Statistics Canada Census. We used univariate weighted linear regression to examine the associations between regions' sociodemographic characteristics and HPV vaccination coverage., Results: Provincial HPV vaccination coverage is generally high (QC:78%; ON:80%; MB:64%, BC:69%, 2012/13). QC had the highest provincial vaccination coverage since the program start, but had the greatest inequalities. In QC, regional HPV vaccination coverage was lower in regions with higher proportions of socially deprived individuals, immigrants, and/or native English speakers (p<0.0001). These inequalities remained stable over time. Regional-level analysis did not reveal inequalities in ON, MB and BC., Conclusion: School-based HPV vaccination programs have resulted in high vaccination coverage in four Canadian provinces. Nonetheless, high overall coverage did not necessarily translate into equality in coverage. Future work is needed to understand underlying causes of inequalities and how this could impact existing inequalities in HPV-related diseases and overall program success., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Randomized clinical trials have shown the 9-valent human papillomavirus (HPV) vaccine to be highly effective against types 31/33/45/52/58 compared with the 4-valent. Evidence on the added health and economic benefit of the 9-valent is required for policy decisions. We compare population-level effectiveness and cost-effectiveness of 9- and 4-valent HPV vaccination in the United States., Methods: We used a multitype individual-based transmission-dynamic model of HPV infection and disease (anogenital warts and cervical, anogenital, and oropharyngeal cancers), 3% discount rate, and societal perspective. The model was calibrated to sexual behavior and epidemiologic data from the United States. In our base-case, we assumed 95% vaccine-type efficacy, lifelong protection, and a cost/dose of $145 and $158 for the 4- and 9-valent vaccine, respectively. Predictions are presented using the mean (80% uncertainty interval [UI] = 10(th)-90(th) percentiles) of simulations., Results: Under base-case assumptions, the 4-valent gender-neutral vaccination program is estimated to cost $5500 (80% UI = 2400-9400) and $7300 (80% UI = 4300-11 000)/quality-adjusted life-year (QALY) gained with and without cross-protection, respectively. Switching to a 9-valent gender-neutral program is estimated to be cost-saving irrespective of cross-protection assumptions. Finally, the incremental cost/QALY gained of switching to a 9-valent gender-neutral program (vs 9-valent girls/4-valent boys) is estimated to be $140 200 (80% UI = 4200->1 million) and $31 100 (80% UI = 2100->1 million) with and without cross-protection, respectively. Results are robust to assumptions about HPV natural history, screening methods, duration of protection, and healthcare costs., Conclusions: Switching to a 9-valent gender-neutral HPV vaccination program is likely to be cost-saving if the additional cost/dose of the 9-valent is less than $13. Giving females the 9-valent vaccine provides the majority of benefits of a gender-neutral strategy., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations., Methods: We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and χ(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure., Findings: We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19-0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22-0·71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54-0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47-0·91]) and in women 20-39 years of age (0·68 [95% CI 0·51-0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34-0·74]) and in anogenital warts (0·86 [95% CI 0·79-0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects., Interpretation: Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement., Funding: The Canadian Institutes of Health Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Inequalities in cervical cancer may be increased following mass vaccination against the human papillomavirus (HPV) if girls with low vaccine uptake also have low future participation in cervical cancer screening. We evaluated how vaccine uptake distribution affects inequalities in squamous cell carcinoma (SCC) incidence between groups with different screening participation., Methods: We used an individual-based transmission dynamic model of HPV infection and disease (HPV-ADVISE). Females were stratified by routine screening frequency. We modeled the impact of vaccination on SCC incidence rate differences (absolute inequality) and incidence rate ratios (relative inequality) between women who have routine screening intervals of <5 years (frequently screened), ≥5 years (underscreened), and who are never screened. We compared simulations with uniform vaccine uptake with scenarios with unequal vaccine uptake, in which never and underscreened women have lower vaccine uptake than frequently screened women., Results: Absolute SCC inequalities between groups with different screening rates were predicted to decrease after vaccination, even when women with the lowest screening participation had the lowest vaccine uptake. Herd effects helped reduce absolute inequalities when vaccine uptake was unequal. Conversely, relative SCC inequalities remained unchanged or increased after vaccination. Results were robust to different overall vaccination coverages and sexual mixing scenarios., Conclusion: Though mass HPV vaccination is predicted to substantially decrease SCC incidence rates, never screened women will still have the highest disease burden after vaccination., Impact: To reduce both absolute and relative SCC inequalities, public health initiatives will need to address inequalities in both vaccine uptake and in cervical cancer screening participation., (©2014 American Association for Cancer Research.)

Background: Recent evidence suggests that two doses of HPV vaccines may be as protective as three doses in the short-term. We estimated the incremental cost-effectiveness of two- and three-dose schedules of girls-only and girls & boys HPV vaccination programmes in Canada., Methods: We used HPV-ADVISE, an individual-based transmission-dynamic model of multi-type HPV infection and diseases (anogenital warts, and cancers of the cervix, vulva, vagina, anus, penis and oropharynx). We conducted the analysis from the health payer perspective, with a 70-year time horizon and 3% discount rate, and performed extensive sensitivity analyses, including duration of vaccine protection and vaccine cost., Findings: Assuming 80% coverage and a vaccine cost per dose of $85, two-dose girls-only vaccination (vs. no vaccination) produced cost/quality-adjusted life-year (QALY)-gained varying between $7900-24,300. The incremental cost-effectiveness ratio of giving the third dose to girls (vs. two doses) was below $40,000/QALY-gained when: (i) three doses provide longer protection than two doses and (ii) two-dose protection was shorter than 30 years. Vaccinating boys (with two or three doses) was not cost-effective (vs. girls-only vaccination) under most scenarios investigated., Interpretation: Two-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Two-dose human papillomavirus (HPV) vaccine schedules may provide short-term protection but their long-term population impact is unknown., Methods: Two models of HPV transmission and associated cervical disease (squamous and glandular, neoplasia and cancer) were fitted to data from England and Canada on HPV epidemiology, sexual behaviour, cervical screening outcomes and cervical cancer incidence., Results: Models suggest that at 40-80% coverage, if two-dose schedules protect vaccinees for 20 years, then the benefits of the third dose are small. If two doses protect for 10 years, then the third dose may prevent as many cancers as the first two. At 80% coverage, numbers needed to receive a third dose to prevent an additional cancer are 5900-110,000 (England), 3000-5100 (Canada) with 20 years two-dose protection, and 2000-5300 (England), 760-950 (Canada) with 10 years two-dose protection., Conclusion: Results enable decision makers to quantify risks associated with two-dose schedules despite remaining uncertainties in vaccine duration and cross-protection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Randomized clinical trials are currently examining the efficacy of a nonavalent human papillomavirus (HPV) vaccine, including HPV-types 6/11/16/18/31/33/45/52/58. Evidence on the cost-effectiveness of the nonavalent is required for timely policy-decisions. We compared the potential cost-effectiveness of the nonavalent and quadrivalent HPV vaccines. We used a multi-type individual-based transmission-dynamic model of HPV infection and diseases, 70-year time-horizon, 3% discount rate and healthcare payer perspective. We calibrated the model to Canadian sexual behavior and epidemiologic data, and estimated Quality-Adjusted Life-Years (QALYs) lost and costs ($CAN 2010) from the literature. Under base-case assumptions (vaccinating 10-year-old girls, 80% coverage, 95$/dose, vaccine-type efficacy = 95%, cross-protection for the quadrivalent vaccine, duration of vaccine-type protection (cross-protection) = 20 (10) years), using the quadrivalent and nonavalent vaccines is estimated to cost $15,528 [12,056; 19,140] and $12,203 [9,331; 17,292] per QALY-gained, respectively. At equal price, the nonavalent vaccine is more cost-effective than the quadrivalent vaccine, even when assuming both shorter duration of protection (nonavalent = 20 years vs. quadrivalent = lifelong) and lower vaccine-type efficacy (nonavalent = 85% vs. quadrivalent = 95%). However, the additional cost per dose of the nonavalent vaccine should not exceed $11 to remain more cost-effective than the quadrivalent vaccine, and $24 to represent a cost-effective alternative to the quadrivalent vaccine (using a $40,000/QALY-gained threshold). The nonavalent vaccine can be a cost-effective alternative to the quadrivalent vaccine, even in scenarios where nonavalent vaccine efficacy is 85%. However, because most cervical cancers are caused by HPV-16/18, it is unlikely that the nonavalent would be used if its efficacy against these types is lower than current HPV vaccines., (© 2013 UICC.)

Background: The quadrivalent and bivalent human papillomavirus (HPV) vaccines are now licensed in several countries. We compared the cost-effectiveness of the HPV vaccines to provide evidence for policy decisions., Methods: We developed HPV-ADVISE, a multi-type individual-based transmission-dynamic model of HPV infection and disease (anogenital warts, and cervical, anogenital and oropharyngeal cancers). We calibrated the model to sexual behavior and epidemiologic data from Canada, and estimated quality-adjusted life-years (QALYs) lost and costs ($CAN 2010) from the literature. Vaccine-type efficacy was based on a systematic literature review. The analysis was performed from the healthcare provider perspective, and costs and benefits were discounted at 3%. Predictions are presented using the median [10th;90th percentiles] of simulations., Results: Under base-case assumptions (vaccinating 10-year-old girls, 80% coverage, $95/dose), using the quadrivalent and bivalent vaccines is estimated to cost $15,528 [12,056;19,140] and $20,182 [15,531;25,240] per QALY-gained, respectively. At equal price, the quadrivalent vaccine is more cost-effective than bivalent under all scenarios investigated, except when assuming longer duration of protection for the bivalent and minimal anogenital warts burden. Under base-case assumptions, the maximum additional cost per dose for the quadrivalent vaccine to remain more cost-effective than the bivalent is $32 [17;46] (using a $40,000/QALY-gained threshold). Results were most sensitive to discounting, time-horizon, differences in durations of protection and anogenital warts burden., Conclusions: Vaccinating pre-adolescent girls against HPV is predicted to be highly cost-effective. If equally priced, the quadrivalent is the most economically desirable vaccine. However, ultimately, the most cost-effective HPV vaccine will be determined by their relative price., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Decision-makers may consider vaccinating girls and boys with different HPV vaccines to benefit from their respective strengths; the quadrivalent (HPV4) prevents anogenital warts (AGW) whilst the bivalent (HPV2) may confer greater cross-protection. We compared, to a girls-only vaccination program with HPV4, the impact of vaccinating: 1) both genders with HPV4, and 2) boys with HPV4 and girls with HPV2., Methods: We used an individual-based transmission-dynamic model of heterosexual HPV infection and diseases. Our base-case scenario assumed lifelong efficacy of 100% against vaccine types, and 46,29,8,18,6% and 77,43,79,8,0% efficacy against HPV-31,-33,-45,-52,-58 for HPV4 and HPV2, respectively., Results: Assuming 70% vaccination coverage and lifelong cross-protection, vaccinating boys has little additional benefit on AGW prevention, irrespective of the vaccine used for girls. Furthermore, using HPV4 for boys and HPV2 for girls produces greater incremental reductions in SCC incidence than using HPV4 for both genders (12 vs 7 percentage points). At 50% vaccination coverage, vaccinating boys produces incremental reductions in AGW of 17 percentage points if both genders are vaccinated with HPV4, but increases female incidence by 16 percentage points if girls are switched to HPV2 (heterosexual male incidence is incrementally reduced by 24 percentage points in both scenarios). Higher incremental reductions in SCC incidence are predicted when vaccinating boys with HPV4 and girls with HPV2 versus vaccinating both genders with HPV4 (16 vs 12 percentage points). Results are sensitive to vaccination coverage and the relative duration of protection of the vaccines., Conclusion: Vaccinating girls with HPV2 and boys with HPV4 can optimize SCC prevention if HPV2 has higher/longer cross-protection, but can increase AGW incidence if vaccination coverage is low among boys.

Background: Papanicolaou smear screening has significantly reduced cervical cancer morbidity and mortality. However, inequalities still persist across different socioeconomic status (SES) groups. These inequalities have been associated with differential participation in screening. However, even with equal participation to screening, some women may still have greater risk of cervical cancer because of sexual behavior. We aim to identify the sociodemographic characteristics of women who reported greater sexual activity and/or screening underuse., Methods: We used data from (i) the Canadian Community Health Survey-2005, a population-based survey of 130,000 Canadians, and (ii) a multicenter study including 952 women screened for cervical cancer., Results: Aboriginals and women with lower SES reported greater sexual activity and lower screening participation, which may produce synergetic effects toward higher cervical cancer risk. Women who did not complete high school and aboriginals were, respectively, 3.6 and 2.5 times more likely to report sexual debut before 15 years old compared with women with university degree and Caucasians. Women who did not complete high school were 2.2 times more likely to have never been screened compared with women with university degree. East and South Asian women were, respectively, 4.3 and 3.1 times more likely to have never been screened than Canadian-born women but reported lower levels of sexual activity and were adherent to screening guidelines when screened at least once., Conclusions: The success of human papillomavirus vaccination at reducing cervical cancer and inequalities will depend on achieving high coverage among high-risk subpopulations., Impact: These groups must be monitored closely, and if need be, targeted for additional interventions.

Background: Differences in sexual behaviour are partly responsible for significant inequalities in human papillomavirus (HPV)-related diseases between sub-populations. Our aim was to illustrate how differential HPV vaccine uptake by sexual behaviour can impact population-level vaccination effectiveness and inequalities in HPV prevalence., Methods: We used a multi-type individual-based transmission-dynamic model of HPV infection. The modelled population is stratified into 4 sexual activity levels (low=L0, high=L3). The model was calibrated to Canadian epidemiological data, including the proportion of sexually active individuals by gender and type-specific HPV prevalence by level of sexual activity. Vaccine uptake by sexual activity level was varied in one-way sensitivity analyses. Uncertainty in model predictions is presented using the median [10-90th percentiles] of simulations., Results: In our pre-vaccination calibrated modelled population, the most sexually active risk groups (L2-L3) account for 43% of prevalent HPV-16/18 infections while only representing 20% of the population. Under base case assumptions (age at vaccination=12 years, vaccine efficacy=100%, average duration of protection=20 years, overall coverage=50%), vaccinating girls is predicted to reduce HPV-16/18 prevalence by 56% [46-69] at equilibrium (70 years post-vaccination) when uptake is uniform across sexual activity levels, and by 35% [28-40] when uptake is maldistributed (L0: 100%, L1: 55%, L2: 0%, L3: 0%). At uniform 50% vaccination coverage across risk groups, HPV-16/18 prevalence is predicted to be reduced by 62% [52-73], 74% [57-82], 40% [24-60], and 28% [7-54] at equilibrium among women in levels of sexual activity L0, L1, L2 and L3, respectively., Conclusions: A low vaccine uptake in girls at highest risk of future HPV acquisition may substantially limit population effectiveness of vaccination. Vaccination effectiveness is lower in more sexually active groups due to smaller herd effects. Uniform vaccination coverage across sub-populations may not be able to decrease existing inequalities in HPV infection and disease unless coverage is high enough to produce herd effects in higher risk groups., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Bivalent and quadrivalent human papillomavirus (HPV) vaccines are now licensed in several countries. Furthermore, clinical trials examining the efficacy of a nonavalent vaccine are underway. We aimed to compare the potential population-level effectiveness of the bivalent, quadrivalent, and candidate nonavalent HPV vaccines., Methods: We developed an individual-based, transmission-dynamic model of HPV infection and disease in a population stratified by age, gender, sexual activity, and screening behavior. The model was calibrated to highly stratified sexual behavior, HPV epidemiology, and cervical screening data from Canada., Results: Under base case assumptions, vaccinating 12-year-old girls (70% coverage) with the bivalent (quadrivalent) vaccine is predicted to reduce the cumulative incidence of anogenital warts (AGWs) by 0.0% (72.1%), diagnosed cervical intraepithelial neoplasia lesions 2 and 3 (CIN2 and -3) by 51.0% (46.1%), and cervical squamous cell carcinoma (SCC) by 31.9% (30.5%), over 70 years. Changing from a bivalent (quadrivalent) to a nonavalent vaccine is predicted to reduce the cumulative number of AGW episodes by an additional 66.7% (0.0%), CIN2 and -3 episodes by an additional 9.3% (12.5%), and SCC cases by an additional 4.8% (6.6%) over 70 years. Differences in predicted population-level effectiveness between the vaccines were most sensitive to duration of protection and the time horizon of analysis. The vaccines produced similar effectiveness at preventing noncervical HPV-related cancers., Conclusions: The bivalent vaccine is expected to be slightly more effective at preventing CIN2 and -3 and SCC in the longer term, whereas the quadrivalent vaccine is expected to substantially reduce AGW cases shortly after the start of vaccination programs. Switching to a nonavalent vaccine has the potential to further reduce precancerous lesions and cervical cancer.

Background: The extent of cross-protection is a key element in the choice of human papillomavirus (HPV) vaccine to use in vaccination programmes. We compared the cross-protective efficacy of the bivalent vaccine (HPV 16 and 18; Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and quadrivalent vaccine (HPV 6, 11, 16, and 18; Gardasil, Merck, Whitehouse Station, NJ, USA) against non-vaccine type HPVs., Methods: We searched Medline and Embase databases, conference abstracts, and manufacturers' websites for randomised clinical trials assessing the efficacy of bivalent and quadrivalent vaccines against persistent infections (lasting ≥6 months) and cervical intraepithelial neoplasia (CIN) associated with the non-vaccine type HPVs (types 31, 33, 45, 52, and 58). We included studies of participants who were HPV DNA negative before vaccination for all HPV types assessed. We assessed heterogeneity in vaccine efficacy estimates between trials with I(2) and χ(2) statistics., Findings: We identified two clinical trials (Females United to Unilaterally Reduce Endo/Ectocervical Disease [FUTURE] I and II) of the quadrivalent vaccine and three (Papilloma Trial Against Cancer In Young Adults [PATRICIA], HPV007, and HPV-023) of the bivalent vaccine. Analysis of the most comparable populations (pooled FUTURE I/II data vs PATRICIA) suggested that cross-protective vaccine efficacy estimates against infections and lesions associated with HPV 31, 33, and 45 were usually higher for the bivalent vaccine than the quadrivalent vaccine. Vaccine efficacy in the bivalent trial was higher than it was in the quadrivalent trial against persistent infections with HPV 31 (77·1% [95% CI 67·2 to 84·4] for bivalent vaccine vs 46·2% [15·3 to 66·4] for quadrivalent vaccine; p=0·003) and HPV 45 (79·0% [61·3 to 89·4] vs 7·8% [-67·0 to 49·3]; p=0·0003), and against CIN grade 2 or worse associated with HPV 33 (82·3% [53·4 to 94·7] vs 24·0% [-71·2 to 67·2]; p=0·02) and HPV 45 (100% [41·7 to 100] vs -51·9% [-1717·8 to 82·6]; p=0·04). We noted substantial heterogeneity between vaccine efficacy in bivalent trials against persistent infections with HPV 31 (I(2)=69%, p=0·04) and HPV 45 (I(2)=70%, p=0·04), with apparent reductions in cross-protective efficacy with increased follow-up., Interpretation: The bivalent vaccine seems more efficacious against non-vaccine HPV types 31, 33, and 45 than the quadrivalent vaccine, but the differences were not all significant and might be attributable to differences in trial design. Efficacy against persistent infections with types 31 and 45 seemed to decrease in bivalent trials with increased follow-up, suggesting a waning of cross-protection; more data are needed to establish duration of cross-protection., Funding: Public Health Agency of Canada., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The burden of anogenital warts will be a determining factor when making decisions about the type of human papillomavirus (HPV) vaccine to be used (bivalent or quadrivalent) and whether to vaccinate males. We conducted a multicenter prospective study to (1) describe the impact of anogenital warts on quality of life and (2) estimate the quality-adjusted life-years (QALYs) lost due to anogenital warts., Methods: Between September 2006 and February 2008, 272 patients with a first or recurrent episode of anogenital warts were recruited from the clinical practices of 42 physicians across Canada. Quality of life was measured at recruitment, and 2 and 6 months later with the EuroQol, Short Form-12, short Spielberg State-Trait Anxiety Inventory, and HPV impact profile. The duration of an episode and QALYs lost due to anogenital warts were estimated among 51 incident cases recruited within 90 days of disease onset., Results: Anogenital warts had a significant impact on the quality of life. This negative impact was similar for first and recurrent episodes, and lasted as long as lesions persisted. Anogenital warts had the greatest negative impact on usual activities, pain/discomfort, and anxiety/depression, and on self-image, sexual activity, and partner issues and possible transmission. The median duration of a first anogenital wart episode amongst incident cases was 125 days and resulted in QALYs lost of 0.017 to 0.041, which is equivalent to 6 to 15 days of healthy life lost., Conclusions: The burden of anogenital warts is substantial and should be considered by physicians and public health officials when making recommendations about HPV vaccination..

Our aim was to examine the potential incremental impact of vaccinating boys against human papillomavirus (HPV) on vaccine-type infection in females and males, using an individual-based HPV transmission-dynamic model. Under base assumptions (vaccine efficacy = 99%, duration of protection = 20 years, coverage = 70%), vaccinating 12-year-old boys, in addition to girls, resulted in an incremental reduction in HPV-16/18 (HPV-6/11) incidence over 70 years of 16% (3%) in females and 23% (4%) in males. The benefit of vaccinating boys decreased with improved vaccination coverage in girls. Given the important predicted herd immunity impact of vaccinating girls under moderate to high vaccine coverage, the potential incremental gains of vaccinating boys are limited.