Background More than ten years have elapsed since human papillomavirus (HPV) vaccination was implemented. We performed a systematic review and meta-analysis of the population-level impact of female-only HPV vaccination on HPV infections, anogenital wart diagnoses (AGW) 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 We updated our prior review (01/01/2007-28/02/2014), by searching Medline and Embase (01/02/2014-11/10/2018) for studies that examined changes, between pre-and post-vaccination periods, in HPV infections, AGW, or CIN2+. We stratified all analyses by sex, age, and years since HPV vaccination introduction. We used random-effects models to estimate pooled relative risks and performed subgroup analysis to identify the main sources of heterogeneity. Findings We identified 65 eligible articles conducted in 14 high-income countries. After 5-8 years of vaccination, HPV-16/18, AGW, and CIN2+ decreased significantly by about 80%, 70%, and 50% among girls aged 15-19 years and by 65%, 55%, and 30% among women aged 20-24 years. Significant cross-protection and herd effects were also observed. HPV-31/33/45 decreased significantly by 50% among girls aged 15-19 years and AGW decreased significantly by 30-50% among boys/men aged 15-24 years. After 5-8 years of vaccination, countries with multi-cohort vaccination and high coverage (≥50%) had greater reductions in AGW, 44 and 85 percentage points among girls and boys aged 15-19 years, respectively, than countries with single-cohort vaccination and/or low vaccination coverage. Interpretation Our meta-analysis, including data from >60 million individuals from 14 high-income countries, shows a substantial impact of female-only HPV vaccination programs on AGW among girls/women and boys/men, and HPV infections and CIN2+ among girls/women. In addition, programs with multi-cohort vaccination and high vaccination coverage lead to greater and faster direct impact and herd effects. CONTRIBUTIONS MD, MB, and MCB conceived the study. MD, EB and NP did the literature search and performed the analysis. MB and MCB participated in the analysis. MD and MB co-drafted the first version of the article.

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 mos...

Background WHO is developing a global strategy towards eliminating cervical cancer as a public health problem, which proposes an elimination threshold of four cases per 100 000 women and includes 2030 triple-intervention coverage targets for scale-up of human papillomavirus (HPV) vaccination to 90%, twice-lifetime cervical screening to 70%, and treatment of pre-invasive lesions and invasive cancer to 90%. We assessed the impact of achieving the 90-70-90 tripleintervention targets on cervical cancer mortality and deaths averted over the next century. We also assessed the potential for the elimination initiative to support target 3.4 of the UN Sustainable Development Goals (SDGs)-a one-third reduction in premature mortality from non-communicable diseases by 2030. MethodsThe WHO Cervical Cancer Elimination Modelling Consortium (CCEMC) involves three independent, dynamic models of HPV infection, cervical carcinogenesis, screening, and precancer and invasive cancer treatment. Reductions in age-standardised rates of cervical cancer mortality in 78 low-income and lower-middle-income countries (LMICs) were estimated for three core scenarios: girls-only vaccination at age 9 years with catch-up for girls aged 10-14 years; girls-only vaccination plus once-lifetime screening and cancer treatment scale-up; and girls-only vaccination plus twice-lifetime screening and cancer treatment scale-up. Vaccination was assumed to provide 100% lifetime protection against infections with HPV types 16, 18, 31, 33, 45, 52, and 58, and to scale up to 90% coverage in 2020. Cervical screening involved HPV testing at age 35 years, or at ages 35 years and 45 years, with scale-up to 45% coverage by 2023, 70% by 2030, and 90% by 2045, and we assumed that 50% of women with invasive cervical cancer would receive appropriate surgery, radiotherapy, and chemotherapy by 2023, which would increase to 90% by 2030. We summarised results using the median (range) of model predictions.Findings In 2020, the estimated cervical cancer mortality rate across all 78 LMICs was 13•2 (range 12•9-14•1) per 100 000 women. Compared to the status quo, by 2030, vaccination alone would have minimal impact on cervical cancer mortality, leading to a 0•1% (0•1-0•5) reduction, but additionally scaling up twice-lifetime screening and cancer treatment would reduce mortality by 34•2% (23•3-37•8), averting 300 000 (300 000-400 000) deaths by 2030 (with similar results for once-lifetime screening). By 2070, scaling up vaccination alone would reduce mortality by 61•7% (61•4-66•1), averting 4•8 million (4•1-4•8) deaths. By 2070, additionally scaling up screening and cancer treatment would reduce mortality by 88•9% (84•0-89•3), averting 13•3 million (13•1-13•6) deaths (with once-lifetime screening), or by 92•3% (88•4-93•0), averting 14•6 million (14•1-14•6) deaths (with twice-lifetime screening). By 2120, vaccination alone would reduce mortality by 89•5% (86•6-89•9), averting 45•8 million (44•7-46•4) deaths. By 2120, additionally scaling up screening and cancer treatment would reduce m...

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Background In 2007, Australia was one of the first countries to introduce a national human papillomavirus (HPV) vaccination programme, and it has since achieved high vaccination coverage across both sexes. In December, 2017, organised cervical screening in Australia transitioned from cytology-based screening every 2 years for women aged from 18-20 years to 69 years, to primary HPV testing every 5 years for women aged 25-69 years and exit testing for women aged 70-74 years. We aimed to identify the earliest years in which the annual age-standardised incidence of cervical cancer in Australia (which is currently seven cases per 100 000 women) could decrease below two annual thresholds that could be considered to be potential elimination thresholds: a rare cancer threshold (six new cases per 100 000 women) or a lower threshold (four new cases per 100 000 women), since Australia is likely to be one of the first countries to reach these benchmarks. MethodsIn this modelling study, we used Policy1-Cervix-an extensively validated dynamic model of HPV vaccination, natural history, and cervical screening-to estimate the age-standardised incidence of cervical cancer in Australia from 2015 to 2100. We incorporated age-specific coverage of the Australian National HPV Vaccination Program in girls, including the catch-up programme, and the inclusion of boys into the vaccine programme from 2013, and a change from the quadrivalent to the nonavalent vaccine from 2018. We also modelled the effects of the transition to primary HPV screening. We considered two scenarios for future screening recommendations regarding the cohorts who will be and who have been offered the nonavalent vaccine: either that HPV screening every 5 years continues, or that no screening would be offered to these women. FindingsWe estimate that, in Australia, the age-standardised annual incidence of cervical cancer will decrease to fewer than six new cases per 100 000 women by 2020 (range 2018-22), and to fewer than four new cases per 100 000 women by 2028 (2021-35). The precise year of attaining these rates is dependent on the population used for age-standardisation, HPV screening behaviour and test characteristics, the incremental effects of vaccination of men on herd immunity in women, and assumptions about the future frequency of benign hysterectomies. By 2066 (2054-77), the annual incidence of cervical cancer will decrease and remain at fewer than one case per 100 000 women if screening for HPV every 5 years continues for cohorts who have been offered the nonavalent vaccine, or fewer than three cases per 100 000 women if these cohorts are not screened. Cervical cancer mortality is estimated to decrease to less than an age-standardised annual rate of one death per 100 000 women by 2034 (2025-47), even if future screening is only offered to older cohorts that were not offered the nonavalent vaccine.Interpretation If high-coverage vaccination and screening is maintained, at an elimination threshold of four new cases per 100 000 women annually, cervical cancer c...

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Canadian Institutes of Health Research.

Background Funding for human papillomavirus (HPV) vaccination in Japan began in 2010 for girls aged 12-16 years, with three-dose coverage initially reaching more than 70%. On June 14, 2013, 2 months after formal inclusion in Japan's national immunisation programme, proactive recommendations for the HPV vaccine were suspended following reports of adverse events since found to be unrelated to vaccination, but which were extensively covered in the media. Vaccine coverage subsequently dropped to less than 1% and has remained this low to date. We aimed to quantify the impact of this vaccine hesitancy crisis, and the potential health gains if coverage can be restored.Methods In this modelling study, we used the Policy1-Cervix modelling platform. We adapted the model for Japan with use of data on HPV prevalence, screening practices and coverage, and cervical cancer incidence and mortality. We evaluated the expected number of cervical cancer cases and deaths over the lifetime of cohorts born from 1994 to 2007 in the context of the vaccine hesitancy crisis. We assessed a range of recovery scenarios from 2020 onwards, including a scenario in which routine coverage is restored to 70%, with 50% catch-up coverage for the missed cohorts (aged 13-20 years in 2020). To estimate the impact of the vaccine crisis to date, we also modelled a counterfactual scenario in which 70% coverage had been maintained in 12-year-olds from 2013 onwards. FindingsThe vaccine crisis from 2013 to 2019 is predicted to result in an additional 24 600-27 300 cases and 5000-5700 deaths over the lifetime of cohorts born between 1994 and 2007, compared with if coverage had remained at around 70% since 2013. However, restoration of coverage in 2020, including catch-up vaccination for missed cohorts, could prevent 14 800-16 200 of these cases and 3000-3400 of these deaths. If coverage is not restored in 2020, an additional 3400-3800 cases and 700-800 deaths will occur over the lifetime of individuals who are 12 years old in 2020 alone. If the crisis continues, 9300-10 800 preventable deaths due to cervical cancer will occur in the next 50 years (2020-69).Interpretation The HPV vaccine crisis to date is estimated to result in around 5000 deaths from cervical cancer in Japan. Many of these deaths could still be prevented if vaccination coverage with extended catch-up can be rapidly restored.