Equity impact of HPV vaccination on lifetime projections of cervical cancer burden among cohorts in 84 countries by global, regional, and income levels, 2010-22: a modelling study.

Background: While human papillomavirus (HPV) vaccines have been available since 2006, the coverage has varied among countries. Our aim is to analyse the equity impact of HPV vaccination on the lifetime projections of cervical cancer burden among vaccinated cohorts of 2010-22 in 84 countries. Methods: We used WHO and UNICEF estimates of national immunisation coverage for HPV vaccination in 84 countries during 2010-22. We used PRIME (Papillomavirus Rapid Interface for Modelling and Economics) to estimate the lifetime health impact of HPV vaccination on cervical cancer burden in terms of deaths, cases, and disability-adjusted life years (DALYs) averted by vaccination in their respective countries. We generated concentration indices and curves to assess the equity impact of HPV vaccination across 84 countries. Findings: The health impact of HPV vaccination varied across the 84 countries and ranged from Switzerland to Tanzania at 2 to 34 deaths, 4 to 47 cases, and 40 to 735 DALYs averted per 1000 vaccinated adolescent girls over the lifetime of the vaccinated cohorts of 2010-22. The concentration index for the distribution of average coverage during 2010-22 among the 84 countries ranked by vaccine impact was 0.33 (95% CI: 0.27-0.40) and highlights the wide inequities in HPV vaccination coverage. Interpretation: Our findings suggested that countries with a relatively higher cervical cancer burden and thereby a relatively higher need for HPV vaccination had relatively lower coverage during 2010-22. Further, there were significant inequities in HPV vaccination coverage within the Americas, Europe, and Western Pacific regions, and in high- and low-income countries with a pro-advantaged and regressive distribution favouring countries with lower vaccine impact. Funding: Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation.

Estimating the health effects of COVID-19-related immunisation disruptions in 112 countries during 2020-30: a modelling study.

BACKGROUND: There have been declines in global immunisation coverage due to the COVID-19 pandemic. Recovery has begun but is geographically variable. This disruption has led to under-immunised cohorts and interrupted progress in reducing vaccine-preventable disease burden. There have, so far, been few studies of the effects of coverage disruption on vaccine effects. We aimed to quantify the effects of vaccine-coverage disruption on routine and campaign immunisation services, identify cohorts and regions that could particularly benefit from catch-up activities, and establish if losses in effect could be recovered. METHODS: For this modelling study, we used modelling groups from the Vaccine Impact Modelling Consortium from 112 low-income and middle-income countries to estimate vaccine effect for 14 pathogens. One set of modelling estimates used vaccine-coverage data from 1937 to 2021 for a subset of vaccine-preventable, outbreak-prone or priority diseases (ie, measles, rubella, hepatitis B, human papillomavirus [HPV], meningitis A, and yellow fever) to examine mitigation measures, hereafter referred to as recovery runs. The second set of estimates were conducted with vaccine-coverage data from 1937 to 2020, used to calculate effect ratios (ie, the burden averted per dose) for all 14 included vaccines and diseases, hereafter referred to as full runs. Both runs were modelled from Jan 1, 2000, to Dec 31, 2100. Countries were included if they were in the Gavi, the Vaccine Alliance portfolio; had notable burden; or had notable strategic vaccination activities. These countries represented the majority of global vaccine-preventable disease burden. Vaccine coverage was informed by historical estimates from WHO-UNICEF Estimates of National Immunization Coverage and the immunisation repository of WHO for data up to and including 2021. From 2022 onwards, we estimated coverage on the basis of guidance about campaign frequency, non-linear assumptions about the recovery of routine immunisation to pre-disruption magnitude, and 2030 endpoints informed by the WHO Immunization Agenda 2030 aims and expert consultation. We examined three main scenarios: no disruption, baseline recovery, and baseline recovery and catch-up. FINDINGS: We estimated that disruption to measles, rubella, HPV, hepatitis B, meningitis A, and yellow fever vaccination could lead to 49 119 additional deaths (95% credible interval [CrI] 17 248-134 941) during calendar years 2020-30, largely due to measles. For years of vaccination 2020-30 for all 14 pathogens, disruption could lead to a 2·66% (95% CrI 2·52-2·81) reduction in long-term effect from 37 378 194 deaths averted (34 450 249-40 241 202) to 36 410 559 deaths averted (33 515 397-39 241 799). We estimated that catch-up activities could avert 78·9% (40·4-151·4) of excess deaths between calendar years 2023 and 2030 (ie, 18 900 [7037-60 223] of 25 356 [9859-75 073]). INTERPRETATION: Our results highlight the importance of the timing of catch-up activities, considering estimated burden to improve vaccine coverage in affected cohorts. We estimated that mitigation measures for measles and yellow fever were particularly effective at reducing excess burden in the short term. Additionally, the high long-term effect of HPV vaccine as an important cervical-cancer prevention tool warrants continued immunisation efforts after disruption. FUNDING: The Vaccine Impact Modelling Consortium, funded by Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation. TRANSLATIONS: For the Arabic, Chinese, French, Portguese and Spanish translations of the abstract see Supplementary Materials section.

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Between now and later: a mixed methods study of HPV vaccination delay among Chinese caregivers in urban Chengdu, China.

BACKGROUND: Adolescent girls in China have a low HPV vaccination rate. Although vaccination is recommended by the Chinese health authorities, the cost is not covered by the national immunisation programme. Vaccination delay, among other reasons such as supply shortage and poor affordability, may contribute to low uptake. This sequential mixed methods study aimed to identify potential factors of delayed HPV vaccination among Chinese adolescent girls. METHODS: Quantitative data about the attitudes and perceptions of HPV vaccination were collected from 100 caregivers of 14-18-year-old girls using an online survey in Chengdu, China. The survey data informed a subsequent qualitative study using four focus group discussions. We conducted a descriptive analysis of the survey data and a thematic analysis of the qualitative data. The findings were interpreted using a health behaviour model adapted from the Health Belief Model and the Andersen's Behavioural Model for Health Services Use. RESULTS: A total of 100 caregivers - 85 were mothers and 15 were fathers - participated in the survey; 21 caregivers joined focus group discussions. When asked about their intended course of action if the 9vHPV vaccine was out-of-stock, 74% chose to delay until the 9vHPV vaccine is available while 26% would consider 2vHPV or 4vHPV vaccines or seek alternative ways to procure the vaccine. Qualitative results confirmed that caregivers preferred delaying HPV vaccination for adolescent girls. The intent to delay was influenced by systemic barriers such as supply shortage and individual-level factors such as a preference for the 9vHPV vaccine, safety concerns, inadequate health communication, and the belief that adolescents were unlikely to be sexually active. CONCLUSION: In urban areas, Chinese caregivers' intent to delay vaccination in favour of 9vHPV vaccine over receiving the more accessible options was influenced by a mix of individual and contextual factors. Focussed health communication strategies are needed to accelerate HPV vaccination among adolescents.

Potential population-level effectiveness of one-dose HPV vaccination in low-income and middle-income countries: a mathematical modelling analysis.

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.

Health and economic impact of delaying large-scale HPV vaccination and screening implementation on cervical cancer in China: a modelling study.

Background: Current uptake of HPV vaccination and screening in China is far below World Health Organization 2030 targets for cervical cancer elimination. We quantified health and economic losses of delaying large-scale HPV vaccination and screening implementation in China. Methods: We used a previously validated transmission model to project lifetime health benefits, costs, effectiveness, and timeline for cervical cancer elimination of alternative scenarios, including combining HPV vaccination initiated from 2022 to 2030 with screening in different modalities and coverage increase rates, as well as screening alone. All women living or projected to be born in China during 2022-2100 were considered. We employed a societal perspective. Findings: Regardless of vaccine type, immediate large-scale vaccination initiated in 2022 and achieving 70% coverage of HPV-based screening in 2030 (no-delay scenario) would be the least costly and most effective. Compared with the no-delay scenario, delaying vaccination by eight years would result in 434,000-543,000 additional cervical cancer cases, 138,000-178,000 deaths, and $2863-4437 million costs, and delay elimination by 9-10 years. Even with immediate vaccination, the gradual scale-up of LBC-based screening to 70% coverage in 2070 would result in 2,530,000-3,060,000 additional cases, 909,000-1,040,000 deaths, and $5098-5714 million costs compared with no-delay scenario, and could not achieve elimination if domestic 2vHPV or 4vHPV vaccines are used (4.09-4.21 cases per 100,000 woman in 2100). Interpretation: Delaying large-scale HPV vaccination and/or high-performance screening implementation has detrimental consequences for cervical cancer morbidity, mortality, and expenditure. These findings should spur health authorities to expedite large-scale vaccine rollout and improve screening. Funding: Bill & Melinda Gates Foundation (INV-031449 and INV-003174) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-004).

Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis.

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.

Maximizing the cost-effectiveness of cervical screening in the context of routine HPV vaccination by optimizing screening strategies with respect to vaccine uptake: a modeling analysis.

BACKGROUND: Regarding primary and secondary cervical cancer prevention, the World Health Organization proposed the cervical cancer elimination strategy that requires countries to achieve 90% uptake of human papillomavirus (HPV) vaccines and 70% screening uptake. The optimal cervical screening strategy is likely different for unvaccinated and vaccinated cohorts upon national HPV immunization. However, health authorities typically only provide a one-size-fits-all recommendation for the general population. We aimed to evaluate the cost-effectiveness for determining the optimal screening strategies for vaccinated and unvaccinated cohorts. METHODS: We considered the women population in Hong Kong which has a unique HPV infection and cervical cancer epidemiology compared to other regions in China and Asia. We used mathematical models which comprise a deterministic age-structured compartmental dynamic component and a stochastic individual-based cohort component to evaluate the cost-effectiveness of screening strategies for cervical screening. Following the recommendations in local guidelines in Hong Kong, we considered strategies that involved cytology, HPV testing, or co-testing as primary cervical screening. We also explored the impacts of adopting alternative de-intensified strategies for vaccinated cohorts. The 3-year cytology screening was used as the base comparator while no screening was also considered for vaccinated cohorts. Women's lifetime life years, quality-adjusted life years, and costs of screening and treatment were estimated from the societal perspective based on the year 2022 and were discounted by 3% annually. Incremental cost-effectiveness ratios (ICERs) were compared to a willingness to pay (WTP) threshold of one gross domestic product per capita (US $47,792). Probabilistic and one-way sensitivity analyses were conducted. RESULTS: Among unvaccinated cohorts, the strategy that adds reflex HPV to triage mild cytology abnormality generated more life years saved than cytology-only screening and could be a cost-effective alternative. Among vaccinated cohorts, when vaccine uptake was 85% (based on the uptake in 2022), all guideline-based strategies (including the cytology-only screening) had ICERs above the WTP threshold when compared with no screening if the vaccine-induced protection duration was 20 years or longer. Under the same conditions, HPV testing with genotyping triage had ICERs (compared with no screening) below the WTP threshold if the routine screening interval was lengthened to 10 and 15 years or screening was initiated at ages 30 and 35 years. CONCLUSIONS: HPV testing is a cost-effective alternative to cytology for vaccinated cohorts, and the associated optimal screening frequency depends on vaccine uptake. Health authorities should optimize screening recommendations by accounting for population vaccine uptake.

Optimal allocation strategies for HPV vaccination introduction and expansion in China accommodated to different supply and dose schedule scenarios: A modelling study.

Background: A key barrier to cervical cancer elimination in China is low human papillomavirus (HPV) vaccine uptake, which is limited by supply constraints, high prices, and restriction to two/three-dose schedule. We explored optimal vaccination strategies for maximizing health and economic benefits accommodated to different supply and dose schedules. Methods: We evaluated different HPV vaccine strategies under 4 scenarios with different assumptions about vaccine availability and dose schedules. Each strategy involved different vaccine types, target ages, and modes of delivery. We used a previously validated transmission model to assess the health impact (cervical cancer cases averted), efficiency (number of doses needed to be given to prevent one case of cervical cancer [NND]), and value for money (incremental cost-effectiveness ratio [ICER] and return on investment [ROI]) of different strategies in Chinese females over a 100-year time horizon. All costs are expressed in 2021 dollars. We adopted a societal perspective and discounted quality-adjusted life-years (QALYs), costs and benefits by 3% annually for cost-effectiveness analysis and ROI calculation. Findings: In a supply-constrained and on-label use scenario, compared with no vaccination, two-dose routine vaccination of 14-year-olds would be the optimal, cost-saving strategy for a future national program (NNDs: 150-220, net cost saving: $15 164 million-$22 034 million, ROIs: 7-14, depending on vaccine type). If the one-dose schedule recommended by WHO is permitted in China, then reallocating the second dose from the routine cohorts to add a catch-up vaccination at 20-year-olds would be the most efficient strategy (NNDs: 73-107), and would be cost-saving compared with routine one-dose vaccination only (net cost saving: $4127 million-$6035 million, ROIs: 19-37). When supply constraints are lifted, scaling up vaccination in older females to 26 years could further expand the health benefits and still be cost-saving compared to maintaining the optimal vaccination strategy in the supply-constrained context. Interpretation: Our study provides timely evidence for the current and future HPV vaccination strategy planning in China, and may also be of value to other countries with supply and dose restrictions. Funding: Bill & Melinda Gates Foundation; CAMS Innovation Fund for Medical Sciences (CIFMS).

The effectiveness of pay-it-forward in addressing HPV vaccine delay and increasing uptake among 15-18-year-old adolescent girls compared to user-paid vaccination: a study protocol for a two-arm randomized controlled trial in China.

BACKGROUND: Human papillomavirus (HPV) vaccination could prevent cervical and other HPV-associated cancers attributable to vaccine-associated HPV types. However, HPV vaccination coverage among women aged 9-18 years old is low in China. Common barriers include poor financial affordability, minimal public engagement, and low confidence in domestically produced HPV vaccines. Pay-it-forward offers an individual a free or subsidized service then an opportunity to voluntarily donate and/or create a postcard message to support future people. This study aims to assess the effectiveness of pay-it-forward as compared to standard-of-care self-paid vaccination to improve HPV vaccine uptake among adolescent girls aged 15-18 years, who are left out in the current pilot free HPV vaccination task force in some parts of China. METHODS: This is a two-arm randomized controlled trial in Chengdu, China. Eligible adolescent girls (via caregivers) will be randomly selected and recruited through four community health centers (one in the most developed urban areas, one in higher middle-income and one in lower middle-income suburban areas, and one in the least developed rural areas) using the resident registration list. A total of 320 participants will be randomized into two study arms (user-paid versus pay-it-forward vaccination) in a 1:1 ratio. The intervention assignment will be blinded to recruiters and participants using envelop concealment until the research assistants open the envelop to determine which treatment to deliver to each individual. The primary outcome of the study will be HPV vaccine uptake by administrative data. Secondary outcomes include costs, vaccine hesitancy, and the completion rates of the 3-dose HPV vaccination series. DISCUSSION: This study will investigate an innovative pay-it-forward strategy's effectiveness and economic costs to improve HPV vaccination among 15-18-year-old adolescent girls. Study findings will have implications for increasing HPV vaccine uptake in places where HPV vaccines are provided for a fee. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR2200055542. Registered on 11 January 2022.

Potential benefit of extended dose schedules of human papillomavirus vaccination in the context of scarce resources and COVID-19 disruptions in low-income and middle-income countries: a mathematical modelling analysis.

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.

Human papillomavirus vaccine effectiveness by number of doses: Updated systematic review of data from national immunization programs.

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.

Effectiveness of CoronaVac and BNT162b2 COVID-19 mass vaccination in Colombia: A population-based cohort study.

Background: In February 2021, Colombia began mass vaccination against COVID-19 using mainly BNT162b2 and CoronaVac vaccines. We aimed to estimate vaccine effectiveness (VE) to prevent COVID-19 symptomatic cases, hospitalization, critical care admission, and deaths in a cohort of 796,072 insured subjects older than 40 years in northern Colombia, a setting with a high SARS-CoV-2 transmission. Methods: We identified individuals vaccinated between March 1st of 2021 and August 15th of 2021. We included symptomatic cases, hospitalizations, critical care admissions, and deaths in patients with confirmed COVID-19 as main outcomes. We calculated VE for each outcome from the hazard ratio in Cox proportionally hazards regressions (adjusted by age, sex, place of residence, diabetes, human immunodeficiency virus, cancer, hypertension, tuberculosis, neurological diseases, and chronic renal disease), with 95% confidence intervals (CI). Findings: A total of 719,735 insured participants of 40 and more years were followed. We found 21,545 laboratory-confirmed symptomatic COVID-19 among unvaccinated population, along with 2874 hospitalizations, 1061 critical care admissions, and 1329 deaths, for a rate of 207.2 per million person-days, 27.1 per million person-days, 10.0 per million person-days, and 12.5 per million person-days, respectively. We found CoronaVac was not effective for any outcome in subjects above 80 years old; but for people 40-79 years of age, we found two doses of CoronaVac reduced hospitalization (33.1%; 95% CI, 14.5-47.7), critical care admission (47.2%; 95% CI, 18.5-65.8), and death (55.7%; 95% CI, 32.5-70.0). We found BNT162b2 was effective for all outcomes in the entire population of subjects above 40 years of age, significantly declining for subjects ≥80 years. Interpretation: Two doses of either CoronaVac in population between 40 and 79 years of age, or BNT162b2 among vaccinated above 40 years old significantly reduced deaths of confirmed COVID-19 in a cohort of individuals from Colombia. Vaccine effectiveness for CoronaVac and BNT162b2 declined with increasing age. Funding: UK National Institute for Health Research, the European Union's Horizon 2020 research and innovation programme, and the Bill & Melinda Gates Foundation.

Now or later: Health impacts of delaying single-dose HPV vaccine implementation in a high-burden setting.

We aimed to quantify the health impact of immediate introduction of a single-dose human papillomavirus (HPV) vaccination program in a high-burden setting, as waiting until forthcoming trials are completed to implement single-dose HPV vaccination may result in health losses, particularly for cohorts who would age-out of vaccination eligibility. Two mathematical models fitted to a high-burden setting projected cervical cancer incidence rates associated with (a) immediate implementation of one-dose HPV vaccination vs (b) waiting 5 years for evidence from randomized trials to determine if one- or two-doses should be implemented. We conducted analyses assuming a single dose was either noninferior or inferior to two doses. The models projected that immediate implementation of a noninferior single-dose vaccine led to a 7.2% to 9.6% increase in cancers averted between 2021 to 2120, compared to waiting 5 years. Health benefits remained greater with immediate implementation despite an inferior single-dose efficacy (80%), but revaccination of one-dose recipients became more important assuming vaccine waning. Under most circumstances, immediate vaccination avoided health losses for those aging out of vaccine eligibility, leading to greater health benefits than waiting for more information in 5 years.

Prevalence and Determinants of Vaginal Infection With Human Papillomavirus Among Female University Students in Vietnam.

BACKGROUND/AIM: Cervical cancer is the second most common malignancy among women in Vietnam, but the country is yet to introduce a national human papillomavirus (HPV) vaccine programme targeted at adolescents. We determined HPV prevalence and HPV vaccine knowledge among female university students in Vietnam. PATIENTS AND METHODS: We surveyed and screened 1,491 female university students in Hanoi, Hue, and Ho Chi Minh City for their sexual behaviours, HPV knowledge and low- and high-risk HPV infection. RESULTS: The prevalence of any HPV infection and any high-risk HPV infection were 4.2% (95%CI=3.3%-5.4%) and 3.4% (95%CI=2.5%-4.4%), respectively. Being sexually active [adjusted prevalence ratio (aPR): 6.22; 95%CI=3.4-11.37] and having ever been pregnant (aPR: 4.82; 95%CI=1.93-12.04) were positively associated with high-risk HPV infection. Whilst 60% of participants had heard of HPV vaccine, only 4.6% had received the vaccine. CONCLUSION: The low HPV prevalence found in university students in Vietnam indicates that they can benefit from HPV vaccination, along with a well-designed HPV health promotion programme.

Prevalence and risk factors for human papillomavirus infection among female sex workers in Hanoi and Ho Chi Minh City, Viet Nam: a cross-sectional study.

Objective: Female sex workers (FSWs) are at high risk of human papillomavirus (HPV) infections and cervical cancer due to their high number of sexual partners. The objectives of this study were to determine the prevalence of HPV and identify risk factors for high-risk HPV infection among FSWs in Hanoi and Ho Chi Minh City (HCMC), Viet Nam. Methods: A cross-sectional study was conducted in Hanoi and HCMC between December 2017 and May 2018. We surveyed and screened 699 FSWs aged 318 years for HPV infection and abnormal cytology. A multivariable modified Cox regression model was used to determine risk factors for high-risk HPV infection. Results: The overall prevalence of any HPV, high-risk HPV and HPV-16/18 infection in the 699 FSWs was 26.3%, 17.6% and 4.0%, respectively, and were similar in both cities. Multiple infections were identified in 127 participants (69.0%). HPV-52 was the most prevalent (7%), followed by HPV-58 (6%). Abnormal cytology was detected in 91 participants (13.0%). FSWs who are divorced (adjusted prevalence ratio [aPR]: 1.96, 95% confidence interval [CI]: 1.01-3.81), widowed (aPR: 3.26, 95% CI: 1.49-7.12) or living alone (aPR: 1.85, 95% CI: 1.01-3.39) were associated with a higher prevalence of high-risk HPV infection. Discussion: Almost one in five FSWs in Viet Nam are infected with high-risk HPV. This highlights the importance of prevention strategies such as HPV vaccination and screening in this high-risk group.

Antimicrobial Resistance: Is Health Technology Assessment Part of the Solution or Part of the Problem?

Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment. Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemiological risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit, design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing resistance, as part of their evaluation criteria alongside immediate health gains.

Projections of human papillomavirus (HPV) vaccination impact in Ethiopia, India, Nigeria and Pakistan: a comparative modelling study.

INTRODUCTION: Cervical cancer is the second most common cancer among women in Ethiopia, India, Nigeria and Pakistan. Our study objective was to assess similarities and differences in vaccine-impact projections through comparative modelling analysis by independently estimating the potential health impact of human papillomavirus (HPV) vaccination. METHODS: Using two widely published models (Harvard and Papillomavirus Rapid Interface for Modelling and Economics (PRIME)) to estimate HPV vaccination impact, we simulated a vaccination scenario of 90% annual coverage among 10 cohorts of 9-year-old girls from 2021 to 2030 in Ethiopia, India, Nigeria and Pakistan. We estimated potential health impact in terms of cervical cancer cases, deaths and disability-adjusted life years averted among vaccinated cohorts from the time of vaccination until 2100. We harmonised the two models by standardising input data to comparatively estimate HPV vaccination impact. RESULTS: Prior to harmonising model assumptions, the range between PRIME and Harvard models for number of cervical cancer cases averted by HPV vaccination was: 262 000 to 2 70 000 in Ethiopia; 1 640 000 to 1 970 000 in India; 330 000 to 3 36 000 in Nigeria and 111 000 to 1 33 000 in Pakistan. When harmonising model assumptions, alignment on HPV type distribution significantly narrowed differences in vaccine-impact estimates. CONCLUSION: Despite model differences, the Harvard and PRIME models yielded similar vaccine-impact estimates. The main differences in estimates are due to variation in interpretation around data on cervical cancer attribution to HPV-16/18. As countries make progress towards WHO targets for cervical cancer elimination, continued explorations of underlying differences in model inputs, assumptions and results when examining cervical cancer prevention policy will be critical.

How to Prevent Vaccines Falling Victim to Their Own Success: Intertemporal Dependency of Incidence Levels on Indirect Effects in Economic Reevaluations.

OBJECTIVES: Incremental cost-effectiveness analyses may inform the optimal choice of healthcare interventions. Nevertheless, for many vaccines, benefits fluctuate with incidence levels over time. Reevaluating a vaccine after it has successfully decreased incidences may eventually cause a disease resurgence if switching to a vaccine with lower indirect benefits. Decisions may successively alternate between vaccines alongside repeated rises and falls in incidence and when indirect effects from historic use are ignored. Our suggested proposal aims to prevent suboptimal decision making. METHODS: We used a conceptual model of demand to illustrate alternating decisions between vaccines because of time-varying levels of indirect effects. Similar to the concept of subsidies, we propose internalizing the indirect effects achievable with vaccines. In a case study over 60 years, we simulated a hypothetical 10-year reevaluation of 2 oncogenic human papillomavirus vaccines, of which only 1 protects additionally against anogenital warts. RESULTS: Our case study showed that the vaccine with additional warts protection is initially valued higher than the vaccine without additional warts protection. After 10 years, this differential decreases because of declines in warts incidence, which supports switching to the nonwarts vaccine that causes a warts resurgence eventually. Instead, pricing the indirect effects separately supports continuing with the warts vaccine. CONCLUSIONS: Ignoring how the observed incidences depend on the indirect effects achieved with a particular vaccine may lead to repeated changes in vaccines at successive reevaluations, with unintended resurgences, economic inefficiencies, and eroding vaccine confidence. We propose internalizing indirect effects to prevent vaccines falling victim to their own success.