Salmonella Combination Vaccines: Moving Beyond Typhoid.

There is now a robust pipeline of licensed and World Health Organization (WHO)-prequalified typhoid conjugate vaccines with a steady progression of national introductions. However, typhoid fever is responsible for less than half the total global burden of Salmonella disease, and even less among children aged <5 years. Invasive nontyphoidal Salmonella disease is the dominant clinical presentation of Salmonella in Africa, and over a quarter of enteric fever in Asia is due to paratyphoid A. In this article, we explore the case for combination Salmonella vaccines, review the current pipeline of these vaccines, and discuss key considerations for their development, including geographies of use, age of administration, and pathways to licensure. While a trivalent typhoid/nontyphoidal Salmonella vaccine is attractive for Africa, and a bivalent enteric fever vaccine for Asia, a quadrivalent vaccine covering the 4 main disease-causing serovars of Salmonella enterica would provide a single vaccine option for global Salmonella coverage.

The Burden of Proof studies: assessing the evidence of risk.

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses-termed the Burden of Proof studies-designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk-outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk-outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk-outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.

Health effects associated with vegetable consumption: a Burden of Proof study.

Previous research suggests a protective effect of vegetable consumption against chronic disease, but the quality of evidence underlying those findings remains uncertain. We applied a Bayesian meta-regression tool to estimate the mean risk function and quantify the quality of evidence for associations between vegetable consumption and ischemic heart disease (IHD), ischemic stroke, hemorrhagic stroke, type 2 diabetes and esophageal cancer. Increasing from no vegetable consumption to the theoretical minimum risk exposure level (306-372 g daily) was associated with a 23.2% decline (95% uncertainty interval, including between-study heterogeneity: 16.4-29.4) in ischemic stroke risk; a 22.9% (13.6-31.3) decline in IHD risk; a 15.9% (1.7-28.1) decline in hemorrhagic stroke risk; a 28.5% (-0.02-51.4) decline in esophageal cancer risk; and a 26.1% (-3.6-48.3) decline in type 2 diabetes risk. We found statistically significant protective effects of vegetable consumption for ischemic stroke (three stars), IHD (two stars), hemorrhagic stroke (two stars) and esophageal cancer (two stars). Including between-study heterogeneity, we did not detect a significant association with type 2 diabetes, corresponding to a one-star rating. Although current evidence supports increased efforts and policies to promote vegetable consumption, remaining uncertainties suggest the need for continued research.

Effectiveness of interventions to improve drinking water, sanitation, and handwashing with soap on risk of diarrhoeal disease in children in low-income and middle-income settings: a systematic review and meta-analysis.

BACKGROUND: Estimates of the effectiveness of water, sanitation, and hygiene (WASH) interventions that provide high levels of service on childhood diarrhoea are scarce. We aimed to provide up-to-date estimates on the burden of disease attributable to WASH and on the effects of different types of WASH interventions on childhood diarrhoea in low-income and middle-income countries (LMICs). METHODS: In this systematic review and meta-analysis, we updated previous reviews following their search strategy by searching MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index for studies of basic WASH interventions and of WASH interventions providing a high level of service, published between Jan 1, 2016, and May 25, 2021. We included randomised and non-randomised controlled trials conducted at household or community level that matched exposure categories of the so-called service ladder approach of the Sustainable Development Goal (SDG) for WASH. Two reviewers independently extracted study-level data and assessed risk of bias using a modified Newcastle-Ottawa Scale and certainty of evidence using a modified Grading of Recommendations, Assessment, Development, and Evaluation approach. We analysed extracted relative risks (RRs) and 95% CIs using random-effects meta-analyses and meta-regression models. This study is registered with PROSPERO, CRD42016043164. FINDINGS: 19 837 records were identified from the search, of which 124 studies were included, providing 83 water (62 616 children), 20 sanitation (40 799 children), and 41 hygiene (98 416 children) comparisons. Compared with untreated water from an unimproved source, risk of diarrhoea was reduced by up to 50% with water treated at point of use (POU): filtration (n=23 studies; RR 0·50 [95% CI 0·41-0·60]), solar treatment (n=13; 0·63 [0·50-0·80]), and chlorination (n=25; 0·66 [0·56-0·77]). Compared with an unimproved source, provision of an improved drinking water supply on premises with higher water quality reduced diarrhoea risk by 52% (n=2; 0·48 [0·26-0·87]). Overall, sanitation interventions reduced diarrhoea risk by 24% (0·76 [0·61-0·94]). Compared with unimproved sanitation, providing sewer connection reduced diarrhoea risk by 47% (n=5; 0·53 [0·30-0·93]). Promotion of handwashing with soap reduced diarrhoea risk by 30% (0·70 [0·64-0·76]). INTERPRETATION: WASH interventions reduced risk of diarrhoea in children in LMICs. Interventions supplying either water filtered at POU, higher water quality from an improved source on premises, or basic sanitation services with sewer connection were associated with increased reductions. Our results support higher service levels called for under SDG 6. Notably, no studies evaluated interventions that delivered access to safely managed WASH services, the level of service to which universal coverage by 2030 is committed under the SDG. FUNDING: WHO, Foreign, Commonwealth & Development Office, and National Institute of Environmental Health Sciences.

Mortality burden attributable to high and low ambient temperatures in China and its provinces: Results from the Global Burden of Disease Study 2019.

Background: Non-optimal temperatures are associated with mortality risk, yet the heterogeneity of temperature-attributable mortality burden across subnational regions in a country was rarely investigated. We estimated the mortality burden related to non-optimal temperatures across all provinces in China in 2019. Methods: The global daily temperature data were obtained from the ERA5 reanalysis dataset. The daily mortality data and exposure-response curves between daily temperature and mortality for 176 individual causes of death were obtained from the Global Burden of Disease Study 2019 (GBD 2019). We estimated the population attributable fraction (PAF) based on the exposure-response curves, daily gridded temperature, and population. We calculated the cause- and province-specific mortality burden based on PAF and disease burden data from the GBD 2019. Findings: We estimated that 593·9 (95% UI:498·8, 704·6) thousand deaths were attributable to non-optimal temperatures in China in 2019 (PAF=5·58% [4·93%, 6·28%]), with 580·8 (485·7, 690·1) thousand cold-related deaths and 13·9 (7·7, 23·2) thousand heat-related deaths. The majority of temperature-related deaths were from cardiovascular diseases (399·7 [322·8, 490·4] thousand) and chronic respiratory diseases (177·4 [141·4, 222·3] thousand). The mortality burdens were observed significantly spatial heterogeneity for both high and low temperatures. For instance, the age-standardized death rates (per 100 000) attributable to low temperature were higher in Western China, with the highest in Tibet (113·7 [82·0, 155·5]), while for high temperature, they were greater in Xinjiang (1·8 [0·7, 3·3]) and Central-Southern China such as Hainan (2·5 [0·9, 5·4]). We also observed considerable geographical variation in the temperature-related mortality burden by causes of death at provincial level. Interpretation: A substantial mortality burden was attributable to non-optimal temperatures across China, and cold effects dominated the total mortality burden in all provinces. Both cold- and heat-related mortality burden showed significantly spatial variations across China. Funding: National Key Research and Development Program.

Estimating the cause-specific relative risks of non-optimal temperature on daily mortality: a two-part modelling approach applied to the Global Burden of Disease Study.

BACKGROUND: Associations between high and low temperatures and increases in mortality and morbidity have been previously reported, yet no comprehensive assessment of disease burden has been done. Therefore, we aimed to estimate the global and regional burden due to non-optimal temperature exposure. METHODS: In part 1 of this study, we linked deaths to daily temperature estimates from the ERA5 reanalysis dataset. We modelled the cause-specific relative risks for 176 individual causes of death along daily temperature and 23 mean temperature zones using a two-dimensional spline within a Bayesian meta-regression framework. We then calculated the cause-specific and total temperature-attributable burden for the countries for which daily mortality data were available. In part 2, we applied cause-specific relative risks from part 1 to all locations globally. We combined exposure-response curves with daily gridded temperature and calculated the cause-specific burden based on the underlying burden of disease from the Global Burden of Diseases, Injuries, and Risk Factors Study, for the years 1990-2019. Uncertainty from all components of the modelling chain, including risks, temperature exposure, and theoretical minimum risk exposure levels, defined as the temperature of minimum mortality across all included causes, was propagated using posterior simulation of 1000 draws. FINDINGS: We included 64·9 million individual International Classification of Diseases-coded deaths from nine different countries, occurring between Jan 1, 1980, and Dec 31, 2016. 17 causes of death met the inclusion criteria. Ischaemic heart disease, stroke, cardiomyopathy and myocarditis, hypertensive heart disease, diabetes, chronic kidney disease, lower respiratory infection, and chronic obstructive pulmonary disease showed J-shaped relationships with daily temperature, whereas the risk of external causes (eg, homicide, suicide, drowning, and related to disasters, mechanical, transport, and other unintentional injuries) increased monotonically with temperature. The theoretical minimum risk exposure levels varied by location and year as a function of the underlying cause of death composition. Estimates for non-optimal temperature ranged from 7·98 deaths (95% uncertainty interval 7·10-8·85) per 100 000 and a population attributable fraction (PAF) of 1·2% (1·1-1·4) in Brazil to 35·1 deaths (29·9-40·3) per 100 000 and a PAF of 4·7% (4·3-5·1) in China. In 2019, the average cold-attributable mortality exceeded heat-attributable mortality in all countries for which data were available. Cold effects were most pronounced in China with PAFs of 4·3% (3·9-4·7) and attributable rates of 32·0 deaths (27·2-36·8) per 100 000 and in New Zealand with 3·4% (2·9-3·9) and 26·4 deaths (22·1-30·2). Heat effects were most pronounced in China with PAFs of 0·4% (0·3-0·6) and attributable rates of 3·25 deaths (2·39-4·24) per 100 000 and in Brazil with 0·4% (0·3-0·5) and 2·71 deaths (2·15-3·37). When applying our framework to all countries globally, we estimated that 1·69 million (1·52-1·83) deaths were attributable to non-optimal temperature globally in 2019. The highest heat-attributable burdens were observed in south and southeast Asia, sub-Saharan Africa, and North Africa and the Middle East, and the highest cold-attributable burdens in eastern and central Europe, and central Asia. INTERPRETATION: Acute heat and cold exposure can increase or decrease the risk of mortality for a diverse set of causes of death. Although in most regions cold effects dominate, locations with high prevailing temperatures can exhibit substantial heat effects far exceeding cold-attributable burden. Particularly, a high burden of external causes of death contributed to strong heat impacts, but cardiorespiratory diseases and metabolic diseases could also be substantial contributors. Changes in both exposures and the composition of causes of death drove changes in risk over time. Steady increases in exposure to the risk of high temperature are of increasing concern for health. FUNDING: Bill & Melinda Gates Foundation.

The effect of air pollution on deaths, disease burden, and life expectancy across China and its provinces, 1990-2017: an analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Air pollution is an important public health concern in China, with high levels of exposure to both ambient and household air pollution. To inform action at provincial levels in China, we estimated the exposure to air pollution and its effect on deaths, disease burden, and loss of life expectancy across all provinces in China from 1990 to 2017. METHODS: In all 33 provinces, autonomous regions, municipalities, and special administrative regions in China, we estimated exposure to air pollution, including ambient particulate matter pollution (defined as the annual gridded concentration of PM2·5), household air pollution (defined as the percentage of households using solid cooking fuels and the corresponding exposure to PM2·5), and ozone pollution (defined as average gridded ozone concentrations). We used the methods of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 to estimate deaths and disability-adjusted life-years (DALYs) attributable to air pollution, and what the life expectancy would have been if air pollution levels had been less than the minimum level causing health loss. FINDINGS: The average annual population-weighted PM2·5 exposure in China was 52·7 µg/m3 (95% uncertainty interval [UI] 41·0-62·8) in 2017, which is 9% lower than in 1990 (57·8 µg/m3, 45·0-67·0). We estimated that 1·24 million (95% UI 1·08-1·40) deaths in China were attributable to air pollution in 2017, including 851 660 (712 002-990 271) from ambient PM2·5 pollution, 271 089 (209 882-346 561) from household air pollution from solid fuels, and 178 187 (67 650-286 229) from ambient ozone pollution. The age-standardised DALY rate attributable to air pollution was 1513·1 per 100 000 in China in 2017, and was higher in males (1839·8 per 100 000) than in females (1198·3 per 100 000). The age-standardised death rate attributable to air pollution decreased by 60·6% (55·7-63·7) for China overall between 1990 and 2017, driven by an 85·4% (83·2-87·3) decline in household air pollution and a 12·0% (1·4-22·1) decline in ambient PM2·5 pollution. 40·0% of DALYs for COPD were attributable to air pollution, as were 35·6% of DALYs for lower respiratory infections, 26·1% for diabetes, 25·8% for lung cancer, 19·5% for ischaemic heart disease, and 12·8% for stroke. We estimated that if the air pollution level in China was below the minimum causing health loss, the average life expectancy would have been 1·25 years greater. The DALY rate per 100 000 attributable to air pollution varied across provinces, ranging from 482·3 (371·1-604·1) in Hong Kong to 1725·6 (720·4-2653·1) in Xinjiang for ambient pollution, and from 18·7 (9·1-34·0) in Shanghai to 1804·5 (1339·5-2270·1) in Tibet for household pollution. Although the overall mortality attributable to air pollution decreased in China between 1990 and 2017, 12 provinces showed an increasing trend during the past 27 years. INTERPRETATION: Pollution from ambient PM2·5 and household burning of solid fuels decreased markedly in recent years in China, after extensive efforts to control emissions. However, PM2·5 concentrations still exceed the WHO Air Quality Guideline for the entire population of China, with 81% living in regions exceeding the WHO Interim Target 1, and air pollution remains an important risk factor. Sustainable development policies should be implemented and enforced to reduce the impact of air pollution on long-term economic development and population health. FUNDING: Bill & Melinda Gates Foundation; and China National Key Research and Development Program.

Assessing the Feasibility of Typhoid Elimination.

In 1993, the International Task Force on Disease Eradication classified the political will for typhoid eradication as "none." Here we revisit the Task Force's assessment in light of developments in typhoid vaccines and increasing antimicrobial resistance in Salmonella Typhi that have served to increase interest in typhoid elimination. Considering the requisite biological and technical factors for elimination, effective interventions exist for typhoid, and humans are the organism's only known reservoir. Improvements in water supply, sanitation, hygiene, and food safety are critical for robust long-term typhoid control, and the recent Strategic Advisory Group of Experts on Immunization recommendation and World Health Organization prequalification should make typhoid conjugate vaccine more accessible and affordable in low-income countries, which will allow the vaccine to offer a critical bridge to quickly reduce burden. While these developments are encouraging, all current typhoid diagnostics are inadequate, having either poor performance characteristics, limited scalability, or both. No clear solution exists, and this should be viewed as a critical challenge to any elimination effort. Moreover, asymptomatic carriers and limited data and surveillance remain major challenges, and countries considering elimination campaigns will need to develop strategies to identify high-risk populations and to monitor progress over time. Finally, policymakers must be realistic in planning, learn from the planning failures of previous elimination and eradication efforts, and expect unforeseeable shocks and setbacks. In the end, if we assume neither unanticipated breakthroughs in typhoid control nor any chaotic shocks, history suggests that we should expect typhoid elimination to take decades.

Global Access to Handwashing: Implications for COVID-19 Control in Low-Income Countries.

BACKGROUND: Low-income countries have reduced health care system capacity and are therefore at risk of substantially higher COVID-19 case fatality rates than those currently seen in high-income countries. Handwashing is a key component of guidance to reduce transmission of the SARS-CoV-2 virus, responsible for the COVID-19 pandemic. Prior systematic reviews have indicated the effectiveness of handwashing to reduce transmission of respiratory viruses. In low-income countries, reduction of transmission is of paramount importance, but social distancing is challenged by high population densities and access to handwashing facilities with soap and water is limited. OBJECTIVES: Our objective was to estimate global access to handwashing with soap and water to inform use of handwashing in the prevention of COVID-19 transmission. METHODS: We utilized observational surveys and spatiotemporal Gaussian process regression modeling in the context of the Global Burden of Diseases, Injuries, and Risk Factors Study to estimate access to a handwashing station with available soap and water for 1,062 locations from 1990 to 2019. RESULTS: Despite overall improvements from 1990 {33.6% [95% uncertainty interval (UI): 31.5, 35.6] without access} to 2019, globally in 2019, 2.02 (95% UI: 1.91, 2.14) billion people, 26.1% (95% UI: 24.7, 27.7) of the global population, lacked access to handwashing with available soap and water. More than 50% of the population in sub-Saharan Africa and Oceania were without access to handwashing in 2019, and in eight countries, 50 million or more persons lacked access. DISCUSSION: For populations without handwashing access, immediate improvements in access or alternative strategies are urgently needed, and disparities in handwashing access should be incorporated into COVID-19 forecasting models when applied to low-income countries. https://doi.org/10.1289/EHP7200.

Improving and Expanding Estimates of the Global Burden of Disease Due to Environmental Health Risk Factors.

BACKGROUND: The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors. Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing cost-effective policies that promote prevention and achieving Sustainable Development Goals. OBJECTIVES: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease-Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden-both current and projected. METHODS: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change. We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment. DISCUSSION: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors. For air pollution, minimal data exist on the exposure-risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority. For lead, the GBD's current methods do not fully account for lead's impact on neurodevelopment; innovative methods to account for subclinical effects are needed. Decisions on inclusion of additional EH risk-outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases. Neurotoxicants, endocrine-disrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study. Enhancing the scope and methods will improve the GBD's estimates and better guide prevention policy. https://doi.org/10.1289/EHP5496.

Slaying little dragons: the impact of the Guinea Worm Eradication Program on dracunculiasis disability averted from 1990 to 2016.

Background: The objective of this study was to document the worldwide decline of dracunculiasis (Guinea worm disease, GWD) burden, expressed as disability-adjusted life years (DALYs), from 1990 to 2016, as estimated in the Global Burden of Disease study 2016 (GBD 2016). While the annual number of cases of GWD have been consistently reported by WHO since the 1990s, the burden of disability due to GWD has not previously been quantified in GBD. Methods: The incidence of GWD was modeled for each endemic country using annual national case reports. A literature search was conducted to characterize the presentation of GWD, translate the clinical symptoms into health sequelae, and then assign an average duration to the infection. Prevalence measures by sequelae were multiplied by disability weights to estimate DALYs. Results: The total DALYs attributed to GWD across all endemic countries (n=21) in 1990 was 50,725 (95% UI: 35,265-69,197) and decreased to 0.9 (95% UI: 0.5-1.4) in 2016. A cumulative total of 12,900 DALYs were attributable to GWD from 1990 to 2016. Conclusions: Using 1990 estimates of burden propagated forward, this analysis suggests that between 990,000 to 1.9 million DALYs have been averted as a result of the eradication program over the past 27 years.

Comparison of Strategies and Incidence Thresholds for Vi Conjugate Vaccines Against Typhoid Fever: A Cost-effectiveness Modeling Study.

Background: Typhoid fever remains a major public health problem globally. While new Vi conjugate vaccines hold promise for averting disease, the optimal programmatic delivery remains unclear. We aimed to identify the strategies and associated epidemiologic conditions under which Vi conjugate vaccines would be cost-effective. Methods: We developed a dynamic, age-structured transmission and cost-effectiveness model that simulated multiple vaccination strategies with a typhoid Vi conjugate vaccine from a societal perspective. We simulated 10-year vaccination programs with (1) routine immunization of infants (aged <1 year) through the Expanded Program on Immunization (EPI) and (2) routine immunization of infants through the EPI plus a 1-time catch-up campaign in school-aged children (aged 5-14 years). In the base case analysis, we assumed a 0.5% case-fatality rate for all cases of clinically symptomatic typhoid fever and defined strategies as highly cost-effective by using the definition of a low-income country (defined as a country with a gross domestic product of $1045 per capita). We defined incidence as the true number of clinically symptomatic people in the population per year. Results: Vi conjugate typhoid vaccines were highly cost-effective when administered by routine immunization activities through the EPI in settings with an annual incidence of >50 cases/100000 (95% uncertainty interval, 40-75 cases) and when administered through the EPI plus a catch-up campaign in settings with an annual incidence of >130 cases/100000 (95% uncertainty interval, 50-395 cases). The incidence threshold was sensitive to the typhoid-related case-fatality rate, carrier contribution to transmission, vaccine characteristics, and country-specific economic threshold for cost-effectiveness. Conclusions: Typhoid Vi conjugate vaccines would be highly cost-effective in low-income countries in settings of moderate typhoid incidence (50 cases/100000 annually). These results were sensitive to case-fatality rates, underscoring the need to consider factors contributing to typhoid mortality (eg, healthcare access and antimicrobial resistance) in the global vaccination strategy.

Existing and potential infection risk zones of yellow fever worldwide: a modelling analysis.

BACKGROUND: Yellow fever cases are under-reported and the exact distribution of the disease is unknown. An effective vaccine is available but more information is needed about which populations within risk zones should be targeted to implement interventions. Substantial outbreaks of yellow fever in Angola, Democratic Republic of the Congo, and Brazil, coupled with the global expansion of the range of its main urban vector, Aedes aegypti, suggest that yellow fever has the propensity to spread further internationally. The aim of this study was to estimate the disease's contemporary distribution and potential for spread into new areas to help inform optimal control and prevention strategies. METHODS: We assembled 1155 geographical records of yellow fever virus infection in people from 1970 to 2016. We used a Poisson point process boosted regression tree model that explicitly incorporated environmental and biological explanatory covariates, vaccination coverage, and spatial variability in disease reporting rates to predict the relative risk of apparent yellow fever virus infection at a 5 × 5 km resolution across all risk zones (47 countries across the Americas and Africa). We also used the fitted model to predict the receptivity of areas outside at-risk zones to the introduction or reintroduction of yellow fever transmission. By use of previously published estimates of annual national case numbers, we used the model to map subnational variation in incidence of yellow fever across at-risk countries and to estimate the number of cases averted by vaccination worldwide. FINDINGS: Substantial international and subnational spatial variation exists in relative risk and incidence of yellow fever as well as varied success of vaccination in reducing incidence in several high-risk regions, including Brazil, Cameroon, and Togo. Areas with the highest predicted average annual case numbers include large parts of Nigeria, the Democratic Republic of the Congo, and South Sudan, where vaccination coverage in 2016 was estimated to be substantially less than the recommended threshold to prevent outbreaks. Overall, we estimated that vaccination coverage levels achieved by 2016 avert between 94 336 and 118 500 cases of yellow fever annually within risk zones, on the basis of conservative and optimistic vaccination scenarios. The areas outside at-risk regions with predicted high receptivity to yellow fever transmission (eg, parts of Malaysia, Indonesia, and Thailand) were less extensive than the distribution of the main urban vector, A aegypti, with low receptivity to yellow fever transmission in southern China, where A aegypti is known to occur. INTERPRETATION: Our results provide the evidence base for targeting vaccination campaigns within risk zones, as well as emphasising their high effectiveness. Our study highlights areas where public health authorities should be most vigilant for potential spread or importation events. FUNDING: Bill & Melinda Gates Foundation.