Search

Summary Background Substantial outbreaks of yellow fever in Angola and Brazil in the past 2 years, combined with global shortages in vaccine stockpiles, highlight a pressing need to assess present control strategies. The aims of this study were to estimate global yellow fever vaccination coverage from 1970 through to 2016 at high spatial resolution and to calculate the number of individuals still requiring vaccination to reach population coverage thresholds for outbreak prevention. Methods For this adjusted retrospective analysis, we compiled data from a range of sources (eg, WHO reports and health-service-provider registeries) reporting on yellow fever vaccination activities between May 1, 1939, and Oct 29, 2016. To account for uncertainty in how vaccine campaigns were targeted, we calculated three population coverage values to encompass alternative scenarios. We combined these data with demographic information and tracked vaccination coverage through time to estimate the proportion of the population who had ever received a yellow fever vaccine for each second level administrative division across countries at risk of yellow fever virus transmission from 1970 to 2016. Findings Overall, substantial increases in vaccine coverage have occurred since 1970, but notable gaps still exist in contemporary coverage within yellow fever risk zones. We estimate that between 393·7 million and 472·9 million people still require vaccination in areas at risk of yellow fever virus transmission to achieve the 80% population coverage threshold recommended by WHO; this represents between 43% and 52% of the population within yellow fever risk zones, compared with between 66% and 76% of the population who would have required vaccination in 1970. Interpretation Our results highlight important gaps in yellow fever vaccination coverage, can contribute to improved quantification of outbreak risk, and help to guide planning of future vaccination efforts and emergency stockpiling. Funding The Rhodes Trust, Bill & Melinda Gates Foundation, the Wellcome Trust, the National Library of Medicine of the National Institutes of Health, the European Union's Horizon 2020 research and innovation programme.

Recent yellow fever (YF) outbreaks have highlighted the increasing global risk of urban spread of the disease. In context of recurrent vaccine shortages, preventive vaccination activities require accurate estimates of existing population-level immunity. We present POLICI (POpulation-Level Immunization Coverage - Imperial), an interactive online tool for visualising and extracting YF vaccination coverage estimates in Africa. We calculated single year age-disaggregated sub-national population-level vaccination coverage for 1950-2050 across the African endemic zone by collating vaccination information and inputting it into a demographic model. This was then implemented on an open interactive web platform. POLICI interactively displays age-disaggregated, population-level vaccination coverages at the first subnational administrative level, through numerous downloadable and customisable visualisations. POLICI is available at https://polici.shinyapps.io/yellow_fever_africa/. POLICI offers an accessible platform for relevant stakeholders in global health to access and explore vaccination coverages. These estimates have already been used to inform the WHO strategy to Eliminate Yellow fever Epidemics (EYE).

Background Yellow fever virus (YFV) is a vector-borne flavivirus endemic to Africa and Latin America. Ninety per cent of the global burden occurs in Africa where it is primarily transmitted by Aedes spp, with Aedes aegypti the main vector for urban yellow fever (YF). Mosquito life cycle and viral replication in the mosquito are heavily dependent on climate, particularly temperature and rainfall. We aimed to assess whether seasonal variations in climatic factors are associated with the seasonality of YF reports. Methodology/Principal findings We constructed a temperature suitability index for YFV transmission, capturing the temperature dependence of mosquito behaviour and viral replication within the mosquito. We then fitted a series of multilevel logistic regression models to a dataset of YF reports across Africa, considering location and seasonality of occurrence for seasonal models, against the temperature suitability index, rainfall and the Enhanced Vegetation Index (EVI) as covariates alongside further demographic indicators. Model fit was assessed by the Area Under the Curve (AUC), and models were ranked by Akaike’s Information Criterion which was used to weight model outputs to create combined model predictions. The seasonal model accurately captured both the geographic and temporal heterogeneities in YF transmission (AUC = 0.81), and did not perform significantly worse than the annual model which only captured the geographic distribution. The interaction between temperature suitability and rainfall accounted for much of the occurrence of YF, which offers a statistical explanation for the spatio-temporal variability in transmission. Conclusions/Significance The description of seasonality offers an explanation for heterogeneities in the West-East YF burden across Africa. Annual climatic variables may indicate a transmission suitability not always reflected in seasonal interactions. This finding, in conjunction with forecasted data, could highlight areas of increased transmission and provide insights into the occurrence of large outbreaks, such as those seen in Angola, the Democratic Republic of the Congo and Brazil., Author summary In this article, we describe the development of a model to quantify the seasonal dynamics of yellow fever virus (YFV) transmission across Africa. YFV is a flavivirus transmitted, within Africa, primarily by Aedes spp where it causes an estimated 78,000 deaths a year despite the presence of a safe and effective vaccine. The importance of sufficient vaccination, made difficult by a global shortage, has been highlighted by recent large scale, devastating, outbreaks in Angola, the Democratic Republic of the Congo and Brazil. Here we describe a novel way of parameterising the effect of temperature on YFV transmission and implement statistical models to predict both the geographic and temporal heterogeneities in transmissions, while demonstrating their robustness in comparison to models simply predicting geographic distribution. We believe this quantification of seasonality could lead to more precise applications of vaccination campaigns and vector-control programmes. In turn this would help maximise their impact, especially vital with limited resources, and could contribute to lessening the risk of large scale outbreaks. Not only this, but the methods described here could be applied to other Aedes-borne diseases and as such provide a useful tool in understanding, and combatting, several other important diseases such as dengue and zika.

Summary 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.

Background The emergence of different viral infections during the last decades like dengue, West Nile, SARS, chikungunya, MERS-CoV, Ebola, Zika and Yellow Fever raised some questions on quickness and reliability of laboratory diagnostic tests for verification of suspected cases. Since sampling of blood requires medically trained personal and comprises some risks for the patient as well as for the health care personal, the sampling by non-invasive methods (e.g. saliva and/ or urine) might be a very valuable alternative for investigating a diseased patient. Main body To analyse the usefulness of alternative non­invasive samples for the diagnosis of emerging infectious viral diseases, a literature search was performed on PubMed for alternative sampling for these viral infections. In total, 711 papers of potential relevance were found, of which we have included 128 in this review. Conclusions Considering the experience using non-invasive sampling for the diagnostic of emerging viral diseases, it seems important to perform an investigation using alternative samples for routine diagnostics. Moreover, during an outbreak situation, evaluation of appropriate sampling and further processing for laboratory analysis on various diagnostic platforms are very crucial. This will help to achieve optimal diagnostic results for a good and reliable case identification. Open-Access-Publikationsfonds 2018

Background Starting in 2008, the Central African Republic (CAR) experienced an unprecedented number of reported yellow fever (YF) cases. A risk assessment of YF virus (YFV) activity was conducted to estimate potential disease risk and vaccine needs. Methods A multistage cluster sampling design was used to sample humans, non-human primates, and mosquitoes in distinct ecologic zones. Humans and non-human primates were tested for YFV-specific antibodies; mosquitoes were tested for YFV RNA. Results Overall, 13.3% (125/938) of humans were found to have naturally-acquired YFV antibodies. Antibody levels were higher in zones in the southern and south central regions of CAR. All sampled non-human primates (n=56) were known YFV reservoirs; one tested positive for YFV antibodies. Several known YF vectors were identified including Aedes africanus, Ae. aegypti, Ae. luteocephalus, and Ae. simpsoni. Several more urban locations were found to have elevated Breateau and Container indices for Ae. aegypti. Conclusions A country-wide assessment of YF risk found YFV to be endemic in CAR. The potential for future YF cases and outbreaks, however, varied by ecologic zone. Improved vaccination coverage through mass campaign and childhood immunization was recommended to mitigate the YF risk.

Current regulations stipulate a yellow fever (YF) booster every 10 years. We conducted a systematic review of the protective efficacy and duration of immunity of YF vaccine in residents of disease-endemic areas and in travelers to assess the need for a booster in these two settings and in selected populations (human immunodeficiency virus-infected persons, infants, children, pregnant women, and severely malnourished persons). Thirty-six studies and 22 reports were included. We identified 12 studies of immunogenicity, 8 of duration of immunity, 8 of vaccine response in infants and children, 7 of human-immunodeficiency virus-infected persons, 2 of pregnant women, and 1 of severely malnourished children. Based on currently available data, a single dose of YF vaccine is highly immunogenic and confers sustained life-long protective immunity against YF. Therefore, a booster dose of YF vaccine is not needed. Special considerations for selected populations are detailed.

Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) is a rare and serious adverse event of the yellow fever (YF) vaccine that mimics wild-type YF. Research shows there may be an increased risk of YEL-AVD among the elderly population (≥ 60-65 years old), however this research has yet to be accumulated and reviewed in order to make policy recommendations to countries currently administering the YF vaccine. This paper systematically reviewed all information available on YEL-AVD to determine if there is an increased risk among the elderly, for both travelers and endemic populations. Age-specific reporting rates (RRs) were re-calculated from the literature using the Brighton Collaboration case definition for YEL-AVD and were then analyzed to determine if there was a significant difference between the RRs of younger and older age groups. Two out of the five studies found a significantly higher rate of YEL-AVD among the elderly population. Our findings suggest unexposed elders may be at an increased risk of developing YEF-AVD, however the evidence remains limited. Therefore, our findings for YF vaccination of elderly populations support the recommendations made by the Strategic Advisory Group of Experts (SAGE) in their April 2013 meeting, mainly vaccination of the elderly should be based on a careful risk-benefit analysis.

Neil Ferguson and colleagues estimate the disease burden of yellow fever in Africa, as well as the impact of mass vaccination campaigns. Please see later in the article for the Editors' Summary, Background Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods. Methods and Findings Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone. The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000–380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000–180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%–31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys. Conclusions With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns. Please see later in the article for the Editors' Summary, Editors' Summary Background Yellow fever is a flavivirus infection that is transmitted to people and to non-human primates through the bites of infected mosquitoes. This serious viral disease affects people living in and visiting tropical regions of Africa and Central and South America. In rural areas next to forests, the virus typically causes sporadic cases or even small-scale epidemics (outbreaks) but, if it is introduced into urban areas, it can cause large explosive epidemics that are hard to control. Although many people who contract yellow fever do not develop any symptoms, some have mild flu-like symptoms, and others develop a high fever with jaundice (yellowing of the skin and eyes) or hemorrhaging (bleeding) from the mouth, nose, eyes, or stomach. Half of patients who develop these severe symptoms die. Because of this wide spectrum of symptoms, which overlap with those of other tropical diseases, it is hard to diagnose yellow fever from symptoms alone. However, serological tests that detect antibodies to the virus in the blood can help in diagnosis. There is no specific antiviral treatment for yellow fever but its symptoms can be treated. Why Was This Study Done? Eradication of yellow fever is not feasible because of the wildlife reservoir for the virus but there is a safe, affordable, and highly effective vaccine against the disease. Large-scale vaccination efforts during the 1940s, 1950s, and 1960s reduced the yellow fever burden for several decades but, after a period of low vaccination coverage, the number of cases rebounded. In 2005, the Yellow Fever Initiative—a collaboration between the World Health Organization (WHO) and the United Nations Children Fund supported by the Global Alliance for Vaccines and Immunization (GAVI Alliance)—was launched to create a vaccine stockpile for use in epidemics and to implement preventive mass vaccination campaigns in the 12 most affected countries in West Africa. Campaigns have now been implemented in all these countries except Nigeria. However, without an estimate of the current yellow fever burden, it is hard to determine the impact of these campaigns. Here, the researchers use recent yellow fever occurrence data, serological survey data, and improved estimation methods to update estimates of the yellow fever burden and to determine the impact of mass vaccination on this burden. What Did the Researchers Do and Find? The researchers developed a generalized linear statistical model and used data on the locations where yellow fever was reported between 1987 and 2011 in Africa, force of infection estimates for a limited set of locations where serological surveys were available (the force of infection is the rate at which susceptible individuals acquire a disease), data on vaccination coverage, and demographic and environmental data for their calculations. They estimate that about 130,000 yellow fever cases with fever and jaundice or hemorrhage occurred in Africa in 2013 and that about 78,000 people died from the disease. By evaluating the difference between this estimate, which takes into account the current vaccination coverage, and a hypothetical scenario that excluded the mass vaccination campaigns, the researchers estimate that these campaigns have reduced the burden of disease by 27% across Africa and by up to 82% in the countries targeted by the campaigns (an overall reduction of 57% in the 12 targeted countries). What Do These Findings Mean? These findings provide a contemporary estimate of the burden of yellow fever in Africa. This estimate is broadly similar to the historic estimate of 200,000 cases and 30,000 deaths annually, which was based on serological survey data obtained from children in Nigeria between 1945 and 1971. Notably, both disease burden estimates are several hundred-fold higher than the average number of yellow fever cases reported annually to WHO, which reflects the difficulties associated with the diagnosis of yellow fever. Importantly, these findings also provide an estimate of the impact of recent mass vaccination campaigns. All these findings have a high level of uncertainty, however, because of the lack of data from both surveillance and serological surveys. Other assumptions incorporated in the researchers' model may also affect the accuracy of these findings. Nevertheless, the framework for burden estimation developed here provides essential new information about the yellow fever burden and the impact of vaccination campaigns and should help the partners of the Yellow Fever Initiative estimate the potential impact of future vaccination campaigns and ensure the efficient allocation of resources for yellow fever control. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001638. The World Health Organization provides detailed information about yellow fever (in several languages), including photo stories about vaccination campaigns in the Sudan and Mali; it also provides information about the Yellow Fever Initiative (in English and French) The GAVI Alliance website includes detailed of its support for yellow fever vaccination The US Centers for Disease Control and Prevention provides information about yellow fever for the public, travelers, and health care providers The UK National Health Service Choices website also has information about yellow fever Wikipedia has a page on yellow fever that includes information about the history of the disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Background Serious, but rare adverse events following immunization (AEFI) have been reported with yellow fever (YF) 17D vaccine, including severe allergic reactions, YF vaccine-associated neurologic disease (YEL-AND) and YF vaccine-associated viscerotropic disease (YEL-AVD). The frequency with which YEL-AND and YEL-AVD occur in YF endemic countries is mostly unknown. Methods From 2007 to 2010, eight African countries – Benin, Cameroon, Guinea, Liberia, Mali, Senegal, Sierra Leone, and Togo- implemented large-scale YF preventive vaccination campaigns. Each country established vaccine pharmacovigilance systems that included standard case definitions, procedures to collect and transport biological specimens, and National Expert Committees to review data and classify cases. Staff in all countries received training and laboratory capacity expanded. Results In total, just over 38 million people were vaccinated against YF and 3116 AEFIs were reported of which 164 (5%) were classified as serious. Of these, 22 (13%) were classified as YF vaccine reactions, including 11 (50%) hypersensitivity reactions, six (27%) suspected YEL-AND, and five (23%) suspected YEL-AVD. The incidence per 100,000 vaccine doses administered was 8.2 for all reported AEFIs, 0.43 for any serious AEFI, 0.058 for YF vaccine related AEFIs, 0.029 for hypersensitivity reactions, 0.016 for YEL-AND, and 0.013 for YEL-AVD. Our findings were limited by operational challenges, including difficulties in obtaining recommended biological specimens leading to incomplete laboratory evaluation, unknown case ascertainment, and variable levels of staff training and experience. Conclusions Despite limitations, active case-finding in the eight different countries did not find an incidence of YF vaccine associated AEFIs that was higher than previous reports. These data reinforce the safety profile of YF vaccine and support the continued use of attenuated YF vaccine during preventive mass vaccination campaigns in YF endemic areas.

The immune response to yellow fever (YF) vaccine and its safety among HIV-infected individuals living in YF endemic areas is not well understood. Following a national YF preventive immunisation campaign in Mali in April 2008, we assessed the immunogenicity and safety of 17D yellow fever vaccine (17DV) among HIV-infected patients in two HIV treatment centres in Bamako, Mali, by testing for neutralising antibodies and identifying serious adverse events following immunisation (AEFI). A YF neutralisation titre (NT) of 1:≥20 was considered to be adequate and protective. A serious AEFI included hospitalisation, any life-threatening condition, or death, occurring within 30 days following 17DV administration. Of 115 HIV-infected patients who reported having received 17DV, 110 (96%) were on combination antiretroviral therapy and 83 patients were tested for neutralising antibodies. Around the time of vaccination, median CD4 cell count was 389 cells/mm(3) (IQR 227-511cells/mm(3)); HIV-RNA was undetectable in 24 of 46 patients tested. Seventy-six (92%) of 83 participants had adequate immune titres 9 months after the immunisation campaign. Previous vaccination or flavivirus exposure could contribute to this finding. No serious AEFI was found in the 115 participants. In this small series, YF vaccine appeared to be immunogenic with a favourable safety profile in HIV-infected patients on antiretroviral therapy. Higher CD4 cell counts and suppressed HIV-RNA were associated with the presence of an adequate immune titre and higher NTs.

Yellow fever (YF) remains an important public health problem in regions where the disease is endemic, with a dramatic upsurge in the number of cases in recent years. So far, extensive YF epizooties occurred in South America in 2008, and during the past year YF outbreaks arose in Cameroon, Democratic

Background Yellow fever (YF) virtually disappeared in francophone West African countries as a result of YF mass vaccination campaigns carried out between 1940 and 1953. However, because of the failure to continue mass vaccination campaigns, a resurgence of the deadly disease in many African countries began in the early 1980s. We developed an original modeling approach to assess YF epidemic risk (vulnerability) and to prioritize the populations to be vaccinated. Methods and Findings We chose a two-step assessment of vulnerability at district level consisting of a quantitative and qualitative assessment per country. Quantitative assessment starts with data collection on six risk factors: five risk factors associated with “exposure” to virus/vector and one with “susceptibility” of a district to YF epidemics. The multiple correspondence analysis (MCA) modeling method was specifically adapted to reduce the five exposure variables to one aggregated exposure indicator. Health districts were then projected onto a two-dimensional graph to define different levels of vulnerability. Districts are presented on risk maps for qualitative analysis in consensus groups, allowing the addition of factors, such as population migrations or vector density, that could not be included in MCA. The example of rural districts in Burkina Faso show five distinct clusters of risk profiles. Based on this assessment, 32 of 55 districts comprising over 7 million people were prioritized for preventive vaccination campaigns. Conclusion This assessment of yellow fever epidemic risk at the district level includes MCA modeling and consensus group modification. MCA provides a standardized way to reduce complexity. It supports an informed public health decision-making process that empowers local stakeholders through the consensus group. This original approach can be applied to any disease with documented risk factors., Author Summary This article describes the use of an original modeling approach to assess the risk of yellow fever (YF) epidemics. YF is a viral hemorrhagic fever responsible in past centuries for devastating outbreaks. Since the 1930s, a vaccine has been available that protects the individual for at least 10 years, if not for life. However, immunization of populations in African countries was gradually discontinued after the 1960s. With the decrease in immunity against YF in African populations the disease reemerged in the 1980s. In 2005, WHO, UNICEF, and the GAVI Alliance decided to support preventive vaccination of at-risk populations in West African endemic countries in order to tackle the reemergence of YF and reduce the risk of urban YF outbreaks. Financial resources were made available to scale up a global YF vaccine stockpile and to support countries with limited resources in the management of preventive vaccination campaigns. This article describes the process we used to determine the most at-risk populations using a mathematical model to prioritize targeted immunization campaigns. We believe that this approach could be useful for other diseases for which decision making process is difficult because of limited data availability, complex risk variables, and a need for rapid decisions and implementation.