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Since late 2015, an epidemic of yellow fever has caused more than 7334 suspected cases in Angola and the Democratic Republic of the Congo, including 393 deaths. We sought to understand the spatial spread of this outbreak to optimise the use of the limited available vaccine stock. We jointly analysed datasets describing the epidemic of yellow fever, vector suitability, human demography, and mobility in central Africa to understand and predict the spread of yellow fever virus. We used a standard logistic model to infer the district-specific yellow fever virus infection risk during the course of the epidemic in the region. The early spread of yellow fever virus was characterised by fast exponential growth (doubling time of 5–7 days) and fast spatial expansion (49 districts reported cases after only 3 months) from Luanda, the capital of Angola. Early invasion was positively correlated with high population density (Pearson's r 0·52, 95% CI 0·34–0·66). The further away locations were from Luanda, the later the date of invasion (Pearson's r 0·60, 95% CI 0·52–0·66). In a Cox model, we noted that districts with higher population densities also had higher risks of sustained transmission (the hazard ratio for cases ceasing was 0·74, 95% CI 0·13–0·92 per log-unit increase in the population size of a district). A model that captured human mobility and vector suitability successfully discriminated districts with high risk of invasion from others with a lower risk (area under the curve 0·94, 95% CI 0·92–0·97). If at the start of the epidemic, sufficient vaccines had been available to target 50 out of 313 districts in the area, our model would have correctly identified 27 (84%) of the 32 districts that were eventually affected. Our findings show the contributions of ecological and demographic factors to the ongoing spread of the yellow fever outbreak and provide estimates of the areas that could be prioritised for vaccination, although other constraints such as vaccine supply and delivery need to be accounted for before such insights can be translated into policy. Wellcome Trust.

Yellow fever (YF) is a re-emerging viral zoonosis caused by the Yellow Fever virus (YFV), affecting humans and non-human primates (NHP). YF is endemic in South America and Africa, being considered a burden for public health worldwide despite the availability of an effective vaccine. Acute infectious disease can progress to severe hemorrhagic conditions and has high rates of morbidity and mortality in endemic countries. In 2016, Brazil started experiencing one of the most significant YF epidemics in its history, with lots of deaths being reported in regions that were previously considered free of the disease. Here, we reviewed the historical aspects of YF in Brazil, the epidemiology of the disease, the challenges that remain in Brazil’s public health context, the main lessons learned from the recent outbreaks, and our perspective for facing future YF epidemics.

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. 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. 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.

Yellow fever (YF) mainly causes severe hepatitis; data on pulmonary pathology remain limited. We investigated respiratory tract pathology in 73 fatal YF cases during the 2017-2019 epidemic in São Paulo, Brazil. All patients died from YF-related fulminant hepatitis. Autopsies revealed frequent tracheitis (91%), pulmonary edema and hemorrhage (100%), diffuse alveolar damage (84%), secondary pneumonia (84%), and bronchoaspiration (60%). Microabscesses, thrombi, and hemophagocytosis were also observed. In 5 cases of vaccine-associated viscerotropic disease, hemorrhage and diffuse alveolar damage were prominent. We detected antigens of YF virus in all cases and viral RNA in 94%. Molecular analysis identified bacterial and fungal pathogens in pneumonia, including gram-negative bacilli, Candida spp., and Aspergillus spp. Electron microscopy did not reveal viral particles in 3 examined cases. Our findings underscore the respiratory tract involvement in severe YF and could help guide diagnosis, intensive care, and public health preparedness in future outbreaks.

Introduction: Yellow fever (YF) is a viral hemorrhagic fever transmitted by mosquitoes, characterized by a high mortality due to kidney and liver failure, massive coagulation disorders, and hemorrhages. With no specific treatment, prevention through vaccination and vector control is essential. This study investigates the epidemiology of YF in Brazil from 2011 to 2020, focusing on its trends and distribution across the territory. Methods: This ecological time-series study analyzed confirmed YF cases in Brazil’s 27 federative units between 2011 and 2020. Data were sourced from DATASUS, IBGE, and IPEA. Incidence rates per 100,000 inhabitants were calculated, and various sociodemographic and health indicators were analyzed. Prais–Winsten autoregressive models assessed the trends, while a spatial analysis identified the risk areas using global and local Moran’s I statistics. The data were processed using Stata and GeoDa® software, version 1.12. Results: YF cases were concentrated in the Amazon and Atlantic Forest biomes. The majority of the cases occurred in males (83.3%), non-white individuals (94.3%), and rural workers. Pará showed an increasing trend in incidence. A higher vaccination coverage correlated with a lower YF incidence, though endemic areas with good vaccination coverage still exhibited high rates. Health and socioeconomic indicators were inversely related to incidence, highlighting disparities in regional development. Conclusion: Effective YF control requires multidisciplinary strategies, including expanded vaccination coverage, intensified vector control, and active surveillance. Research should focus on developing better vaccines, monitoring immunity, and improving the global response coordination.

Background Case fatality risk (CFR), commonly referred to as a case fatality ratio or rate, represents the probability of a disease case being fatal. It is often estimated for various diseases through analysis of surveillance data, case reports, or record examinations. Reported CFR values for Yellow Fever vary, offering wide ranges. Estimates have not been found through systematic literature review, which has been used to estimate CFR of other diseases. This study aims to estimate the case fatality risk of severe Yellow Fever cases through a systematic literature review and meta-analysis. Methods A search strategy was implemented in PubMed and Ovid Medline in June 2019 and updated in March 2021, seeking reported severe case counts, defined by fever and either jaundice or hemorrhaging, and the number of those that were fatal. The searches yielded 1,133 studies, and title/abstract review followed by full text review produced 14 articles reporting 32 proportions of fatal cases, 26 of which were suitable for meta-analysis. Four studies with one proportion each were added to include clinical case data from the recent outbreak in Brazil. Data were analyzed through an intercept-only logistic meta-regression with random effects for study. Values of the I 2 statistic measured heterogeneity across studies. Results The estimated CFR was 39 % (95 % CI: 31 %, 47 %). Stratifying by continent showed that South America observed a higher CFR than Africa, though fewer studies reported estimates for South America. No difference was seen between studies reporting surveillance data and studies investigating outbreaks, and no difference was seen among different symptom definitions. High heterogeneity was observed across studies. Conclusions Approximately 39 % of severe Yellow Fever cases are estimated to be fatal. This study provides the first systematic literature review to estimate the CFR of Yellow Fever, which can provide insight into outbreak preparedness and estimating underreporting.

The live, attenuated yellow fever (YF) 17D vaccine provides highly effective and durable immunity and is widely used for travelers to and residents of endemic areas of South America and Africa. Neurotropic and viscerotropic serious adverse events associated with these vaccines occur rarely, but YF 17D vaccine-associated viscerotropic disease (YEL-AVD) is notable for its lethality. There appear to be two distinct patterns of risk for YEL-AVD: the first in younger persons, particularly women, with defects in innate immunity, in whom the case-fatality rate is higher; and the second in elderly persons, particularly men with age-related immune senescence and a lower case-fatality rate. From 1990 to the present, the number of cases (n = 31) and deaths (n = 12) from YEL-AVD in travelers has exceeded the reports of YF (n = 6) acquired by natural infection, raising the question whether the risk of vaccination exceeds the benefit in travelers. To provide some guidance on this point, the rate of vaccine-related injury is compared with the rate of naturally acquired disease in a new analysis that estimates the immunologically susceptible denominator population in YF endemic and epidemic areas. For many years, the risk of vaccine-related illness and death was similar to the risk of illness and death from natural infection with YF in South America. Africa posed a substantially higher estimated risk of wild-type YF than vaccine-related injury. Multiple factors should be considered in making decisions about YF vaccination, including specific destination, season of the year, local evidence for YF transmission, likelihood of exposure to vector mosquitoes and individual risk factors for YEL-AVD, with the goal of increasing vaccine coverage for travel to high-risk areas and reducing unnecessary vaccination. Prospects for future, safer vaccines are also described.

Necroptosis is a regulated form of cell death implicated in several pathological conditions, including viral infections. In this study, we investigated the expression and correlation of necroptosis markers MLKL, RIP1 and RIP3 in human liver tissue from fatal cases of yellow fever (YF) using immunohistochemistry (IHC). The liver samples were obtained from 21 YF-positive individuals and five flavivirus-negative controls with preserved liver parenchymal architecture. The cases underwent histopathological analysis, followed by tissue immunostaining with the immunohistochemical method of streptavidin–biotin peroxidase. Using the in situ method, we evaluated the centrilobular zone (Z3), midzonal zone (Z2), periportal zone and portal tract (PT) of human liver parenchyma with markers for necroptosis, RIPK1, RIPK3 and MLKL. A quantitative analysis revealed a significantly higher expression of MLKL, RIP1 and RIP3 in the liver parenchyma of YF cases compared to controls in different zones (Z3, Z2, Z1) and portal tracts (PTs) of the liver, especially in zone 2. Immunostaining confirmed the localization of MLKL, RIP1 and RIP3 in hepatocytes and inflammatory infiltrates, highlighting their involvement in the pathogenesis of YF. A Pearson correlation analysis demonstrated significant correlations among necroptosis markers, which indicates their coordinated regulation during YF-induced liver injury.

Live, attenuated yellow fever (YF) 17D vaccine is highly efficacious but causes rare, serious adverse events resulting from active replication in the host and direct viral injury to vital organs. We recently reported development of a potentially safer β-propiolactone-inactivated whole virion YF vaccine (XRX-001), which was highly immunogenic in mice, hamsters, monkeys, and humans [10,11]. To characterize the protective efficacy of neutralizing antibodies stimulated by the inactivated vaccine, graded doses of serum from hamsters immunized with inactivated XRX-001 or live 17D vaccine were transferred to hamsters by the intraperitoneal (IP) route 24 h prior to virulent, viscerotropic YF virus challenge. Neutralizing antibody (PRNT 50) titers were determined in the sera of treated animals 4 h before challenge and 4 and 21 days after challenge. Neutralizing antibodies were shown to mediate protection. Animals having 50% plaque reduction neutralization test (PRNT 50) titers of ≥40 4 h before challenge were completely protected from disease as evidenced by viremia, liver enzyme elevation, and protection against illness (weight change) and death. Passive titers of 10–20 were partially protective. Immunization with the XRX-001 vaccine stimulated YF neutralizing antibodies that were equally effective (based on dose response) as antibodies stimulated by live 17D vaccine. The results will be useful in defining the level of seroprotection in clinical studies of new yellow fever vaccines.

Yellow fever virus (YFV) infection is fatal in 5%-10% of the 200,000 yearly cases. There is currently no available antiviral treatment. We showed previously that administration of 50 mg/kg of a YFV-specific neutralizing monoclonal antibody (nmAb) at 2 days postinfection (dpi), prior to the onset of severe disease, protected YFV-infected rhesus macaques from death. To further explore the clinical applicability of our nmAb MBL-YFV-01, we treated rhesus macaques with a lower dose (10 mg/kg) of this nmAb prophylactically or therapeutically at 3.5 dpi. We show that a single prophylactic or therapeutic i.v. dose of our nmAb protects rhesus macaques from death following challenge. A comprehensive analysis of 167 inflammatory cytokine and chemokines revealed that protection was associated with significantly reduced expression of 125 of these markers, including type I IFN, IL-6, and CCL2. This study further expands the potential clinical use of our YFV-specific nmAb, which could be used during an outbreak for immediate prophylactic immunity or for patients with measurable serum viremia.