Endothelium Activation during Severe Yellow Fever Triggers an Intense Cytokine-Mediated Inflammatory Response in the Liver Parenchyma

Yellow fever (YF) is a pansystemic disease caused by the yellow fever virus (YFV), the prototype species of the family Flaviviridae and genus Flavivirus, and has a highly complex host-pathogen relationship, in which endothelial dysfunction reflects viral disease tropism. In this study, the in situ endothelial response was evaluated. Liver tissue samples were collected from 21 YFV-positive patients who died due to the disease and five flavivirus-negative controls who died of other causes and whose hepatic parenchyma architecture was preserved. Immunohistochemical analysis of tissues in the hepatic parenchyma of YF cases showed significantly higher expression of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and very late antigen-4 in YFV-positive cases than in flavivirus-negative controls. These results indicate that endothelium activation aggravates the inflammatory response by inducing the expression of adhesion molecules that contribute to the rolling, recruitment, migration, and construction of the inflammatory process in the hepatic parenchyma in fatal YF cases.

Pneumococcal conjugate vaccination schedules in infants—acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study

Background Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. Methods PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. Trial registration International Standard Randomised Controlled Trial Number 72821613.

Ecological and environmental factors affecting transmission of sylvatic yellow fever in the 2017–2019 outbreak in the Atlantic Forest, Brazil

Background Yellow fever virus (YFV) is an arbovirus that, despite the existence of a safe and effective vaccine, continues to cause outbreaks of varying dimensions in the Americas and Africa. Between 2017 and 2019, Brazil registered un unprecedented sylvatic YFV outbreak whose severity was the result of its spread into zones of the Atlantic Forest with no signals of viral circulation for nearly 80 years. Methods To investigate the influence of climatic, environmental, and ecological factors governing the dispersion and force of infection of YFV in a naïve area such as the landscape mosaic of Rio de Janeiro (RJ), we combined the analyses of a large set of data including entomological sampling performed before and during the 2017–2019 outbreak, with the geolocation of human and nonhuman primates (NHP) and mosquito infections. Results A greater abundance of Haemagogus mosquitoes combined with lower richness and diversity of mosquito fauna increased the probability of finding a YFV-infected mosquito. Furthermore, the analysis of functional traits showed that certain functional groups, composed mainly of Aedini mosquitoes which includes Aedes and Haemagogus mosquitoes, are also more representative in areas where infected mosquitoes were found. Human and NHP infections were more common in two types of landscapes: large and continuous forest, capable of harboring many YFV hosts, and patches of small forest fragments, where environmental imbalance can lead to a greater density of the primary vectors and high human exposure. In both, we show that most human infections (~ 62%) occurred within an 11-km radius of the finding of an infected NHP, which is in line with the flight range of the primary vectors. Conclusions Together, our data suggest that entomological data and landscape composition analyses may help to predict areas permissive to yellow fever outbreaks, allowing protective measures to be taken to avoid human cases. Graphical Abstract

An evaluation of the diagnostic performance characteristics of the Yellow Fever IgM immunochromatographic rapid diagnostic test kit from SD Biosensor in Ghana

Yellow fever is endemic in Ghana and outbreaks occur periodically. The prodromal signs due to Yellow Fever Virus (YFV) infection are non-specific, making clinical signs unreliable as the sole criteria for diagnosis. Accurate laboratory confirmation of suspected yellow fever cases is therefore vital in surveillance programs. Reporting of ELISA IgM testing results by laboratories can delay due to late arrival of samples from the collection sites as well as limited availability of ELISA kits. In this study, the diagnostic performance characteristics of a rapid immunochromatographic Standard Q Yellow Fever IgM test kit (SD Biosensor) was evaluated for the rapid diagnosis of Yellow Fever infection in Ghana. A panel of 275 sera, comprising 81 confirmed YFV positives and 194 negatives were re-tested in this study using the Standard Q Yellow Fever IgM test kit. Using the CDC/WHO Yellow Fever IgM capture ELISA as a benchmark, the sensitivity, specificity and accuracy of the Standard Q Yellow Fever test kit were 96.3%, 97.9% and 97.5%, respectively. The false positivity rate was 5.1% and there was no cross-reactivity when the Standard Q Yellow Fever test kit was tested against dengue, malaria and hepatitis B and C positive samples. In addition, inter-reader variability and invalid rate were both zero. The results indicate that the diagnostic performance of the Standard Q Yellow Fever IgM test kit on serum or plasma is comparable to the serum IgM detection by ELISA and can be used as a point of care rapid diagnostic test kit for YFV infection in endemic areas.

Mapping environmental suitability of Haemagogus and Sabethes spp. mosquitoes to understand sylvatic transmission risk of yellow fever virus in Brazil

Background Yellow fever (YF) is an arboviral disease which is endemic to Brazil due to a sylvatic transmission cycle maintained by infected mosquito vectors, non-human primate (NHP) hosts, and humans. Despite the existence of an effective vaccine, recent sporadic YF epidemics have underscored concerns about sylvatic vector surveillance, as very little is known about their spatial distribution. Here, we model and map the environmental suitability of YF’s main vectors in Brazil, Haemagogus spp. and Sabethes spp., and use human population and NHP data to identify locations prone to transmission and spillover risk. Methodology/Principal findings We compiled a comprehensive set of occurrence records on Hg. janthinomys, Hg. leucocelaenus, and Sabethes spp. from 1991–2019 using primary and secondary data sources. Linking these data with selected environmental and land-cover variables, we adopted a stacked regression ensemble modelling approach (elastic-net regularized GLM, extreme gradient boosted regression trees, and random forest) to predict the environmental suitability of these species across Brazil at a 1x1 km resolution. We show that while suitability for each species varies spatially, high suitability for all species was predicted in the Southeastern region where recent outbreaks have occurred. By integrating data on NHP host reservoirs and human populations, our risk maps further highlight municipalities within the region that are prone to transmission and spillover. Conclusions/Significance Our maps of sylvatic vector suitability can help elucidate potential locations of sylvatic reservoirs and be used as a tool to help mitigate risk of future YF outbreaks and assist in vector surveillance. Furthermore, at-risk regions identified from our work could help disease control and elucidate gaps in vaccination coverage and NHP host surveillance.

Prevalence and evolution of clinical cases of Yellow Fever in Brazil between the years 2007 to 2016

Yellow Fever (YF) is a non-contagious infectious disease of variable symptoms that occurs mainly in tropical forests regions of the Americas and Africa and is caused by a Flavivirus belonging to the Flaviviridae family. Its vectors are mosquitoes of the genus Haemagogus, Sabethes and Aedes, and these have non-human primates as the main source of infection. In Brazil, there has been no record of urban AF since 1942, although the increase in cases of the wild form combined with low vaccination coverage contribute to the risk of re-urbanization of the disease Material and methods: For the study, epidemiological data were obtained from confirmed cases of Yellow Fever reported in the Notification System for Health Disorders (SINAN) available at the Informatics Department of the Unified Health System (DATASUS). Results and discussion: A total of 177 cases of were reported in Brazil, the year with the highest notification was in 2016 (52). The region with the highest occurrence of cases were the Southeast (95). Regarding the clinical evolution, of the 177 cases, 68 affected patients were cured, while 89 died from the reported injury, evidencing a high rate of lethality (50.2%). Conclusion: YF remains a public health problem, over the years there was a decrease in cases, this was due to immunization campaigns in the country, however, there was a significant increase in notifications in 2016, this whole panorama reinforces the need intensifying surveillance and expanding vaccine coverage.