Yellow fever (YF) is an acute viral disease, affecting humans and non-human primates (NHP), caused by the yellow fever virus (YFV). Despite the existence of a safe vaccine, YF continues to cause morbidity and mortality in thousands of people in Africa and South America. Since 2016, massive YF outbreaks have taken place in Brazil, reaching YF–free zones, causing thousands of deaths of humans and NHP. Here we reviewed the main epidemiological aspects, new clinical findings in humans, and issues regarding YFV infection in vectors and NHP in Brazil. The 2016–2019 YF epidemics have been considered the most significant outbreaks of the last 70 years in the country, and the number of human cases was 2.8 times higher than total cases in the previous 36 years. A new YFV lineage was associated with the recent outbreaks, with persistent circulation in Southeast Brazil until 2019. Due to the high number of infected patients, it was possible to evaluate severity and death predictors and new clinical features of YF.Haemagogus janthinomysandHaemagogus leucocelaenuswere considered the primary vectors during the outbreaks, and no human case suggested the occurrence of the urban transmission cycle. YFV was detected in a variety of NHP specimens presenting viscerotropic disease, similar to that described experimentally. Further studies regarding NHP sensitivity to YFV, YF pathogenesis, and the duration of the immune response in NHP could contribute to YF surveillance, control, and future strategies for NHP conservation.

The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of smallpox, emerging zoonotic orthopoxviruses, such as monkeypox, cowpox, and vaccinia viruses continue to infect humans as well as wild and domestic animals. Currently, the geographical distribution of poxviruses in a broad range of hosts worldwide raises concerns regarding the possibility of outbreaks or viral dissemination to new geographical regions. Here, we review the global host ranges and current epidemiological understanding of zoonotic orthopoxviruses while focusing on orthopoxviruses with epidemic potential, including monkeypox, cowpox, and vaccinia viruses.

From the end of 2016 until the beginning of 2019, Brazil faced a massive sylvatic yellow fever (YF) outbreak. The 2016–2019 YF epidemics affected densely populated areas, especially the Southeast region, causing thousands of deaths of humans and non-human primates (NHP). We conducted a molecular investigation of yellow fever virus (YFV) RNA in 781 NHP carcasses collected in the urban, urban-rural interface, and rural areas of Minas Gerais state, from January 2017 to December 2018. Samples were analyzed according to the period of sampling, NHP genera, sampling areas, and sampling areas/NHP genera to compare the proportions of YFV-positive carcasses and the estimated YFV genomic loads. YFV infection was confirmed in 38.1% of NHP carcasses (including specimens of the genera Alouatta, Callicebus, Callithrix, and Sapajus), from the urban, urban-rural interface, and rural areas. YFV RNA detection was positively associated with epidemic periods (especially from December to March) and the rural environment. Higher median viral genomic loads (one million times) were estimated in carcasses collected in rural areas compared to urban ones. The results showed the wide occurrence of YF in Minas Gerais in epidemic and non-epidemic periods. According to the sylvatic pattern of YF, a gradient of viral dissemination from rural towards urban areas was observed. A high YF positivity was observed for NHP carcasses collected in urban areas with a widespread occurrence in 67 municipalities of Minas Gerais, including large urban centers. Although there was no documented case of urban/Aedes YFV transmission to humans in Brazil during the 2016–2019 outbreaks, YFV-infected NHP in urban areas with high infestation by Aedes aegypti poses risks for YFV urban/Aedes transmission and urbanization. Brazil faced the most massive sylvatic yellow fever (YF) outbreak in 2016–2019. The outbreak affected highly densely populated areas, and Minas Gerais was the most affected state with thousands of deaths of human and non-human primates (NHP). We investigated the yellow fever virus (YFV) RNA in NHP carcasses collected throughout Minas Gerais in 2017 and 2018. We demonstrated the wide occurrence of YFV-infected NHP, including the viral persistence during the non-epidemic dry season of 2017. YFV RNA was detected in NHP carcasses in the urban, urban-rural interface and rural areas. We have also detected new YF cases in 49 municipalities where YF cases have not been previously detected during the outbreaks. Estimates of YFV genomic load in naturally infected NHP carcasses showed high and similar loads in specimens (Alouatta, Callithrix, and Callicebus) collected in rural areas and lower genomic loads in the urban-rural interface and urban Callithrix specimens. The presence of YFV inside urban areas poses an imminent risk, although no human case was epidemiologically linked to urban/Aedes transmission during the last outbreaks in Brazil.

Optimise control strategies of infectious diseases, identify factors that favour the circulation of pathogens, and propose risk maps are crucial challenges for global health. Ecological niche modelling, once relying on an adequate framework and environmental descriptors can be a helpful tool for such purposes. Despite the existence of a vaccine, yellow fever (YF) is still a public health issue. Brazil faced massive sylvatic YF outbreaks from the end of 2016 up to mid-2018, but cases in human and non-human primates have been recorded until the beginning of 2020. Here we used both human and monkey confirmed YF cases from two epidemic periods (2016/2017 and 2017/2018) to describe the spatial distribution of the cases and explore how biotic and abiotic factors drive their occurrence. The distribution of YF cases largely overlaps for humans and monkeys, and a contraction of the spatial extent associated with a southward displacement is observed during the second period of the epidemics. More contributive variables to the spatiotemporal heterogeneity of cases were related to biotic factors (mammal richness), abiotic factors (temperature and precipitation), and some human-related variables (population density, human footprint, and human vaccination coverage). Both projections of the most favourable conditions showed similar trends with a contraction of the more at-risk areas. Once extrapolated at a large scale, the Amazon basin remains at lower risk, although surrounding forest regions and notably the North-West region, would face a higher risk. Spatial projections of infectious diseases often relied on climatic variables only; here for both models, we instead highlighted the importance of considering local biotic conditions, hosts vulnerability, social and epidemiological factors to run the spatial risk analysis correctly: all YF cases occurring later on, in 2019 and 2020, were observed in the predicted at-risk areas. Yellow fever (YF) is a vector-borne disease and from December 2016 until 2020, caused infection and death in humans and monkeys in the Southeast and South of Brazil. The transmission cycle includes hosts and vectors whose presence and abundance are driven by environmental conditions. Ecological niche models are expected to identify biotic and abiotic conditions favourable to a species and to predict its likelihood of presence. Such models have shown their relevance to determine the environmental and anthropogenic variables favourable for host and vector species of infectious diseases, and consequently for highlighting more at-risk areas. Relying on human and monkey populations, we showed how temperature, rain, predicted mammal density, human impact, and vaccination coverage explained the occurrence of YF cases in 2017–2018 Brazilian epidemics. We predicted at-risk areas for future outbreaks, including areas outside and surrounding the Amazon basin, YF cases occurring later, in 2019 and 2020, were observed in the predicted at-risk areas using our modelling approach. This modelling approach, relying on ecology theory and methodological framework for using epidemiological data, helps to identify human threatened populations, for which vaccination efforts should be oriented, and also for monkeys whose preservation is the main biodiversity concern.

Mosquito-borne dengue (DENV) and Zika (ZIKV) viruses originated in Old World sylvatic (forest) cycles involving monkeys and canopy-living Aedes mosquitoes. Both viruses spilled over into human transmission and were translocated to the Americas, opening a path for spillback into Neotropical sylvatic cycles. Studies of the trade-offs that shape within-host dynamics and transmission of these viruses are lacking, hampering efforts to predict spillover and spillback. We infected a native, Asian host species (cynomolgus macaque) and a novel, American host species (squirrel monkey) with sylvatic strains of DENV-2 or ZIKV via mosquito bite. We then monitored aspects of viral replication (viremia), innate and adaptive immune response (natural killer (NK) cells and neutralizing antibodies, respectively), and transmission to mosquitoes. In both hosts, ZIKV reached high titers that translated into high transmission to mosquitoes; in contrast DENV-2 replicated to low levels and, unexpectedly, transmission occurred only when serum viremia was below or near the limit of detection. Our data reveal evidence of an immunologically-mediated trade-off between duration and magnitude of virus replication, as higher peak ZIKV titers are associated with shorter durations of viremia, and higher NK cell levels are associated with lower peak ZIKV titers and lower anti-DENV-2 antibody levels. Furthermore, patterns of transmission of each virus from a Neotropical monkey suggest that ZIKV has greater potential than DENV-2 to establish a sylvatic transmission cycle in the Americas.