Yellow Fever Virus Reemergence and Spread in Southeast Brazil, 2016-2019.

The recent reemergence of yellow fever virus (YFV) in Brazil has raised serious concerns due to the rapid dissemination of the virus in the southeastern region. To better understand YFV genetic diversity and dynamics during the recent outbreak in southeastern Brazil, we generated 18 complete and nearly complete genomes from the peak of the epidemic curve from nonhuman primates (NHPs) and human infected cases across the Espírito Santo and Rio de Janeiro states. Genomic sequencing of 18 YFV genomes revealed the estimated timing, source, and likely routes of yellow fever virus transmission and dispersion during one of the largest outbreaks ever registered in Brazil. We showed that during the recent epidemic, YFV was reintroduced from Minas Gerais to the Espírito Santo and Rio de Janeiro states multiple times between 2016 and 2019. The analysis of data from portable sequencing could identify the corridor of spread of YFV. These findings reinforce the idea that continued genomic surveillance strategies can provide information on virus genetic diversity and transmission dynamics that might assist in understanding arbovirus epidemics.IMPORTANCE Arbovirus infections in Brazil, including yellow fever, dengue, zika, and chikungunya, result in considerable morbidity and mortality and are pressing public health concerns. However, our understanding of these outbreaks is hampered by the limited availability of genomic data. In this study, we investigated the genetic diversity and spatial distribution of YFV during the current outbreak by analyzing genomic data from areas in southeastern Brazil not covered by other previous studies. To gain insights into the routes of YFV introduction and dispersion, we tracked the virus by sequencing YFV genomes sampled from nonhuman primates and infected patients from the southeastern region. Our study provides an understanding of how YFV initiates transmission in new Brazilian regions and illustrates that genomics in the field can augment traditional approaches to infectious disease surveillance and control.

Isolation and sequencing of Orthoflavivirus ilheusense from mosquitoes collected in the Brazilian cerrado, West-Central region, Brazil.

The Orthoflavivirus ilheusense (ILHV) is an arbovirus that was first isolated in Brazil in 1944 during an epidemiologic investigation of yellow fever. Is a member of the Flaviviridae family and it belongs to the antigenic complex of the Ntaya virus group. Psorophora ferox is the primary vector of ILHV and this study presents the isolation and phylogenetic analysis of ILHV in a pool of Ps. ferox collected in the state of Goiás in 2021. Viral isolation tests were performed on Vero cells and C6/36 clones. The indirect immunofluorescence test (IFI) was used to confirm the positivity of the sample. The positive sample underwent RT-qPCR, sequencing, and phylogenetic analysis. This is the first report of ILHV circulation in this municipality and presented close relationship between this isolate and another ILHV isolate collected in the city of Belém (PA).

The Importance of Entomo-Virological Investigation of Yellow Fever Virus to Strengthen Surveillance in Brazil.

The largest outbreak of sylvatic yellow fever virus (YFV) in eight decades was recorded in Brazil between 2016-2018. Besides human and NHP surveillance, the entomo-virological approach is considered as a complementary tool. For this study, a total of 2904 mosquitoes of the Aedes, Haemagogus and Sabethes genera were collected from six Brazilian states (Bahia, Goiás, Mato Grosso, Minas Gerais, Pará, and Tocantins) and grouped into 246 pools, which were tested for YFV using RT-qPCR. We detected 20 positive pools from Minas Gerais, 5 from Goiás, and 1 from Bahia, including 12 of Hg. janthinomys and 5 of Ae. albopictus. This is the first description of natural YFV infection in this species and warns of the likelihood of urban YFV re-emergence with Ae. albopictus as a potential bridge vector. Three YFV sequences from Hg. janthinomys from Goiás and one from Minas Gerais, as well as one from Ae. albopictus from Minas Gerais were clustered within the 2016-2018 outbreak clade, indicating YFV spread from Midwest and its infection in a main and likely novel bridging vector species. Entomo-virological surveillance is critical for YFV monitoring in Brazil, which could highlight the need to strengthen YFV surveillance, vaccination coverage, and vector control measures.

Habitat suitability of Anopheles vector species and association with human malaria in the Atlantic Forest in south-eastern Brazil.

Every year, autochthonous cases of Plasmodium vivax malaria occur in low-endemicity areas of Vale do Ribeira in the south-eastern part of the Atlantic Forest, state of São Paulo, where Anopheles cruzii and Anopheles bellator are considered the primary vectors. However, other species in the subgenus Nyssorhynchus of Anopheles (e.g., Anopheles marajoara) are abundant and may participate in the dynamics of malarial transmission in that region. The objectives of the present study were to assess the spatial distribution of An. cruzii, An. bellator and An. marajoara and to associate the presence of these species with malaria cases in the municipalities of the Vale do Ribeira. Potential habitat suitability modelling was applied to determine both the spatial distribution of An. cruzii, An. bellator and An. marajoara and to establish the density of each species. Poisson regression was utilized to associate malaria cases with estimated vector densities. As a result, An. cruzii was correlated with the forested slopes of the Serra do Mar, An. bellator with the coastal plain and An. marajoara with the deforested areas. Moreover, both An. marajoara and An. cruzii were positively associated with malaria cases. Considering that An. marajoara was demonstrated to be a primary vector of human Plasmodium in the rural areas of the state of Amapá, more attention should be given to the species in the deforested areas of the Atlantic Forest, where it might be a secondary vector.

Seasonality of agricultural exposure as an important predictor of seasonal yellow fever spillover in Brazil.

Yellow fever virus (YFV) is a zoonotic arbovirus affecting both humans and non-human primates (NHP's) in Africa and South America. Previous descriptions of YF's seasonality have relied purely on climatic explanations, despite the high proportion of cases occurring in people involved in agriculture. We use a series of random forest classification models to predict the monthly occurrence of YF in humans and NHP's across Brazil, by fitting four classes of covariates related to the seasonality of climate and agriculture (planting and harvesting), crop output and host demography. We find that models captured seasonal YF reporting in humans and NHPs when they considered seasonality of agriculture rather than climate, particularly for monthly aggregated reports. These findings illustrate the seasonality of exposure, through agriculture, as a component of zoonotic spillover. Additionally, by highlighting crop types and anthropogenic seasonality, these results could directly identify areas at highest risk of zoonotic spillover.

CCL3, CCL5, IL-15, IL-1Ra and VEGF compose a reliable algorithm to discriminate classes of adverse events following 17DD-YF primary vaccination according to cause-specific definitions.

In the present study, a range of serum biomarkers were quantified in suspected cases of adverse events following YF immunization (YEL-AEFI) to propose a reliable laboratorial algorithm to discriminate confirmed YEL-AEFI ("A1" class) from cases with other illnesses ("C" class). Our findings demonstrated that increased levels of CXCL8, CCL2, CXCL10, IL-1ß, IL-6 and TNF-α were observed in YEL-AEFI ("A1" and "C" classes) as compared to primary vaccines without YEL-AEFI [PV(day 3-28)] and reference range (RR) controls. Notably, increased levels of CCL3, CCL4, CCL2, CCL5, IL-1ß, IL-15, IL-1Ra and G-CSF were found in "A1" as compared to "C" class. Venn diagrams analysis allowed the pre-selection of biomarkers for further analysis of performance indices. Data demonstrated that CCL3, CCL5, IL-15 and IL-1Ra presented high global accuracy (AUC = 1.00) to discriminate "A1" from "C". Decision tree was proposed with a reliable algorithm to discriminate YEL-AEFI cases according to cause-specific definitions with outstanding overall accuracy (91%). CCL3, CCL5, IL-15 and IL-1Ra appears as root attributes to identify "A1" followed by VEGF as branch nodes to discriminate Wild Type YFV infection ("C(WT-YFV)") from cases with other illnesses ("C*"). Together, these results demonstrated the applicability of serum biomarker measurements as putative parameters towards the establishment of accurate laboratorial tools for complementary differential diagnosis of YEL-AEFI cases.

Distinct YFV Lineages Co-circulated in the Central-Western and Southeastern Brazilian Regions From 2015 to 2018.

The current outbreak of yellow fever virus (YFV) that is afflicting Brazil since the end of 2016 probably originated from a re-introduction of YFV from endemic areas into the non-endemic Southeastern Brazil. However, the lack of genomic sequences from endemic regions hinders the tracking of YFV's dissemination routes. We assessed the origin and spread of the ongoing YFV Brazilian outbreak analyzing a new set of YFV strains infecting humans, non-human primates (NHPs) and mosquitoes sampled across five Brazilian states from endemic and non-endemic regions between 2015 and 2018. We found two YFV sub-clade 1E lineages circulating in NHP from Goiás state (GO), resulting from independent viral introductions into the Araguaia tributary river basin: while one strain from 2017 clustered intermingled with Venezuelan YFV strains from 2000, the other YFV strains sampled in 2015 and 2017 clustered with sequences of the current YFV outbreak in the Brazilian Southeastern region (named YFV2015-2018 lineage), displaying the same molecular signature associated to the current YFV outbreak. After its introduction in GO at around mid-2014, the YFV2015-2018 lineage followed two paths of dissemination outside GO, originating two major YFV sub-lineages: (1) the YFVMG/ES/RJ sub-lineage spread sequentially from the eastern area of Minas Gerais state to Espírito Santo and then to Rio de Janeiro states, following the Southeast Atlantic basin; (2) the YFVMG/SP sub-lineage spread from the southwestern area of Minas Gerais to the metropolitan region of São Paulo state, following the Paraná basin. These results indicate the ongoing YFV outbreak in Southeastern Brazil originated from a dissemination event from GO almost 2 years before its recognition at the end of 2016. From GO this lineage was introduced in Minas Gerais state at least two times, originating two sub-lineages that followed different routes toward densely populated areas. The spread of YFV outside endemic regions for at least 4 years stresses the imperative importance of the continuous monitoring of YFV to aid decision-making for effective control policies aiming the increase of vaccination coverage to avoid the YFV transmission in densely populated urban centers.

Yellow Fever outbreaks in unvaccinated populations, Brazil, 2008-2009.

Due to the risk of severe vaccine-associated adverse events, yellow fever vaccination in Brazil is only recommended in areas considered at risk for disease. From September 2008 through June 2009, two outbreaks of yellow fever in previously unvaccinated populations resulted in 21 confirmed cases with 9 deaths (case-fatality, 43%) in the southern state of Rio Grande do Sul and 28 cases with 11 deaths (39%) in Sao Paulo state. Epizootic deaths of non-human primates were reported before and during the outbreak. Over 5.5 million doses of yellow fever vaccine were administered in the two most affected states. Vaccine-associated adverse events were associated with six deaths due to acute viscerotropic disease (0.8 deaths per million doses administered) and 45 cases of acute neurotropic disease (5.6 per million doses administered). Yellow fever vaccine recommendations were revised to include areas in Brazil previously not considered at risk for yellow fever.

Spatial distribution of arboviral mosquito vectors (Diptera, Culicidae) in Vale do Ribeira in the South-eastern Brazilian Atlantic Forest.

Mosquitoes are vectors of arboviruses that can cause encephalitis and hemorrhagic fevers in humans. Aedes serratus (Theobald), Aedes scapularis (Rondani) and Psorophora ferox (Von Humboldt) are potential vectors of arboviruses and are abundant in Vale do Ribeira, located in the Atlantic Forest in the southeast of the State of São Paulo, Brazil. The objective of this study was to predict the spatial distribution of these mosquitoes and estimate the risk of human exposure to mosquito bites. Results of the analyses show that humans are highly exposed to bites in the municipalities of Cananéia, Iguape and Ilha Comprida. In these localities the incidence of Rocio encephalitis was 2% in the 1970s. Furthermore, Ae. serratus, a recently implicated vector of yellow fever virus in the State of Rio Grande do Sul, should be a target for the entomological surveillance in the southeastern Atlantic Forest. Considering the continental dimensions of Brazil and the inherent difficulties in sampling its vast area, the habitat suitability method used in the study can be an important tool for predicting the distribution of vectors of pathogens.

[Patterns of antiretroviral therapy adoption by the Brazilian public health system]. / Padrão de incorporação de fármacos antiretrovirais pelo sistema público de saúde no Brasil.

OBJECTIVE: The aim of the present scientific study is to evaluate the patterns of antiretroviral technology adoption by the Brazilian Public Health System (SUS). METHODS: Based on previous articles published in scientific medical literature, three indicators to assess antiretroviral technology adoption by SUS were proposed: knowledge-adoption interval; critical mass of knowledge; and validation-adoption interval. Using the databases from the SUS Department of Information Technology (DATASUS) and from the Brazilian Logistic Center for Medication Control (SICLOM), two pharmaceutical groups were selected (antiretroviral medications and a group of high cost medications). RESULTS: Antiretroviral medications were adopted faster than the high cost medication group when assessed on the basis of "knowledge-adoption" interval and "validation-adoption" interval. Yet, they require a lower "critical mass of knowledge" before adoption. CONCLUSION: Antiretroviral medications have been adopted faster and based on a lower number of scientific medical articles than a selected group of high cost medications.

Spatial distribution of arboviral mosquito vectors (Diptera, Culicidae) in Vale do Ribeira in the South-eastern Brazilian Atlantic Forest / Distribuição espacial de mosquitos (Diptera, Culicidae) vetores de arbovírus no Vale do Ribeira, sudeste da Mata Atlântica, Brasil

Mosquitoes are vectors of arboviruses that can cause encephalitis and hemorrhagic fevers in humans. Aedes serratus (Theobald), Aedes scapularis (Rondani) and Psorophora ferox (Von Humboldt) are potential vectors of arboviruses and are abundant in Vale do Ribeira, located in the Atlantic Forest in the southeast of the State of São Paulo, Brazil. The objective of this study was to predict the spatial distribution of these mosquitoes and estimate the risk of human exposure to mosquito bites. Results of the analyses show that humans are highly exposed to bites in the municipalities of Cananéia, Iguape and Ilha Comprida. In these localities the incidence of Rocio encephalitis was 2 percent in the 1970s. Furthermore, Ae. serratus, a recently implicated vector of yellow fever virus in the State of Rio Grande do Sul, should be a target for the entomological surveillance in the southeastern Atlantic Forest. Considering the continental dimensions of Brazil and the inherent difficulties in sampling its vast area, the habitat suitability method used in the study can be an important tool for predicting the distribution of vectors of pathogens.

Mosquitos são vetores de arbovírus que podem causar encefalites e febres hemorrágicas em humanos. Aedes serratus (Theobald), Aedes scapularis (Rondani), e Psorophora ferox (Von Humboldt) são vetores potenciais de arbovírus e são abundantes no Vale do Ribeira, Mata Atlântica, sudeste do Estado de São Paulo, Brasil. O objetivo desse estudo foi inferir a distribuição espacial desses mosquitos e estimar o risco da exposição humana às picadas de mosquitos. Os resultados das análises indicaram que os humanos estão altamente expostos às picadas nos municípios de Cananéia, Iguape e Ilha Comprida. Nessas localidades a incidência de encefalite Rocio foi 2 por cento na década de 1970. Adicionalmente, Ae. serratus, que foi recentemente implicado vetor do vírus da febre amarela no estado do Rio Grande do Sul, deveria ser alvo da vigilância entomológica no sudeste da Mata Atlântica. Considerando a extensão territorial do Brasil e as inerentes dificuldades em amostrar esse vasto território, a modelagem de habitat empregada nesse trabalho poderia ser utilizada para a vigilância de vetores de patógenos.

Padrão de incorporação de fármacos antiretrovirais pelo sistema público de saúde no Brasil / Patterns of antiretroviral therapy adoption by the Brazilian public health system

OBJETIVO: avaliar o padrão de incorporação de fármacos antiretrovirais pelo Sistema Público de Saúde no Brasil (SUS). MÉTODOS: baseando-se em trabalhos prévios publicados na literatura médica foram propostos três indicadores a serem utilizados na análise da incorporação de fármacos: intervalo conhecimento-incorporação, massa crítica de conhecimento e intervalo validação-incorporação. Utilizando-se as bases de dados do Departamento de Informática do SUS (Datasus) e do Sistema de Controle Logístico de Medicamentos (SICLOM) foram selecionados dois grupos de tecnologias farmacológicas (medicações antiretrovirais e medicações de dispensação em caráter excepcional). RESULTADOS: os medicamentos antiretrovirais analisados foram incorporados de maneira mais precoce que os medicamentos de dispensação em caráter excepcional, tanto no que se refere ao intervalo "conhecimento-incorporação" quanto ao intervalo "validação-incorporação", e apresentam uma menor "massa crítica de conhecimento" para a incorporação. CONCLUSÃO: Os medicamentos antiretrovirais têm sido incorporados de maneira mais rápida, e após a publicação de um menor número de artigos científicos, quando em comparação aos medicamentos de dispensação em caráter excepcional.

OBJECTIVE: The aim of the present scientific study is to evaluate the patterns of antiretroviral technology adoption by the Brazilian Public Health System (SUS). METHODS: Based on previous articles published in scientific medical literature, three indicators to assess antiretroviral technology adoption by SUS were proposed: knowledge-adoption interval; critical mass of knowledge; and validation-adoption interval. Using the databases from the SUS Department of Information Technology (DATASUS) and from the Brazilian Logistic Center for Medication Control (SICLOM), two pharmaceutical groups were selected (antiretroviral medications and a group of high cost medications). RESULTS: Antiretroviral medications were adopted faster than the high cost medication group when assessed on the basis of "knowledge-adoption" interval and "validation-adoption" interval. Yet, they require a lower "critical mass of knowledge" before adoption. CONCLUSION: Antiretroviral medications have been adopted faster and based on a lower number of scientific medical articles than a selected group of high cost medications.

Habitat suitability of Anopheles vector species and association with human malaria in the Atlantic Forest in south-eastern Brazil

Every year, autochthonous cases of Plasmodium vivax malaria occur in low-endemicity areas of Vale do Ribeira in the south-eastern part of the Atlantic Forest, state of São Paulo, where Anopheles cruzii and Anopheles bellator are considered the primary vectors. However, other species in the subgenus Nyssorhynchus of Anopheles (e.g., Anopheles marajoara) are abundant and may participate in the dynamics of malarial transmission in that region. The objectives of the present study were to assess the spatial distribution of An. cruzii, An. bellator and An. marajoara and to associate the presence of these species with malaria cases in the municipalities of the Vale do Ribeira. Potential habitat suitability modelling was applied to determine both the spatial distribution of An. cruzii, An. bellator and An. marajoara and to establish the density of each species. Poisson regression was utilized to associate malaria cases with estimated vector densities. As a result, An. cruzii was correlated with the forested slopes of the Serra do Mar, An. bellator with the coastal plain and An. marajoara with the deforested areas. Moreover, both An. marajoara and An. cruzii were positively associated with malaria cases. Considering that An. marajoara was demonstrated to be a primary vector of human Plasmodium in the rural areas of the state of Amapá, more attention should be given to the species in the deforested areas of the Atlantic Forest, where it might be a secondary vector.

Epizootias em primatas não humanos durante reemergência do vírus da febre amarela no Brasil, 2007 a 2009 / Epizootics in nonhuman primates during reemergence of yellow fever virus in Brazil, 2007 to 2009

Objetivo: descrever e analisar a mudança do perfil epidemiológico da febre amarela silvestre no Brasil – que passa a ocorrer fora da Amazônia – a partir de 1999, quando a detecção do vírus em primatas permitiu a aplicação oportuna de novas medidas de vigilância. Metodologia: este estudo faz uma análise descritiva das epizootias em primatas notificadas ao Ministério da Saúde (MS) entre 2007 e 2009; para captação dos dados, foram utilizadas a Ficha de Notificação de Epizootia do Sistema de Informação de Agravos de Notificação (Sinan) e planilha de notificação diária. Resultados: No período, foram notificadas 1.971 epizootias em primatas, sendo 73 no ano de 2007, 1.050 em 2008 e 848 em 2009; essas epizootias ocorreram em 520 municípios de 19 estados; do total de epizootias notificadas, 209 (10,6 por cento) foram confirmadas para febre amarela. Conclusão: as informações aqui discutidas são fundamentais para o aperfeiçoamento da vigilância e a consolidação da notificação de epizootias em primatas, como instrumento de prevenção de casos humanos da doença.

Objective: to describe and analyze the change in the epidemiological profile of sylvatic yellow fever – whose cases began to occur outside the Amazon region, in Brazil – from 1999, when the detection of the virus in primates has led to the timely implementation of new surveillance measures. Methodology: this study is a descriptive analysis of epizootics in primates notified to the Ministry of Health between 2007 and 2009; data were captured using the Epizootic Notification Form of the Brazilian Information System for Notifiable Diseases (Sinan) and daily reporting spreadsheet. Results: from 1,971 epizootics reported during the period, 73 occurred in 2007, 1,050 in 2008, and 848 in 2009; and 209 (10.6 per cent) were confirmed for yellow fever; these epizootics have been registered in 520 municipalities of 19 states. Conclusion: the information discussed herein is fundamental for improving the surveillance and consolidating the notification of epizootics in primates, as a tool for preventing human cases of the disease.

Aspectos ecológicos de Anopheles (Nyssorhynchus) marajoara e outros Culicidae na Ilha Comprida, Estado de São Paulo / Ecological aspects of Anopheles (Nyssorhynchus) marajoara and other Culicidae in Comprida Island, State of São Paulo

Anopheles marajoara vem ganhando destaque como vetor potencial de plamodium nas regiões onde ocorre. Tal fato está relacionado aos avanços na taxonomia do Complexo Albitarsis e aos outros direcionados ao conhecimento dos hábitos da espécie. Este trabalho teve como objetivo caracterizar a comunidade Culicidae, destacando Na. marajoara, em função da heterogeneidade ambiental da Ilha Comprida. Para tanto, foram utilizados indicadores de diversidade aplicados às comunidades culicídeas imaturas e adultas presentes na ilha. Foi analisada a atividade hematofágica da espécie, considerando-se as interações interespecíficas naquela comunidade. An. marajoara se mostrou uma das espécies dominantes, com acentuada antropofilia. A espécie foi encontrada em criadouros artificiais, o que denota expressiva valência ecológica. Observou-se deslocamento do pico de atividade hematofágica em relação às populações de An. albitarsis s.l. de outros estados e países, provavelmente como estratégia para evitar competição com outras espécies, permitindo sua coexistência. An. marajoara e outros Culicidae têm potencial como vetores de Plamodium e arbovírus, respectivamente, na Ilha Comprida, dadas as características das espécies e da localidade.