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A major outbreak of yellow fever (YF) occurred in Brazil during 2016-2018. Epizootics in New World nonhuman primates are sentinel events for YF virus circulation. However, genus-specific susceptibilities and suitability for YF surveillance remain poorly understood. We obtained and compared epidemiologic, histopathologic, immunohistochemical, and molecular results from 93 human and 1,752 primate cases submitted during the recent YF outbreak in Brazil (2017), with the support of the Brazilian National YF Surveillance Program. We detected heterogeneous YF-associated profiles among the various genera of primates we analyzed. Alouatta primates were the most reliable sentinel; Sapajus and Callicebus primates had higher viral loads but lower proportional mortality rates. Callithrix primates were the least sensitive, showing lower viral loads, lower proportional mortality rates, and no demonstrable YF virus antigen or extensive lesions in liver, despite detectable viral RNA. These differences in susceptibility, viral load, and mortality rates should be considered in strategic surveillance of epizootics and control measures for YF. [ABSTRACT FROM AUTHOR]

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spill over to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHP in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species. Author summary: Since July 2016, the southeast region of Brazil has experienced the largest yellow fever virus (YFV) outbreak in decades. São Paulo is the most densely populated state in southeast Brazil. The outbreak has caused serious public health concern in the state, as YFV does not normally circulate widely there and most of the 21 million inhabitants were correspondingly unvaccinated against YFV when the outbreak began. In Brazil, YFV typically circulates among non-human primates (NHPs), and human cases represent isolated spill over events from this predominantly sylvatic cycle. Understanding the epidemiological dynamics and spread of YFV in NHPs is therefore critical for contextualising human cases, and guiding vaccination strategies that can better protect local human populations. Here, we aim to contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo. We analyse the geographic and temporal distribution of observed cases of YFV in NHPs in São Paulo state, and identify three distinct phases of the epizootic. We generate virus genome sequences from 51 YFV-positive cases and perform phylogenetic and phylogeographic analyses aimed at understanding the spatial spread of YFV in São Paulo state. Analyses of these data indicate that YFV spread from the north of São Paulo state into more densely populated southern regions. Although we observe substantial heterogeneity in the rate at which different sampled YFV lineages spread, the typical rate of spread was low with a mean rate of ~1 km per day. This is consistent with a scenario in which the majority of transmission events occurred between NHPs primates and sylvatic vectors across forested patches. [ABSTRACT FROM AUTHOR]