Assessing yellow fever outbreak potential and implications for vaccine strategy

Background Yellow fever (YF), a vector-borne viral hemorrhagic fever, is endemic in tropical regions of Africa and South America, with large vaccination programmes being used for control. However, significant outbreaks have occurred in recent years. Data on infection rates and seroprevalence is often sparse, requiring robust mathematical models to estimate the burden of yellow fever. In particular, modelling is required to estimate the risk of outbreaks and inform policy decisions regarding the targeting of vaccination. Methods We present a dynamic, stochastic model of YF transmission which uses environmental covariates to estimate the force of infection due to spillover from the sylvatic (non-human primate) reservoir and the basic reproduction number for human-to-human transmission. We examine the potential for targets identified by the World Health Organization EYE Strategy (50%, 60% or 80% vaccination coverage in 1-60 year olds) to achieve different threshold values for the effective reproduction number. Threshold values are chosen to reflect the potential for seasonal and/or climatic variation in YF transmission even in a scenario where vaccination lowers the median reproduction number below 1. Results Based on parameter estimates derived from epidemiological data, it is found that the 2022 EYE Strategy target coverage is sufficient to reduce the static averaged annual effective reproduction number R below 1 across most or all regions in Africa depending on the effectiveness of reported vaccinations, but insufficient to reduce it below 0.5 and thereby eliminate outbreaks in areas with high seasonal range. Coverage levels aligned with the 2026 targets are found to significantly decrease the proportion of regions where R is greater than 0.5. ### Competing Interest Statement This research was carried out as part of the Vaccine Impact Modelling Consortium (VIMC, [www.vaccineimpact.org][1]), and funded in whole, or in part, by the Bill Melinda Gates Foundation [Grant Numbers INV-034281 and INV-009125 / OPP1157270]; Gavi, the Vaccine Alliance; and the Wellcome Trust [Grant ID: 226727\_Z\_22\_Z]. For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission. The views expressed are those of the authors and not necessarily those of the Consortium or its funders. The funders of the study had no role in data collection, data analysis, data interpretation, study design, or writing of the report. The funders were given the opportunity to review this paper prior to publication, but the final decisions on content, and to submit the paper for publication, were taken by the authors. KF and KAMG received funding from Gavi, BMGF and/or the Wellcome Trust via VIMC during the course of the study. KF, AH, NMF, and KAMG also acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union; and acknowledge funding by Community Jameel. ### Funding Statement This research was carried out as part of the Vaccine Impact Modelling Consortium (VIMC, [www.vaccineimpact.org][1]), and funded in whole, or in part, by the Bill Melinda Gates Foundation [Grant Numbers INV-034281 and INV-009125 / OPP1157270]; Gavi, the Vaccine Alliance; and the Wellcome Trust [Grant ID: 226727\_Z\_22\_Z]. For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission. The views expressed are those of the authors and not necessarily those of the Consortium or its funders. The funders of the study had no role in data collection, data analysis, data interpretation, study design, or writing of the report. The funders were given the opportunity to review this paper prior to publication, but the final decisions on content, and to submit the paper for publication, were taken by the authors. KF and KAMG received funding from Gavi, BMGF and/or the Wellcome Trust via VIMC during the course of the study. KF, AH, NMF, and KAMG also acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union; and acknowledge funding by Community Jameel. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data on reported yellow fever case and death numbers used in this study are publicly available. Seroprevalence data used in this study is partially available in referenced publications, but this study used raw data which is confidential. All code used for the numerical modelling work in this study will be made available on request. The software package containing the model code and functions used to handle input and output data is publicly available with documentation at . [1]: http://www.vaccineimpact.org