Title: Ecogeographic drivers of the spatial spread of highly pathogenic avian influenza outbreaks in Europe and North America, 2016-2022Authors: Jonathon D. Gass, Jr.1,2, Nichola J. Hill3, Elena N. Naumova4, Felicia B. Nutter1, Jonathan A. Runstadler11 Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA2 Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA3 Department of Biology, University of Massachusetts, Boston, Boston, MA, USA4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USACorresponding author email: Jonathon.gass@tufts.eduSummary H5Nx highly pathogenic avian influenza (HPAI) viruses of clade 2.3.4.4. have caused outbreaks in Europe since 2016, and most recently these viruses were introduced to North America via avian migratory transport in December 2021. We sought to analyze the spatiotemporal extent of these viruses within the two continent outbreak system, and to characterize predictors of virus spread between geographic regions through a Bayesian phylodynamic generalized linear model (phylodynamic-GLM). Findings from this study reveal for the first time the geographic extent and directionality of the H5Nx HPAI virus outbreak system in Europe and North America during 2016-2022. Data demonstrate localized epidemics of H5Nx throughout Europe in the first several years of the epizootic, followed by a singular branching point where H5N1 viruses were introduced to North America via wild migratory birds, likely via stopover locations in the North Atlantic. Once in the US, H5Nx HPAI viruses spread at a greater rate between US-based regions along migratory flyways, and no evidence points to spread back to any European region. Our GLM demonstrated that geographic proximity is a predictor of virus spread between regions, which implies that inter-continental transport across the Atlantic is relatively rare and may require northward virus movement that coincides with spring migration of susceptible avian species to regions in the North Atlantic, possibly Iceland and Greenland. Finally, mean change in precipitation at destinations of viral transitions along phylogenetic branches was predicted to reduce H5Nx HPAI virus spread, which may reflect the effect of climate change on declines in host species abundance or changes in migratory patterns as a result of ecological alterations. Our data provide new knowledge about the spread and directionality of H5Nx HPAI virus dispersal in Europe and North America during an actively evolving outbreak, including predictors of virus movement between regions, which will contribute to surveillance and mitigation strategies as the outbreak unfolds, and in future instances of uncontained avian spread of HPAI viruses.Keywords: Influenza A virus, North Atlantic, wild birds, phylodynamic-GLM, outbreak, spatial spread