Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics of Human Influenza H3N2

Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evolutionary analyses of pathogen genome sequences increasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largely neglected the wealth of information on human mobility, mainly because no statistical framework exists within which viral gene sequences and empirical data on host movement can be combined. Here, we address this problem by applying a phylogeographic approach to elucidate the global spread of human influenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A viruses worldwide. Using a framework that estimates the migration history of human influenza while simultaneously testing and quantifying a range of potential predictive variables of spatial spread, we show that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more local scales spread is also determined by processes that correlate with geographic distance. Our analyses further confirm a central role for mainland China and Southeast Asia in maintaining a source population for global influenza diversity. By comparing model output with the known pandemic expansion of H1N1 during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data on human mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza viruses are best explained by combining human mobility data with the spatial information inherent in sampled viral genomes. The integrated approach introduced here offers great potential for epidemiological surveillance through phylogeographic reconstructions and for improving predictive models of disease control. Author Summary What explains the geographic dispersal of emerging pathogens? Reconstructions of evolutionary history from pathogen gene sequences offer qualitative descriptions of spatial spread, but current approaches are poorly equipped to formally test and quantify the contribution of different potential explanatory factors, such as human mobility and demography. Here, we use a novel phylogeographic method to evaluate multiple potential predictors of viral spread in human influenza dynamics. We identify air travel as the predominant driver of global influenza migration, whilst also revealing the contribution of other mobility processes at more local scales. We demonstrate the power of our inter-disciplinary approach by using it to predict the global pandemic expansion of H1N1 influenza in 2009. Our study highlights the importance of integrating evolutionary and ecological information when studying the dynamics of infectious disease.