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Abstract
Influenza continues to pose global public health threats, including several pandemics in history, heavy disease burdens in humans with annual seasonal outbreaks, and high economic loss with highly pathogenic virus causing large outbreaks in poultry. In addition, seasonal influenza requires tremendous efforts to update and distribute vaccines annually, while zoonosis of potential pandemic strains poses another threat of no stockpile of effective vaccines. To overcome the predicament of influenza vaccine and disease prevention, phylogenetic modeling with currently advanced mathematical models, global genomic data sharing and increased computing capability becomes a powerful tool to understand rapidly evolving pathogens and ultimately achieve the goal of effective prevention. In this dissertation, I aimed to develop novel models and apply advanced models to study the evolutionary and epidemiological dynamics of influenza virus across ecological scales in order to improve disease control. Specifically, aim 1 focused on developing a model to incorporating hemagglutinin (HA) protein structure to better understand the evolution of vaccine targets. The new phylogenetic model that accounted for rate variations across protein structural domains and across codon positions significantly improved the reconstruction of influenza viruses. It revealed valuable biological insights on protein structural domain-specific evolutionary characteristics and approximate selection pressure on these domains, which can provide new approach for broadly-reactive vaccine design. Aim 2 explored viral diffusion patterns and ecological factors that potentially affect the diffusion in the U.S. via phylodynamic modeling. It identified regions with busiest airports played as a primary hub for viral diffusions in the U.S. Higher proportion of high-risk populations including the youth and the elderly and more flight connections may significantly increase viral migration rates. Aim 3 explored the impacts of H3N2 live attenuated influenza vaccine (LAIV) on viral genetic diversity and diffusion dynamics in Central Texas via discrete trait analysis and structured coalescent model. The vaccinated population needed more external introductions to sustain the epidemics and disseminated less to external regions, which provided the phylogenetic evidence of vaccination benefits. Taken together, findings from these studies provided instructive insights/recommendations on vaccine design, administration strategy and effective prevention measures of influenza viruses.