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The prospect of universal influenza vaccines is generating much interest and research at the intersection of immunology, epidemiology, and viral evolution. While the current focus is on developing a vaccine that elicits a broadly cross-reactive immune response in clinical trials, there are important downstream questions about global deployment of a universal influenza vaccine that should be explored to minimize unintended consequences and maximize benefits. Here, we review and synthesize the questions most relevant to predicting the population benefits of universal influenza vaccines and discuss how existing information could be mined to begin to address these questions. We review three research topics where computational modeling could bring valuable evidence: immune imprinting, viral evolution, and transmission. We address the positive and negative consequences of imprinting, in which early childhood exposure to influenza shapes and limits immune responses to future infections via memory of conserved influenza antigens. However, the mechanisms at play, their effectiveness, breadth of protection, and the ability to "reprogram" already imprinted individuals, remains heavily debated. We describe instances of rapid influenza evolution that illustrate the plasticity of the influenza virus in the face of drug pressure and discuss how novel vaccines could introduce new selective pressures on the evolution of the virus. We examine the possible unintended consequences of broadly protective (but infection-permissive) vaccines on the dynamics of epidemic and pandemic influenza, compared to conventional vaccines that have been shown to provide herd immunity benefits. In conclusion, computational modeling offers a valuable tool to anticipate the benefits of ambitious universal influenza vaccine programs, while balancing the risks from endemic influenza strains and unpredictable pandemic viruses. Moving forward, it will be important to mine the vast amount of data generated in clinical studies of universal influenza vaccines to ensure that the benefits and consequences of these vaccine programs have been carefully modeled and explored. Author summary: There is a lot of interest in developing universal influenza vaccines that could elicit broad protection against multiple strains of influenza viruses. This impetus is generating intense basic science research in the field of influenza immunology, in the hope that new vaccine candidates can be identified, reach clinical trials, and deliver robust influenza responses. However, there are important downstream questions about using universal influenza vaccines in large populations that should be considered during the development and implementation of these novel products. Important questions include how early childhood influenza exposure limits immune responses to future influenza infections, how universal influenza vaccines could drive viral evolution, and how these new vaccines could impact the epidemiology of influenza in epidemic and pandemic seasons. Here, we synthesize the questions most relevant to predicting the population impacts of universal influenza vaccines and discuss how existing data could be analyzed to address these questions. [ABSTRACT FROM AUTHOR]