We present a comprehensive approach to designing and optimizing infectious disease mitigation strategies, with a focus on COVID-19 and closed communities like college campuses. By integrating vaccination and routine screening, we first develop a model to evaluate the efficacy of various strategies in reducing infections, hospitalizations, and deaths on a college campus during the Fall 2021 semester. The findings emphasize the importance of customizing interventions based on factors such as initial vaccine coverage, vaccine effectiveness, compliance rates, and disease transmission dynamics. As COVID-19 variants continue to emerge, we highlight the necessity for adaptive screening strategies that account for the existing variants and differences in transmission and outcomes among population groups, such as faculty/staff, and students, based on their vaccination status and level of natural immunity. Using the Spring 2022 academic semester as a case study, we study various routine screening strategies and find that screening faculty and staff less frequently than students, and/or screening the boosted and vaccinated less frequently than the unvaccinated, may avert a higher number of infections per test compared to universal screening of the entire population at a common frequency. We also discuss key policy issues, including the need to revisit the mitigation objectives over time and determine if and when screening alone can compensate for low booster coverage. In contexts where mandates are not feasible and vaccine hesitancy is prevalent, we explore the role of voluntary vaccination compliance, supported by monetary incentives and routine screening. We introduce an optimization framework that considers the dual role of screening as both a mitigation tool and a non-monetary incentive. This framework necessitates a novel optimization model for incentive design, integrated with a utility-based decision model that accounts for resource constraints and uncertainties in community response to mitigation efforts. We establish structural properties of Pareto sets of strategies and analyze how they adjust with community characteristics, leading to key insights. Our findings offer actionable strategies for diverse communities and underscore the substantial value of tailoring mitigation efforts to community characteristics and incorporating the incentive effect of routine screening. Overall, this research provides actionable insights into the development of targeted and adaptive mitigation strategies that can be applied in diverse community settings, ensuring safe operations and effective disease control amidst evolving epidemiological challenges. The methodologies and insights from our study are poised to inform and guide the design of mitigation strategies in a variety of institution and community settings, contributing significantly to the collective efforts against infectious diseases. / Doctor of Philosophy / This research focuses on developing strategies to reduce the spread of infectious diseases like COVID-19, particularly in communities such as college campuses. We explore how combining vaccination and regular testing can help reduce the number of infections, hospitalizations, and deaths. By studying different approaches during the Fall 2021 semester, we found that strategies need to be adjusted based on factors like how many people are vaccinated, how effective the vaccines are, and how willing people are to follow the guidelines. As new COVID-19 variants appear, it is important to adapt testing plans based on how these variants spread and how they affect different groups, such as students and faculty, depending on their vaccination and immunity levels. In our study of the Spring 2022 semester, we found that testing faculty less frequently than students, or testing those who are vaccinated less often than those who are unvaccinated, can be more effective than testing everyone at the same rate. We also discuss when testing alone might be enough if vaccination rates are low. In situations where vaccines aren't mandatory and some people are hesitant to get vaccinated, we explore how offering a monetary incentive and regular testing can encourage more people to get vaccinated. We introduce a model that helps decision makers choose the best monetary incentive amount and testing rate, considering the dual role of testing both as a health measure and as an incentive to encourage vaccination. Our findings show that communities can benefit from strategies that are tailored to their specific needs and that include both vaccination incentives and testing. Overall, this research provides practical recommendations for creating flexible strategies that help communities stay safe and control the spread of disease, even as conditions change.