The outbreak of seasonal flu costs billions of dollars in health care utilization and lost productivity. Despite the effectiveness of vaccination and antiviral medications to prevent serious flu-related complications and slow down the spread of an influenza epidemic, only 52% of the U.S. population aged 6 months and older received flu vaccines in the 2019-20 flu season. In addition, a costly out-of-pocket expense results in fewer patients seeking treatment, leading to potential hospitalizations and even flu-related deaths. In this study, we develop an integrated healthcare insurance mechanism that optimizes two incentive policies, vaccination reward and cost-sharing, to alleviate the medical cost and disease burden while preventing the outbreak of seasonal influenza. We model the dynamic interaction between a single insurer and multiple insureds as a Stackelberg vaccination game; we then embed the game into an agent-based simulation to model the spread of flu in a population under different policies. Finally, we apply machine learning and simulation optimization to optimize healthcare incentive policies in a large-scale flu transmission simulation. Simulation results indicate that the proposed methodology efficiently identifies a set of good incentive policies under different scenarios of flu vaccine efficacy and reproduction numbers.