Abstract Hacking Epidemics: Unlocking the Drivers of Transmission Seasonality to Battle Vaccine-Preventable Diseases The UN estimates that 94.4 million children under 5 will die between 2016 and 2030 if the under-5 mortality rate is not decreased. Currently, infectious diseases that are preventable or treatable cause about half of childhood deaths. I work on childhood infectious diseases because major improvements can be achieved by optimizing the administration of existing vaccines and treatments. There is a need for smarter vaccination strategies that are adaptable to changing epidemiology and grounded from an understanding in human immunobiology. We have three studies that seek to fulfill this need. First, we will develop a statistical toolset to measure vaccine efficacy in real-time using both traditional and new data streams (internet query data). By applying our toolset, we will evaluate the impact of the chickenpox vaccine in the US. Second, we aim to quantify the transmission and reactivation dynamics of herpesviruses in order to make recommendations regarding vaccination efforts and timing, while anticipating treatment needs. To do so, we will use data on hospitalized chickenpox, shingles, herpes simplex, and cytomegalovirus cases from California, spanning 3 decades. Hospital data, vaccine coverage, demography data, and dynamic mathematical models will be combined to estimate transmission and reactivation rates for each of virus. We will determine if reactivation is seasonal, which we hypothesize is a manifestation of seasonal immunity. Third, we will conduct a human clinical study to determine if immunity undergoes functional changes throughout the year that affect susceptibility to infection. We will characterize both circadian (24-hr) and seasonal rhythms in the immune system and interactions among rhythms. We propose an innovative sampling scheme involving multi-day clinical sessions in winter, spring, summer, and fall, which would provide snapshots of immune cell activity around the 24-hr cycle, and across seasons. This study would advance our knowledge of the inseparable interplay between human immunobiology and infectious disease dynamics.