Numerous challenges have been identified in vaccine development, including variable efficacy as a function of population demographics and a lack of characterization and mechanistic understanding of immune correlates of protection able to guide delivery and dosing. There is tremendous opportunity in recent technological and computational advances to elucidate systems level understanding of pathogen-host interactions and correlates of immunity. A systems biology approach to vaccinology provides a new paradigm for rational vaccine design in a ‘precision medicine’ context.