A systems framework for vaccine design

•System-level approaches will provide a more complete picture of the immune response.•Omic studies will allow identification of signatures of immune protection.•Network-based methods are powerful tools for multi-omic data integration.•Discovery of host–virus interactions will improve vaccine development.•An emphasis on producing clinically actionable findings is necessary.

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.