Vaccines are the most cost effective public health measure for preventing viral infection and limiting epidemic spread within susceptible populations. However, the efficacy of current protective vaccines is highly variable, particularly in aging populations. In addition, there have been a number of challenges in the development of new vaccines due to a lack of detailed understanding of the immune correlates of protection. To identify the mechanisms underlying the variability of the immune response to vaccines, system-level tools need to be developed that will further our understanding of virus-host interactions and correlates of vaccine efficacy. This will provide critical information for rational vaccine design and allow the development of an analog to the "precision medicine" framework (already acknowledged as a powerful approach in medicine and therapeutics) to be applied to vaccinology.