(Top) For vaccines for which correlates or protection are known (Table A15-1), systems approaches can be used to identify early signatures of protection in a phase 1 trial. The key genes from these signatures can be incorporated into a vaccine chip or ELISA kit, which can then be used to identify nonresponders or suboptimal responders, particularly in special populations such as immunocompromised patients, the elderly, and infants. (Bottom) For new and emerging vaccines, for which correlates of protection are unknown, signatures that predict various aspects of immunogenicity (e.g., CD8⁺ T cell responses or neutralizing antibody responses) can be assessed in phase I trials. Such signatures can then be incorporated into a vaccine chip or ELISA kit that can then be used in phase II and III trials to determine their capacity to predict protection. Alternatively, a retrospective nested case-control study could be done in a phase II and III trial to identify signatures of protection.