  Enumerated threat agent lists have long driven biodefense priorities. The
global SARS-CoV-2 pandemic demonstrated the limitations of searching for known
threat agents as compared to a more agnostic approach. Recent technological
advances are enabling agent-agnostic biodefense, especially through the
integration of multi-modal observations of host-pathogen interactions directed
by a human immunological model. Although well-developed technical assays exist
for many aspects of human-pathogen interaction, the analytic methods and
pipelines to combine and holistically interpret the results of such assays are
immature and require further investments to exploit new technologies. In this
manuscript, we discuss potential immunologically based bioagent-agnostic
approaches and the computational tool gaps the community should prioritize
filling.
