Our interferon-associated signature of early SARS-CoV-2 infection characterises a subgroup of exposed, uninfected contacts in three independent cohorts who may have successfully aborted infection prior to induction of adaptive immunity. The earlier transient upregulation of signature genes in PCR-negative compared to PCR-positive CHIM volunteers suggests that ultra-early interferon-associated innate immune responses correlate with, and may contribute to, protection against SARS-CoV-2 infection.