Abstract
Identifying host factors that mediate protection against newly-emergent viruses is needed for improved pandemic preparedness. Here, we analysed pre- and early post-exposure immune factors associated with resisting SARS-CoV-2 infection after human challenge in seronegative individuals, using multiplex protein, cytometric and RNA sequencing approaches in the nasopharynx and circulation. Pre-existing cross-reactive antibodies correlate poorly with clinical outcome. Instead, protection is associated with heightened nasopharyngeal CCL13 levels locally produced by conventional dendritic cells and monocytes, along with cross-reactive T cells and less differentiated NK cells. Conditional independence network analysis implicates nasal CCL13 as the central node connected to pre-existing non-structural protein-specific T cells by CD1c+ DCs. In those who became infected, baseline cross-reactive T cell and less differentiated NK cell frequencies also correlate with shorter infection duration. Thus, pre-existing mucosal chemokine levels may promote rapid innate and innate-like responses that effectively block infection. ClinicalTrials.gov identifier NCT04865237.