Helen R. Wagstaffe, Ryan S. Thwaites, Jasmin Sidhu, Rik G.H. Lindeboom, Lorenz Kretschmer, Kaylee B. Worlock, Lisa M. Dratva, Anhui Huang, Stephanie Ascough, Loukas Papargyris, Richard McKendry, Ashley M. Collins, Jiayun Xu, Nana‐Marie Lemm, Ben Killingley, Mariya Kalinova, Alex Mann, Andrew Catchpole, Leo Swadling, John S. Tsang, Mala K. Maini, Mahdad Noursadeghi, Marko Nikolić, Sarah A. Teichmann, Peter Openshaw, Christopher Chiu
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.