Pre-existing and early cellular immune factors correlate with functionally complete protection against primary controlled human SARS-CoV-2 infection
- Helen R. Wagstaffe
- Ryan S. Thwaites
- Jasmin K. Sidhu
- Rik G. H. Lindeboom
- Lorenz Kretschmer
- Kaylee B. Worlock
- Lisa M. Dratva
- Ao 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 Z. Nikolić
- Sarah A. Teichmann
- Peter J. M. Openshaw
- Christopher Chiu
2025-12-07
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.