Pre-existing and early cellular immune factors correlate with functionally complete protection against primary controlled human SARS-CoV-2 infection
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<sup>+</sup> 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.
Authors
- Ben Killingley
- Jasmin Sidhu
- Kaylee B. Worlock (ORCID: https://orcid.org/0000-0002-5656-7634)
- Alex Mann (ORCID: https://orcid.org/0000-0002-3744-4604)
- Peter Openshaw (ORCID: https://orcid.org/0000-0002-7220-2555)
- Mahdad Noursadeghi (ORCID: https://orcid.org/0000-0002-4774-0853)
- Christopher Chiu (ORCID: https://orcid.org/0000-0003-0914-920X)
- Andrew Catchpole (ORCID: https://orcid.org/0000-0003-1795-1008)
- Stephanie Ascough (ORCID: https://orcid.org/0000-0001-6969-6403)
- Lisa M. Dratva (ORCID: https://orcid.org/0000-0002-2873-6787)
- Sarah Amalia Teichmann (ORCID: https://orcid.org/0000-0002-6294-6366)
- John S. Tsang (ORCID: https://orcid.org/0000-0003-3186-3047)
- Lorenz Kretschmer (ORCID: https://orcid.org/0000-0003-0987-8429)
- Rik G.H. Lindeboom (ORCID: https://orcid.org/0000-0002-3660-504X)
- Marko Nikolić (ORCID: https://orcid.org/0000-0001-6304-6848)
- Helen R. Wagstaffe (ORCID: https://orcid.org/0000-0002-4462-7484)
- Ashley M. Collins (ORCID: https://orcid.org/0009-0006-1205-4366)
- Richard McKendry
- Anhui Huang
- Leo Swadling (ORCID: https://orcid.org/0000-0002-0537-6715)
- Ryan S. Thwaites (ORCID: https://orcid.org/0000-0003-3052-2793)
- Loukas Papargyris (ORCID: https://orcid.org/0000-0002-5803-5826)
- Mariya Kalinova
- Nana‐Marie Lemm
- Mala K. Maini (ORCID: https://orcid.org/0000-0001-6384-1462)
- Jiayun Xu
Institutions
- University College Hospital (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- The Netherlands Cancer Institute (NL)
- Yale University (US)
- hVIVO (United Kingdom) (GB)
- University College London (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-07
- DOI
- https://doi.org/10.1038/s41467-025-67017-8
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute for Health and Care Research
- Imperial College London
- Imperial College Healthcare NHS Trust
- NIHR Imperial Biomedical Research Centre