Pre-existing and early cellular immune factors correlate with functionally complete protection against primary controlled human SARS-CoV-2 infection
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Identifying host factors that mediate protection during first exposure to newly emergent viruses may assist in responding to future pandemics. Here, we report correlates of protection in a controlled human infection model of SARS-CoV-2 in serologically naïve individuals (n=34, aged 18-29 years) inoculated with 10 TCID50 of a D614G-containing pre-Alpha variant SARS-CoV-2. Eighteen developed “sustained infection” and seroconverted, while the remaining 16 did not. Pre-exposure and early immune factors associated with resisting infection were comprehensively analysed using multiplex protein, cytometric and RNA sequencing approaches in the upper respiratory mucosa and circulation. Associations between pre-existing antibody level and outcome suggested a modest role for cross-reactive antibodies in protection, with baseline nasal anti-SARS-CoV-2 Spike IgM levels correlating with delayed infection onset. Instead, resistance to infection was associated with heightened nasopharyngeal CCL13 levels produced locally by conventional dendritic cells and monocytes. Cross-reactive IL-2 producing T cells against SARS-CoV-2 non-structural proteins and less differentiated NK cells were also enriched at the time of inoculation in these individuals. This was followed by increased numbers of innate and adaptive cellsin the nasopharynx, including resident memory T cells, within 24 hours of virus exposure. Conditional independence network analysis revealed nasal CCL13 as the central node in a module associated with protection, connected to pre-existing RTC-specific T cells by CD1c+ DCs. In those who became infected, higher baseline cross-reactive T cell and less differentiated NK cell frequencies also correlated with shorter duration of infection. Thus, enhanced pre-existing mucosal chemokine levels may enable rapid immune cell recruitment and antigen-presentation to resident T cells in respiratory mucosa, effectively blocking infection. Where this local response fails to contain viral replication, mucosal innate and adaptive cellular immunity can nevertheless predispose to enhanced viral control, thus providing multiple layers of transmission-reducing resistance to the novel pathogen.
Date Issued
2026-01-09
Date Acceptance
2025-11-20
Citation
Nature Communications, 2026, 17
ISSN
2041-1723
Publisher
Nature Portfolio
Journal / Book Title
Nature Communications
Volume
17
Copyright Statement
© The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Publication Status
Published
Article Number
312
Date Publish Online
2025-12-07