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<p>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.</p>

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Pre-existing and early cellular immune factors correlate with functionally complete protection against primary controlled human SARS-CoV-2 infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • 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

摘要

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.