Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2

Leo Swadling (), Mariana O. Diniz, Nathalie M. Schmidt, Oliver E. Amin, Aneesh Chandran, Emily Shaw, Corinna Pade, Joseph M. Gibbons, Nina Bert, Anthony T. Tan, Anna Jeffery-Smith, Cedric C. S. Tan, Christine Y. L. Tham, Stephanie Kucykowicz, Gloryanne Aidoo-Micah, Joshua Rosenheim, Jessica Davies, Marina Johnson, Melanie P. Jensen, George Joy, Laura E. McCoy, Ana M. Valdes, Benjamin M. Chain, David Goldblatt, Daniel M. Altmann, Rosemary J. Boyton, Charlotte Manisty, Thomas A. Treibel, James C. Moon, Lucy Dorp, Francois Balloux, Áine McKnight, Mahdad Noursadeghi, Antonio Bertoletti and Mala K. Maini ()
Additional contact information
Leo Swadling: University College London
Mariana O. Diniz: University College London
Nathalie M. Schmidt: University College London
Oliver E. Amin: University College London
Aneesh Chandran: University College London
Emily Shaw: University College London
Corinna Pade: Queen Mary University of London
Joseph M. Gibbons: Queen Mary University of London
Nina Bert: Duke-NUS Medical School
Anthony T. Tan: Duke-NUS Medical School
Anna Jeffery-Smith: University College London
Cedric C. S. Tan: University College London
Christine Y. L. Tham: Duke-NUS Medical School
Stephanie Kucykowicz: University College London
Gloryanne Aidoo-Micah: University College London
Joshua Rosenheim: University College London
Jessica Davies: University College London
Marina Johnson: University College London
Melanie P. Jensen: St Bartholomew’s Hospital, Barts Health NHS Trust
George Joy: St Bartholomew’s Hospital, Barts Health NHS Trust
Laura E. McCoy: University College London
Ana M. Valdes: Nottingham City Hospital
Benjamin M. Chain: University College London
David Goldblatt: University College London
Daniel M. Altmann: Imperial College London
Rosemary J. Boyton: Imperial College London
Charlotte Manisty: St Bartholomew’s Hospital, Barts Health NHS Trust
Thomas A. Treibel: St Bartholomew’s Hospital, Barts Health NHS Trust
James C. Moon: St Bartholomew’s Hospital, Barts Health NHS Trust
Lucy Dorp: University College London
Francois Balloux: University College London
Áine McKnight: Queen Mary University of London
Mahdad Noursadeghi: University College London
Antonio Bertoletti: Duke-NUS Medical School
Mala K. Maini: University College London

Nature, 2022, vol. 601, issue 7891, 110-117

Abstract: Abstract Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

Date: 2022
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DOI: 10.1038/s41586-021-04186-8

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