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Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
Nature  (IF49.962),  Pub Date : 2021-11-10, DOI: 10.1038/s41586-021-04186-8
Leo Swadling, Mariana O. Diniz, Nathalie M. Schmidt, Oliver E. Amin, Aneesh Chandran, Emily Shaw, Corinna Pade, Joseph M. Gibbons, Nina Le 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 van Dorp, Francois Balloux, Áine McKnight, Mahdad Noursadeghi, Antonio Bertoletti, Mala K. Maini

Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24–11, 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 (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, 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 (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. 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.