Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
Authors: Swadling Leo , Diniz Mariana O. , Schmidt Nathalie M. , Amin Oliver E. , Chandran Aneesh , Shaw Emily , Pade Corinna , Gibbons Joseph M. , Le Bert Nina , Tan Anthony T. , Jeffery-Smith Anna , Tan Cedric C. S. , Tham Christine Y. L. , Kucykowicz Stephanie , Aidoo-Micah Gloryanne , Rosenheim Joshua , Davies Jessica , Johnson Marina , Jensen Melanie P. , Joy George , McCoy Laura E. , Valdes Ana M. , Chain Benjamin M. , Goldblatt David , Altmann Daniel M. , Boyton Rosemary J. , Manisty Charlotte , Treibel Thomas A. , Moon James C. ,   COVIDsortium Investigators, Abbass Hakam , Abiodun Aderonke , Alfarih Mashael , Alldis Zoe , Andiapen Mervyn , Artico Jessica , Augusto João B. , Baca Georgina L. , Bailey Sasha N. L. , Bhuva Anish N. , Boulter Alex , Bowles Ruth , Boyton Rosemary J. , Bracken Olivia V. , O’Brien Ben , Brooks Tim , Bullock Natalie , Butler David K. , Captur Gabriella , Champion Nicola , Chan Carmen , Collier David , de Sousa Jorge Couto , Couto-Parada Xose , Cutino-Mogue Teresa , Davies Rhodri H. , Douglas Brooke , Di Genova Cecilia , Dieobi-Anene Keenan , Ellis Anaya , Feehan Karen , Finlay Malcolm , Fontana Marianna , Forooghi Nasim , Gaier Celia , Gilroy Derek , Hamblin Matt , Harker Gabrielle , Hewson Jacqueline , Hickling Lauren M. , Hingorani Aroon D. , Howes Lee , Hughes Alun , Hughes Gemma , Hughes Rebecca , Itua Ivie , Jardim Victor , Lee Wing-Yiu Jason , Jensen Melanie Petra , Jones Jessica , Jones Meleri , Joy George , Kapil Vikas , Kurdi Hibba , Lambourne Jonathan , Lin Kai-Min , Louth Sarah , Mandadapu Vineela , McKnight Áine , Menacho Katia , Mfuko Celina , Mitchelmore Oliver , Moon Christopher , Munoz-Sandoval Diana , Murray Sam M. , Noursadeghi Mahdad , Otter Ashley , Palma Susana , Parker Ruth , Patel Kush , Pawarova Babita , Petersen Steffen E. , Piniera Brian , Pieper Franziska P. , Pope Daniel , Prossora Mary , Rannigan Lisa , Rapala Alicja , Reynolds Catherine J. , Richards Amy , Robathan Matthew , Sambile Genine , Semper Amanda , Seraphim Andreas , Simion Mihaela , Smit Angelique , Sugimoto Michelle , Taylor Stephen , Temperton Nigel , Thomas Stephen , Thornton George D. , Tucker Art , Veerapen Jessry , Vijayakumar Mohit , Welch Sophie , Wodehouse Theresa , Wynne Lucinda , Zahedi Dan , van Dorp Lucy , Balloux Francois , McKnight Áine , Noursadeghi Mahdad , Bertoletti Antonio , Maini Mala K. 
Published: November 2021

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.