Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
Leo Swadling, Mariana O. Diniz, Nathalie Schmidt, Oliver E. Amin, Aneesh Chandran, Emily Shaw, Corinna Pade, Joseph M. Gibbons, Nina Le Bert, Anthony T. Tan, Anna Jeffery-Smith, Cedric Tan, C Tham, Stephanie Kucykowicz, Gloryanne Aidoo-Micah, Joshua Rosenheim, Jessica Davies, Marina Johnson, Melanie Jensen, George Joy, Laura E. McCoy, Ana M. Valdes, Benny Chain, David Goldblatt, Daniel M. Altmann, Rosemary J. Boyton, Charlotte Manisty, Thomas A. Treibel, James Moon, COVIDsortium Investigators, Hakam Abbass, Aderonke Abiodun, Mashael Alfarih, Zoe Alldis, Mervyn Andiapen, Jessica Artico, João B. Augusto, Georgina L. Baca, Sasha N. L. Bailey, Anish Bhuva, Alex Boulter, Ruth Bowles, Rosemary J. Boyton, Olivia V. Bracken, Benjamin O’Brien, Tim Brooks, Natalie Bullock, David K. Butler, Gabriella Captur, Nicola Champion, Carmen K. M. Chan, David Collier, Jorge Couto de Sousa, Xosé Couto‐Parada, Teresa Cutino-Mogue, Rhodri Davies, Brooke Douglas, Cecilia Di Genova, Keenan Dieobi-Anene, Anaya Ellis, Karen Feehan, Malcolm Finlay, Marianna Fontana, Nasim Forooghi, Celia Gaier, Derek W. Gilroy, Matt Hamblin, Gabrielle Harker, Jacqueline Hewson, Lauren M. Hickling, Aroon D. Hingorani, Lee Hamill Howes, Alun D. Hughes, Gemma Hughes, Rebecca Hughes, Ivie Itua, Victor Jardim, Wing-Yiu Jason Lee, Melanie Jensen, Jessica Jones, Meleri Jones, George Joy, Vikas Kapil, Hibba Kurdi, Jonathan Lambourne, Kai‐Min Lin, Sarah Louth, Vineela Mandadapu, Áine McKnight, Katia Menacho, Celina Mfuko, Oliver Mitchelmore, Christopher Moon, Diana Mūnoz Sandoval, Sam M. Murray, Mahdad Noursadeghi, Ashley Otter, Susana Palma, Ruth Parker, Kush Patel
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 infections 1–3 . 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 .