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



Contributing to research themes:

This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv. This is a preliminary report that should not be regarded as conclusive, guide clinical practice/health-related behaviour, or be reported in news media as established information.

Individuals with likely exposure to the highly infectious 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 infections1-5. We hypothesised that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-26-12, would expand in vivo to mediate rapid viral control, potentially aborting infection. We studied T cells against the replication transcription complex (RTC) of SARS-CoV-2 since this is transcribed first in the viral life cycle13-15 and should be highly conserved. We measured SARS-CoV-2-reactive T cells in a cohort of intensively monitored healthcare workers (HCW) who remained repeatedly negative by PCR, antibody binding, and neutralisation for SARS-CoV-2 (exposed seronegative, ES). 16-weeks post-recruitment, ES had memory T cells that were stronger and more multispecific 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). The postulate that HCW with the strongest RTC-specific T cells had an abortive infection was supported by a low-level increase in IFI27 transcript, a robust early innate signature of SARS-CoV-2 infection16. We showed that the RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and was preferentially targeted by T cells from UK and Singapore pre-pandemic cohorts and from ES. RTC epitope-specific T cells capable of cross-recognising HCoV variants were identified in ES. Longitudinal samples from ES and an additional validation cohort, showed pre-existing RNA-polymerase-specific T cells expanded in vivo following SARS-CoV-2 exposure, becoming enriched in the memory response of those with abortive compared to overt infection. In summary, we provide evidence of abortive seronegative SARS-CoV-2 infection with expansion of cross-reactive RTC-specific T cells, highlighting these highly conserved proteins as targets for future vaccines against endemic and emerging Coronaviridae.

Author list:


  1. Division of Infection and Immunity, University College London, London, UK.
  2. Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  3. Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore.
  4. UCL Genetics Institute, University College London, London, UK.
  5. Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  6. Department of Cellular Pathology, Northwest London Pathology, Imperial College London NHS Trust, London, UK.
  7. Institute of Cardiovascular Science, University College London, UK.
  8. Academic Rheumatology, Clinical Sciences, Nottingham City Hospital, Nottingham, UK.
  9. NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
  10. Department of Immunology and Inflammation, Imperial College London, London, UK.
  11. Department of Infectious Disease, Imperial College London, London, UK.
  12. Lung Division, Royal Brompton and Harefield Hospitals, London, UK.
  13. Singapore Immunology Network, A*STAR, Singapore.

^ These authors contributed equally.

V These authors contributed equally.

$ The members of the COVIDsortium investigators and COVIDsortium immune correlates network can be found at the end of the  acknowledgments.

*Corresponding author


Leo Swadling1*, Mariana O. Diniz1^, Nathalie M. Schmidt1^, Oliver E. Amin1^, Aneesh Chandran1^, Emily Shaw1^, Corinna Pade2, Joseph M. Gibbons2, Nina Le Bert3, Anthony T. Tan3, Anna Jeffery-Smith1,2, Cedric Tan4, Christine Y. L. Tham3, Stephanie Kucyowicz1, Gloryanne
Aidoo-Micah1, Joshua Rosenheim1, Jessica Davies1, Melanie P. Jensen5,6, George Joy5,7, Laura E McCoy, Ana M Valdes8,9, Lucy van Dorp4, Daniel M. Altmann10, Rosemary J. Boyton11,12,
Charlotte Manisty5,7, Thomas A. Treibel5,7, James C. Moon5,7 , COVIDsortium investigators$, Francois Balloux4, Áine McKnight2,, Mahdad Noursadeghi1v, Antonio Bertoletti3,13v, Mala K. Maini1*