Divergent trajectories of antiviral memory after SARS-Cov-2 infection


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This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv.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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is normally controlled by effective host immunity including innate, humoral and cellular responses. However, the trajectories and correlates of acquired immunity, and the capacity of memory responses months after infection to neutralise variants of concern - which has important public health implications - is not fully understood. To address this, we studied a cohort of 78 UK healthcare workers who presented in April to June 2020 with symptomatic PCR-confirmed infection or who tested positive during an asymptomatic screening programme and tracked virus-specific B and T cell responses longitudinally at 5-6 time points each over 6 months, prior to vaccination. We observed a highly variable range of responses, some of which - T cell interferon-gamma (IFN-γ) ELISpot, N-specific antibody waned over time across the cohort, while others (spike-specific antibody, B cell memory ELISpot) were stable. In such cohorts, antiviral antibody has been linked to protection against re-infection. We used integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling Over Night) to explore this heterogeneity and to identify predictors of sustained immune responses. Hierarchical clustering defined a group of high and low antibody responders, which showed stability over time regardless of clinical presentation. These antibody responses correlated with IFN-γ ELISpot measures of T cell immunity and represent a subgroup of patients with a robust trajectory for longer term immunity. Importantly, this immune-phenotype associates with higher levels of neutralising antibodies not only against the infecting (Victoria) strain but also against variants B.1.1.7 (alpha) and B.1.351 (beta). Overall memory responses to SARS-CoV-2 show distinct trajectories following early priming, that may define subsequent protection against infection and severe disease from novel variants.

Author list:


  1. Oxford Vaccine Group, Department of Paediatrics, University of Oxford, UK
  2. Peter Medawar Building for Pathogen Research, Nuffield Dept. of Clinical Medicine, University of Oxford, UK
  3. Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  4. Nuffield Dept of Clinical Neuroscience, University of Oxford, UK
  5. Public Health England, Porton Down, England
  6. Department of Clinical Biochemistry, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  7. Jenner Institute, University of Oxford, UK
  8. The Florey Institute for Host-Pathogen Interactions and Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, UK
  9. Big Data Institute, Nuffield Dept. of Population Health, University of Oxford, UK
  10. Department of Physiology, Anatomy, and Genetics, University of Oxford, UK
  11. James & Lillian Martin Centre, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
  12. NIHR Oxford Biomedical Research Centre, Oxford, UK
  13. Oxford University Medical School, Medical Sciences Division, University of Oxford, Oxford, UK
  14. Oxford Centre For Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford, UK
  15. Monogram Biosciences LabCorp, San Francisco, CA, USA
  16. Wellcome Centre for Human Genetics, University of Oxford, UK
  17. HPRU in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
  18. Tropical and Infectious Disease Unit, Liverpool University Hospitals NHS Foundation Trust (a member of Liverpool Health Partners), Liverpool, UK
  19. Peter Medawar Building for Pathogen Research, Department of Paediatrics, University of Oxford, Oxford, UK 
  20. Nuffield Department of Medicine, University of Oxford, Oxford, UK
  21. Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  22. Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand

* These authors contributed equally

# These athors jointly supervised this work and contributed equally


Adriana Tomic1 *, Donal T. Skelly2,3,4*, Ane Ogbe2* , Daniel O’Connor1*, Matthew Pace2 , Emily Adland2 3 , Frances Alexander5 , Mohammad Ali2 , Kirk Allott6 , M. Azim Ansari2 , Sandra Belij-Rammerstorfer7 4 , Sagida Bibi1 , Luke Blackwell1 , Anthony Brown2 , Helen Brown2 , Breeze Cavell5 5 , Elizabeth A. Clutterbuck1 , Thushan de Silva8 , David Eyre3,9, Amy Flaxman7 , James Grist10 , Carl-Philipp Hackstein2 6 , Rachel Halkerston5 , Adam C. Harding11 , Jennifer Hill1,12 , Tim James6 , Cecilia Jay2 , Síle A. Johnson2,3,13 7 , Barbara Kronsteiner2,14 , Yolanda Lie15 , Aline Linder1,12 , Stephanie Longet5,16 , Spyridoula Marinou1,12 8 , Philippa C. Matthews2,3,12 , Jack Mellors5 , Christos Petropoulos15 , Patpong Rongkard2 , Cynthia Sedik15 9 , Laura Silva-Reyes1,12 , Holly Smith7 , Lisa Stockdale1,12 , Stephen Taylor5 , Stephen Thomas5 10 , Timothy Tipoe2 , Lance Turtle17,18 , Vinicius Adriano Vieira19 , Terri Wrin15 11 , OPTIC Clinical Group, PITCH Study Group, C-MORE Group, Andrew J. Pollard1,12, Teresa Lambe7 , Chris P. Conlon20, Katie Jeffery3 12 , Simon Travis3,21 , Philip Goulder19, John Frater2,3 , Alex J. Mentzer3,16, Lizzie Stafford20, Miles W. Carroll5,16 13 , William S. James11 , Paul Klenerman2,3,12#, Eleanor Barnes2,3,12#, Christina Dold1,12 14 #, Susanna J. Dunachie2,3,14,21 15 #