Time series analysis and mechanistic modelling of heterogeneity and sero-reversion in antibody responses to mild SARS‑CoV-2 infection
Charlotte Manisty,
Thomas Alexander Treibel,
Melanie Jensen,
Amanda Semper,
George Joy,
Rishi K Gupta,
Teresa Cutino-Moguel,
Mervyn Andiapen,
Jessica Jones,
Stephen Taylor,
Ashley Otter,
Corrina Pade,
Joseph Gibbons,
Jason Lee,
Joanna Bacon,
Steve Thomas,
Chris Moon,
Meleri Jones,
Dylan Williams,
Jonathan Lambourne,
Marianna Fontana,
Daniel M Altmann,
Rosemary Boyton,
Mala Maini,
Aine McKnight,
Benjamin Chain,
Mahdad Noursadeghi,
James C Moon
Affiliations
Charlotte Manisty
Institute of Cardiovascular Sciences, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
Thomas Alexander Treibel
Institute of Cardiovascular Sciences, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
Melanie Jensen
Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
Amanda Semper
National Infection Service, Public Health England, Porton Down, UK
George Joy
Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
Rishi K Gupta
Division of Infection and Immunity, University College London, London, UK
Teresa Cutino-Moguel
Department of Virology, Barts Health NHS Trust, London, UK
Mervyn Andiapen
Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, UK
Jessica Jones
National Infection Service, Public Health England, Porton Down, UK
Stephen Taylor
National Infection Service, Public Health England, Porton Down, UK
Ashley Otter
National Infection Service, Public Health England, Porton Down, UK
Corrina Pade
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Joseph Gibbons
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Jason Lee
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Joanna Bacon
National Infection Service, Public Health England, Porton Down, UK
Steve Thomas
National Infection Service, Public Health England, Porton Down, UK
Chris Moon
National Infection Service, Public Health England, Porton Down, UK
Meleri Jones
Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Dylan Williams
MRC Unit for Lifelong Health and Ageing, University College London, London, UK; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Jonathan Lambourne
Department of Infection, Barts Health NHS Trust, London, UK
Marianna Fontana
Royal Free London NHS Foundation Trust, London, UK; Division of Medicine, University College London, London, UK
Daniel M Altmann
Department of Immunology and Inflammation, Imperial College London, London, UK
Rosemary Boyton
Department of Infectious Disease, Imperial College London, London, UK
Mala Maini
Division of Infection and Immunity, University College London, London, UK
Aine McKnight
Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Benjamin Chain
Division of Infection and Immunity, University College London, London, UK
Mahdad Noursadeghi
Division of Infection and Immunity, University College London, London, UK; Corresponding author.
James C Moon
Institute of Cardiovascular Sciences, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
Background: SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. Methods: Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16–21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. Findings: A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p<0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16–18 weeks, r = 0.57, p<0.0001). By 21 weeks’ follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). Interpretation: Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. In mild infection, anti-S1 serology alone may underestimate incident infections. The mechanisms that underpin faster clearance and lower rates of sustained anti-S1 production may impact on the longevity of humoral immunity. Funding: Charitable donations via Barts Charity, Wellcome Trust, NIHR.
