• Lisa Mumford, Rachel Hogg, Adam Taylor, Peter Lanyon, Mary Bythell, Sean McPhail, Joseph Chilcot, Gillian Powter, Graham S Cooke, Helen Ward, Helen Thomas, Stephen P McAdoo, Liz Lightstone, Sean H Lim, Gavin J Pettigrew, Fiona A Pearce, and Michelle Willicombe.
• Statistics and Clinical Research, NHS Blood and Transplant, Bristol, UK.
• Lancet. 2025 Jan 25; 405 (10475): 314328314-328.

BackgroundIn the UK, booster COVID-19 vaccinations have been recommended biannually to people considered immune vulnerable. We investigated, at a population level, whether the absence of detectable anti-SARS-CoV-2 spike protein IgG antibody (anti-S Ab) following three or more vaccinations in immunosuppressed individuals was associated with greater risks of infection and severity of infection.MethodsIn this prospective cohort study using UK national disease registers, we recruited participants with solid organ transplants (SOTs), rare autoimmune rheumatic diseases (RAIRDs), and lymphoid malignancies. All participants were tested for anti-S Ab using a lateral flow immunoassay, completed a questionnaire on sociodemographic and clinical characteristics, and were followed up for 6 months using linked data from the National Health Service in England. SARS-CoV-2 infection was primarily defined using UK Health Security Agency data and supplemented with hospitalisation and therapeutics data, and hospitalisation due to SARS-CoV-2 was defined as an admission within 14 days of a positive test.FindingsBetween Dec 7, 2021, and June 26, 2022, we recruited 21 575 participants. Anti-S Ab was detected in 6519 (77·0%) of 8466 participants with SOTs, 5594 (85·9%) of 6516 with RAIRDs, and 5227 (79·3%) of 6593 with lymphoid malignancies. COVID-19 infection was recorded in 3907 (18·5%) participants, with 556 requiring a COVID-19-related hospital admission and 17 dying within 28 days of infection. Rates of infection varied by sociodemographic and clinical characteristics but, in adjusted analysis, having detectable anti-S Ab was independently associated with a reduced incidence of infection, with incident rate ratios (IRRs) of 0·69 (95% CI 0·65-0·73) in the SOT cohort, 0·57 (0·49-0·67) in the RAIRD cohort, and 0·62 (0·54-0·71) in the lymphoid malignancy cohort. In adjusted analysis, having detectable anti-S Ab was also associated with a reduced incidence of hospitalisation, with IRRs of 0·40 (0·35-0·46) in the SOT cohort, 0·32 (0·22-0·46) in the RAIRD cohort, and 0·41 (0·29-0·58) in the lymphoid malignancy cohort.InterpretationAll people with immunosuppression require ongoing access to COVID-19 protection strategies. Assessment of anti-S Ab responses, which can be performed at scale, can identify people with immunosuppression who remain most at risk, providing a mechanism to further individualise protection approaches.FundingUK Research and Innovation, Kidney Research UK, Blood Cancer UK, Vasculitis UK, and Cystic Fibrosis Trust.Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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