HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19

COVIDsortium Investigators*, Stuart Astbury, Catherine J. Reynolds, David K. Butler, Diana C. Muñoz-Sandoval, Kai Min Lin, Franziska P. Pieper, Ashley Otter, Afroditi Kouraki, Lola Cusin, Jessica Nightingale, Amrita Vijay, Simon Craxford, Guruprasad P. Aithal, Patrick J. Tighe, Joseph M. Gibbons, Corinna Pade, George Joy, Mala Maini, Benny ChainAmanda Semper, Timothy Brooks, Benjamin J. Ollivere, Áine McKnight, Mahdad Noursadeghi, Thomas A. Treibel, Charlotte Manisty, James C. Moon, Ana M. Valdes, Rosemary J. Boyton, Daniel M. Altmann

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SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.

Original languageEnglish
Pages (from-to)68-77
Number of pages10
Issue number1
Early online date8 Mar 2022
Publication statusPublished - 18 Apr 2022

Bibliographical note

Funding Information: Supported by the UKRI Covid-19 Rapid Response grant COV0331 (MR/V027883/1). The PANTHER cohort was supported by funding from the NIHR Nottingham Biomedical Research Centre. The COVIDsortium is supported by funding donated by individuals, charitable Trusts, and corporations including Goldman Sachs, Citadel and Citadel Securities, The Guy Foundation, GW Pharmaceuticals, Kusuma Trust, and Jagclif Charitable Trust, and enabled by Barts Charity with support from UCLH Charity. Wider support is acknowledged on the COVIDsortium website. Institutional support from Barts Health NHS Trust and Royal Free NHS Foundation Trust facilitated study processes, in partnership with University College London and Queen Mary University of London. RJB and DMA are supported by MRC (MR/S019553/1, MR/R02622X/1, MR/V036939/1, MR/W020610/1), NIHR Imperial Biomedical Research Centre (BRC):ITMAT, Cystic Fibrosis Trust SRC (2019SRC015), NIHR EME Fast Track (NIHR134607), NIHR Long Covid (COV-LT2-0027), Innovate Uk (SBRI 10008614) and Horizon 2020 Marie Skłodowska-Curie Innovative Training Network (ITN) European Training Network (No. 860325). ÁM is supported by ÁM is supported by MRC (MR/W020610/1), NIHR EME Fast Track (NIHR134607), Rosetrees Trust, The John Black Charitable Foundation, and Medical College of St Bartholomew's Hospital Trust. JCM, CM and TAT are directly and indirectly supported by the University College London Hospitals (UCLH) and Barts NIHR Biomedical Research Centres and through the British Heart Foundation (BHF) Accelerator Award (AA/18/6/34223). TAT is funded by a BHF Intermediate Research Fellowship (FS/19/35/34374). MN is supported by the Wellcome Trust (207511/Z/17/Z) and by NIHR Biomedical Research Funding to UCL and UCLH. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Open Access: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Publisher Copyright: © 2022 The Authors. Immunology published by John Wiley & Sons Ltd.

Citation: Astbury S, Reynolds CJ, Butler DK, Muñoz-Sandoval DC, Lin K-M, Pieper FP, et al; COVIDsortium Investigators. HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19. Immunology. 2022;166:68–77.

DOI: https://doi.org/10.1111/imm.13450


  • COVID-19
  • HLA
  • SARS-CoV-2
  • T-cell immunity
  • immunogenetics
  • vaccine


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