DPhil Candidate & Research Assistant Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Oxfordshire, United Kingdom
Background: The human leukocyte antigen (HLA) genes play a critical role in the regulation of the adaptive immune response. Recent laboratory studies have suggested that these highly polymorphic genes may contribute to the heterogeneity of antibody responses following COVID-19 vaccination across individuals and populations
Objectives: To evaluate the association of HLA class I and II genetic variations with serological response 12 weeks after the first dose vaccination against SARS-CoV-2.
Methods: We used data from UK Biobank (UKBB) SARS-CoV-2 coronavirus self-test antibody study, where eligible UKBB participants were recruited to complete a brief questionnaire and SARS-CoV-2 antibody test using a lateral flow device, during the period from 02/2021 to 07/2021. The positive serological response was defined by the detection of IgM or IgG antibody against SARS-CoV-2. The participants’ genotypes were measured using two close arrays, and HLA alleles were imputed by a bespoke algorithm as described previously. In this analysis, people who were naïve to COVID-19 infection (confirmed by non-detection of nucleocapsid antibodies), and vaccinated with 1 dose of vaccine were included. We analysed the association between the serological response and 3 class I genes (-A, -B-, -C) and 8 class II genes (-DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4 and -DRB5), covering 141 alleles at 2-digit resolution (such as HLA-A*01). We used logistic regression adjusted for age, sex, ethnicity, genetic ancestry, genotyping arrays, and serologic test arrays. Alleles with a prevalence of less than 1/1000 were excluded.
Results: 107,175 participants had 1 dose of COVID-19 vaccine in the 12 weeks before their antibody test, with a mean [standard deviation] age of 67.2 [7.6 years]. The median time since the vaccination was 52 days, with lower and upper quartiles of 36 and 64 respectively. Among them, 25,369 (23.6%) individuals showed a positive serological response. Of the 115 alleles finally included in the association test, 24 were significantly associated with the serological response after Bonferroni correction. All studied HLA genes had at least 1 significant allele, except for the DPA1 and DRB4 genes. The strongest associations were with DRB3*01 [odd ratio,1.15 95% 1.12-1.19], followed by DQB1*06 [1.13, 95% 1.10-1.16], and DQB1*05 [0.86, 95% 0.84-0.89].
Conclusions: Our pharmacogenetic study is the first and largest one to systematically evaluate the relationship between variations in a range of HLA genes and the serological response to COVID-19 vaccination in a real-world setting. These findings offer valuable insights into why some individuals may exhibit stronger or faster immune responses following COVID-19 vaccination and pave the way for personalized approaches to vaccination.
