The impact of HLA-DQB1*06 alleles on COVID-19 vaccine effectiveness: an analysis of SARS-CoV-2 antibodies and breakthrough infections based on UK Biobank

Background: Previous studies have shown evidence of the role of HLA genes in immune responses to various vaccines. A recent study reported an association between the HLA-DQB1*06 alleles and levels of antibodies following COVID-19 vaccination and risk of breakthrough infections in participants from vaccine efficacy trials.

Objectives: To replicate whether HLA-DQB1*06 alleles are associated with serological or clinical response to COVID-19 vaccines in real-world settings.

Methods: We used data from UK Biobank (UKBB) linked to primary care and hospital records, and SARS-CoV-2 national polymerase chain reaction test data from 1st Dec 2020 to 30th Sep 2021. Additionally, a sub-cohort took SARS-CoV-2 serum rapid tests between Feb 2021 and July 2021. HLA-DQB1*06 alleles were imputed using the HLA*IMP:02 algorithm, as previously described. COVID-19 vaccination status was obtained from primary care records and self-reported questionnaires. We conducted a case-control study to analyse the relationship between HLA-DQB1*06 alleles (present vs not present) and SARS-CoV-2 antibody status (a binary outcome: positive vs negative) using logistic regression. Second, we prospectively assessed the association between HLA-DQB1*06 alleles and breakthrough infection and hospitalisation using Cox regression models, with follow-up from the first dose to nine months after vaccination. Both models were adjusted for age, sex, ethnicity, genetic ancestry, genotyping arrays, and serologic test arrays. Participants with a previous infection were excluded as confirmed by the N-protein serology test.

Results: In the case-control study of 142,784 vaccinated participants, 33,315 (30.4%) were SARS-CoV-2 antibody positive and 109,469 (69.6%) negative. Among them, 43.0% and 41.5% carried HLA-DQB1*06 alleles respectively, corresponding to an adjusted odd ratio of 1.07 (1.05 to 1.09).
For the cohort analysis of 152,235 HLA-DQB1*06 allele carriers and 207,158 non-carriers, 4,806 and 6,671 had a breakthrough infection, equating to 9-month cumulative incidences of 37.8 and 38.2 per 1,000 persons, respectively, and adjusted hazard ratio of 0.98 (95% CI 0.94 to 1.02). The cumulative incidence of COVID-19 hospitalisation was also similar in HLA-DQB1*06 allele carriers (3.2 per 1000 persons) vs non-carriers (3.3 per 1000 persons): adjusted hazard of 1.01 (0.89 to 1.14).

Conclusions: In this large population-based cohort, we confirmed the previous association between HLA-DQB1*06 alleles and serological response to COVID-19 vaccines. However, no evidence was found that individuals carrying HLA-DQB1*06 alleles were less likely to experience breakthrough infections or hospitalisations in the real-world setting.