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

Abstract

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.

Keywords: COVID-19; HLA; SARS-CoV-2; T-cell immunity; immunogenetics; vaccine.

FIGURE 1

Association between HLA DRB1 alleles, the presence of case definition symptoms and T cell immune responses to SARS‐CoV‐2 following natural infection: (a) consistent association of DRB1*13:02 with the presence of case definition symptoms; (b) Association between the absence of HLA‐DRB1*15:02 and T‐cell responses against nucleoprotein peptide pool (HLA‐DRB1*15:02 −, n = 68, HLA‐DRB1*15:02 +, n = 5). Bars show mean with SD. P value calculated using a Mann–Whitney U test. PBMC for T cell assays were taken on average 121 (range 71–174) days following first presentation of case definition symptoms. HLA, human leukocyte antigen; PBMC, peripheral blood mononuclear cells

FIGURE 2

HLA DRB1 alleles not associated with enhanced antibody responses but DR15:01 associated with higher T cell responses to spike in prior SARS‐CoV‐2 infected HCW: (a) Anti‐spike titres after two doses of COVID vaccine were evaluated in the context of the top 12 most frequent DR alleles in HCW from the COVIDsortium (n = 251) and PANTHER (n = 169) cohorts. (b–d) Association between the presence of the DRB1*1501 allele and T‐cell responses against (b) spike protein in single dose vaccinated HCW, (c) spike peptide pool in single dose vaccinated HCW and (d) spike peptide pool in two dose vaccinated HCW with prior SARS‐Co‐V‐2 infection (upper panel, n = 23) and SARS‐CoV‐2 naïve vaccinees (lower panel, n = 23). P values were calculated using a Mann‐Whitney U test. Data are shown as box and whisker plots. HCW, healthcare worker; HLA, human leukocyte antigen