Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we found that inter-individual variation in normalized antibody responses against SARS-CoV-2 spike and its receptor-binding domain (RBD) at 28 days after first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P = 3.2 × 10−9), which we replicated in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha variant waves compared to non-carriers (hazard ratio = 0.63, 0.42–0.93, P = 0.02). We identified a distinct spike-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared to other similar alleles, and we found evidence of increased spike-specific memory B cell responses in HLA-DQB1*06 carriers at 84 days after first vaccination. Our results demonstrate association of HLA type with Coronavirus Disease 2019 (COVID-19) vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

High titre neutralizing antibodies in response to SARS–CoV–2 infection require RBD–specific CD4 T cells that include proliferative memory cells

“…Importantly, however, it appears that RBD-specific CD4 T cells could be boosted to some extent by vaccination. A very recently published study of vaccination shows an association between carriage of the HLA-DQB1*06 allele and combined higher antibody and CD4 T cell proliferation responses to RBD, following vaccination, which was postulated to be due to improved presentation of an epitope adjacent to the RBD ( 87 ). Our results suggest that booster efficacy would be improved by concentrating on CD4 T cell epitopes in and around the RBD, which may be the optimal regimen for generation and longevity of neutralizing antibodies.…”

Regarding: Factors associated with severe or fatal clinical manifestations of SARS‐CoV‐2 infection after receiving the third dose of vaccine

“…The presence of the HLA DQB1*06 allele also appeared to confer some protection against breakthrough SARS-CoV-2 infection as shown by the observation that HLA-DQB1*06 was present in 45.6% of individuals who did not have breakthrough infection compared with presence of that allele in 33.9% of individuals who experienced breakthrough infection [2]. This difference in prevalence of HLA-DQB1*06 was significant at the level of p = 0.02.…”

“…Dear Editor, Among the wide range of variables which are associated with severe or fatal clinical manifestations of SARS-CoV-2 infection after receiving the third dose of vaccine [1], one also ought to include human leukocyte antigen (HLA) allele status [2]. The rationale is that HLA status significantly influences SARS-CoV-2 vaccine immunogenicity as well as liability to develop breakthrough infection attributable either to the ancestral SAR-CoV-2 infection or the alpha variant [2]. In the latter study, the authors analysed data from 1076 participants enrolled in ChAdOx1nCov-19 vaccine efficacy trials in the United Kingdom.…”

Omicron variants of SARS-CoV-2 and long COVID

“…In a recent study, Naranbhai and colleagues showed that spike mutations in Omicron could escape T-cell responses in an HLA-dependent manner (12). Notably, a research group at the Oxford University recently reported an association of HLA alleles, specifically the HLA-DQB1*06 alleles with higher antibody response following immunization against the SARS-COV-2 vaccine and with a lower risk of breakthrough SARS-COV-2 infection (13).…”