Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection.
Mentzer AJ., O'Connor D., Bibi S., Chelysheva I., Clutterbuck EA., Demissie T., Dinesh T., Edwards NJ., Felle S., Feng S., Flaxman AL., Karp-Tatham E., Li G., Liu X., Marchevsky N., Godfrey L., Makinson R., Bull MB., Fowler J., Alamad B., Malinauskas T., Chong AY., Sanders K., Shaw RH., Voysey M., Oxford COVID Vaccine Trial Genetics Study Team Group None., Snape MD., Pollard AJ., Lambe T., Knight JC.
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 find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following 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 replicate 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 with non-carriers (HR 0.63, 0.42-0.93, P = 0.02). We identify a distinct S-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared with other similar alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days following first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.