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.

SARS-CoV-2 疫苗的免疫原性因人而异，免疫反应与疫苗功效相关。使用英国参加 ChAdOx1 nCov-19 疫苗功效试验的 1,076 名参与者的数据，我们发现针对 SARS-CoV-2 刺突 (S) 及其受体结合域 (RBD) 的标准化抗体反应在 28 时存在个体间差异。第一次接种疫苗后的几天显示出全基因组与主要组织相容性复合物 (MHC) II 类等位基因的显着关联。与较高水平的抗 RBD 抗体最具有统计学意义的关联是 HLA-DQB1*06 ( P  = 3.2 × 10 ^-9 )，我们在另外 1,677 名疫苗接种者中复制了该关联。与非携带者相比，携带 HLA-DQB1*06 等位基因的个体在祖先 SARS-CoV-2 病毒和随后的 Alpha 变异波期间经历 PCR 确认的突破性感染的可能性较小（HR 0.63、0.42–0.93，P = 0.02  ） 。我们鉴定了一种独特的 S 衍生肽，与其他类似的等位基因相比，预计该肽与 HLA-DQB1*06 的结合存在差异，并发现 HLA-DQB1*06 携带者在 84 天后尖峰特异性记忆 B 细胞反应增加的证据第一次接种疫苗。我们的结果表明 HLA 类型与 COVID-19 疫苗抗体反应和突破性感染的风险相关，对未来的疫苗设计和实施具有影响。