The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.

COVID-19 疫苗在全球范围内迅速分发，已注射超过 10 亿剂，这是前所未有的。然而，与大多数已确定的临床决定因素相比，个体遗传因素对 COVID-19 疫苗接种后抗体反应的影响仍然难以捉摸。在这里，我们进行了一项基于人群的研究，包括 357,806 名接种疫苗的参与者，并提供高分辨率 HLA 基因分型数据，以及 175,000 名参与者的子集，其中包括抗体血清学测试结果。我们证实了之前的发现，即与抗体反应相关的单核苷酸多态性主要位于主要组织相容性复合体区域，广泛的 HLA-DQB1*06 基因等位基因与抗体反应的改善有关。然而，我们的结果并不支持这种突变本身就可以显着降低普通人群中的 COVID-19 风险的说法。此外，我们发现并验证了 6 个独立的 HLA 等位基因（A*03:01、C*16:01、DQA1*01:02、DQA1*01:01、DRB3*01:01 和 DPB1*10:01）影响抗体反应，并证明 HLA 基因对突破性 COVID-19 结果风险的综合影响。最后，我们估计 COVID-19 疫苗诱导的抗体阳性可提供大约 20% 的感染保护和 50% 的严重程度保护。这些发现对 HLA 分子的功能研究具有直接影响，并可为未来的个性化疫苗接种策略提供信息。