Data Sheet 5_A genome-wide association study identifies new loci associated with response to SARS-CoV-2 mRNA-1273 vaccine in a cohort of healthy healthcare workers.pdf

IntroductionThe COVID-19 pandemic had significant global public health consequences, affecting over 200 countries and regions by 2020. The development and efficacy of specific vaccines, such as the mRNA-1273 (Spikevax®) vaccine developed by Moderna Inc., have substantially reduced the impact of the pandemic and mitigated its consequences. This study aims to identify novel genetic loci associated with the effectiveness of the mRNA-1273 vaccine, as measured by elevated anti-Spike (anti-S) IgG levels at multiple time points post-vaccination.
Materials and methodsWe conducted three genome-wide association studies (GWAS) in a cohort of Spanish healthcare workers, analyzing anti-S IgG levels at one-month post-vaccination (n=567), at three months post-vaccination (n=447), and the difference in circulating anti-S IgG levels between these two time points (n=447).
ResultsWe identified fourteen novel loci associated with increasing concentrations of anti-S IgG post-vaccination (p=5.01×10-13 and p=2.81×10-8). Functional results showed that some of the novel risk alleles influence the absolute counts of specific B cell subsets (p=2.57×10-5-8.82×10-3), which are involved in immune signaling pathways and metabolic processes. Furthermore, these variants co-localize with multiple QTLs and epigenetic marks, suggesting that the GWAS hits may affect regulatory activity in promoters, enhancers, and transcriptional regions, thereby modulating gene expression relevant to the humoral immune response.
DiscussionIn conclusion, this study highlights the complex interplay of genetic factors influencing the immune response to vaccination, particularly through modulation of B cell activity, immune signaling pathways, and metabolic processes. The identification of genetic variants could inform future strategies to enhance vaccine efficacy and provide a deeper understanding of individual variability in vaccine responses, especially for COVID-19 and other viral infections.

引言
新型冠状病毒肺炎（COVID-19）大流行造成了广泛的全球公共卫生后果，截至2020年已波及200余个国家和地区。诸如莫德纳公司（Moderna Inc.）开发的mRNA-1273（Spikevax®）疫苗在内的特定疫苗的研发与有效性，已大幅降低了大流行的影响并缓解了其带来的后果。本研究旨在鉴定与mRNA-1273疫苗有效性相关的新型遗传位点，该有效性以疫苗接种后多个时间点升高的抗刺突蛋白（anti-Spike，anti-S）IgG水平作为衡量指标。

材料与方法
我们在西班牙医护人员队列中开展了三项全基因组关联研究（genome-wide association studies, GWAS），分别分析了疫苗接种后1个月（n=567）、3个月（n=447）的抗S IgG水平，以及这两个时间点循环抗S IgG水平的差值（n=447）。

结果
我们鉴定出14个与疫苗接种后抗S IgG浓度升高相关的新型遗传位点（p=5.01×10^-13 及 p=2.81×10^-8）。功能研究结果显示，部分新型风险等位基因会影响特定B细胞亚群的绝对计数（p=2.57×10^-5 至 8.82×10^-3），而这些亚群参与免疫信号通路与代谢过程。此外，这些变异位点与多个数量性状位点（quantitative trait loci, QTL）及表观遗传标记共定位，提示本研究的全基因组关联研究信号可能影响启动子、增强子及转录区域的调控活性，从而调节与体液免疫应答相关的基因表达。

讨论
综上，本研究揭示了影响疫苗免疫应答的遗传因素间的复杂相互作用，尤其是通过调控B细胞活性、免疫信号通路及代谢过程实现的。本研究鉴定出的遗传变异可为未来提升疫苗有效性的策略提供参考，并有助于更深入理解个体在疫苗应答上的差异，尤其是针对新型冠状病毒肺炎及其他病毒感染的疫苗应答差异。